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The Prescriber’s Guide is the latest addition to the Essential Psychopharmacology collection. In full color throughout, this volume presents to clinicians pragmatic guidance that complements the conceptual approach of Essential Psychopharmacology. With four or more pages for each of over 100 psychotropic drugs, Stephen Stahl gives all the information a prescriber needs to treat patients effectively. For each drug the information comes in five categories: general therapeutics, dosing and use, side effects, special populations, and pearls. General Therapeutics covers the class of drug, what the drug is prescribed for, how the drug works, how long it takes to work, what happens if it works, what happens if it doesn’t, best augmentation/combination strategies, and any required tests. Dosing and use covers usual dosage, dosage forms, how to dose, dosing tips, overdose, long-term use, habit formation, how to stop, pharmacokinetics, drug interactions, warnings/precautions, and contraindications. Side effects covers how the drug causes side effects, notable side effects, life-threatening or dangerous side effects, weight gain, sedation, what to do about side effects, and best augmenting agents for side effects. Special populations covers renal impairment, hepatic impairment, cardiac impairment, the elderly, children and adolescents, and key phases of a woman’s lifecycle. Pearls covers potential advantages, potential disadvantages, pearls, and suggested reading. Target icons appear next to key categories for each drug so that the prescriber can go easily and instantly to the information needed. Several indices are included, one consisting of a comprehensive list of both generic and proprietary names for all the drugs featured, one categorizing the generic drugs by use, and one listing the generic drugs by class.

Stephen M. Stahl is Adjunct Professor of Psychiatry at the University of California, San Diego, and Chairman, Neuroscience Education Institute, Carlsbad. He has conducted numerous research projects awarded by the National Institute of Mental Health, the Veteran’s Administration, and the pharmaceutical industry. The author of more than 300 articles and chapters, Stephen Stahl is an internationally recognized clinician, researcher and teacher in psychiatry with subspecialty expertise in psychopharmacology.

From the reviews of Essential Psychopharmacology

“essential reading . . . I would thoroughly recommend this book to anyone who works with psychotropic drugs – or who has the task of teaching others about them!”

American Journal of Psychiatry

“Firmly grounded in contemporary neuroscience . . . an excellent and comprehensive account of the pharmacology of drugs currently used to treat psychiatric disorders. “

Psychological Medicine

“This masterful production will benefit a broad spectrum of readers, from students to knowledgeable and experienced psychopharmacologists.”

Psychiatric Times

“Finally, an elegant and beautiful psychopharmacology text written by a basic scientist who is also a clinician.”

Journal of Clinical Psychiatry

Essential Psychopharmacology

The Prescriber’s Guide

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Stephen M. Stahl, M.D., Ph.D. Adjunct Professor of Psychiatry

University of California, San Diego

Chairman Neuroscience Education Institute

Editorial assistant

Meghan M. Grady

With illustrations by

Nancy Muntner

Essential Psychopharmacology The Prescriber’s

Guide

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To members of the Neuroscience Education Institute and prescribers of psychopharmacologic agents everywhere. Your relentless determination to find the best portfolio of treatments for each individual patient within your practice is my inspiration.

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Introduction xi

List of icons xiii

1. alprazolam 1 2. amisulpride 7 3. amitriptyline 13 4. amoxapine 19 5. aripiprazole 25 6. atomoxetine 31 7. bupropion 37 8. buspirone 43 9. carbamazepine 47

10. chlordiazepoxide 53 11. chlorpromazine 57 12. citalopram 63 13. clomipramine 69 14. clonazepam 75 15. clonidine 81 16. clorazepate 87 17. clozapine 91 18. d-amphetamine 97 19. desipramine 103 20. diazepam 109 21. d,l-amphetamine 115 22. d,l-methylphenidate 121 23. d-methylphenidate 127 24. donepezil 133 25. dothiepin 139 26. doxepin 145 27. duloxetine 151 28. escitalopram 157 29. estazolam 163 30. flumazenil 167 31. flunitrazepam 171 32. fluoxetine 175 33. flupenthixol 181

vii

Table of contents

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34. fluphenazine 185 35. flurazepam 191 36. fluvoxamine 195 37. gabapentin 201 38. galantamine 207 39. haloperidol 213 40. hydroxyzine 219 41. imipramine 223 42. isocarboxazid 229 43. lamotrigine 235 44. levetiracetam 243 45. lithium 247 46. lofepramine 253 47. loflazepate 259 48. lorazepam 265 49. loxapine 271 50. maprotiline 277 51. memantine 283 52. mesoridazine 287 53. midazolam 291 54. milnacipran 295 55. mirtazapine 301 56. moclobemide 307 57. modafinil 313 58. molindone 319 59. nefazodone 323 60. nortriptyline 329 61. olanzapine 335 62. oxazepam 341 63. oxcarbazepine 345 64. paroxetine 351 65. pemoline 357 66. perospirone 361 67. perphenazine 365 68. phenelzine 371 69. pimozide 377 70. pipothiazine 383 71. pregabalin 387 72. protriptyline 391 73. quazepam 397

viii

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74. quetiapine 401 75. reboxetine 407 76. risperidone 411 77. rivastigmine 417 78. selegiline 423 79. sertraline 429 80. sulpiride 435 81. tacrine 439 82. temazepam 443 83. thioridazine 447 84. thiothixene 453 85. tiagabine 457 86. tianeptine 461 87. topiramate 465 88. tranylcypromine 471 89. trazodone 477 90. triazolam 483 91. trifluoperazine 487 92. trimipramine 493 93. valproate 499 94. venlafaxine 505 95. zaleplon 511 96. ziprasidone 515 97. zolpidem 521 98. zonisamide 525 99. zopiclone 529

100. zotepine 533 101. zuclopenthixol 539

Index by drug name 545 (generic and international trade names)

Index by use 559 Index by class 565

Abbreviations 569

(FDA) Use-In-Pregnancy Ratings 571

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This Guide is intended to complement Essential Psychopharmacology. Essential Psychopharmacology emphasizes mechanisms of action and how psychotropic drugs work upon receptors and enzymes in the brain. This Guide gives practical information on how to use these drugs in clinical practice.

It would be impossible to include all available information about any drug in a single work and no attempt is made here to be comprehensive. The purpose of this Guide is instead to integrate the art of clinical practice with the science of psychopharmacology. That means including only essential facts in order to keep things short. Unfortunately that also means excluding less critical facts as well as extraneous information, which may nevertheless be useful to the reader but would make the book too long and dilute the most important information. In deciding what to include and what to omit, the author has drawn upon common sense and 30 years of clinical experience with patients. He has also consulted with many experienced clinicians and analysed the evidence from controlled clinical trials and regulatory filings with government agencies.

In order to meet the needs of the clinician and to facilitate future updates of this Guide, the opinions of readers are sincerely solicited. Feedback can be emailed to [email protected]. Specifically, are the best and most essential psychotropic drugs included here? Do you find any factual errors? Are there agreements or disagreements with any of the opinions expressed here? Are there suggestions for any additional tips or pearls for future editions? Any and all sug- gestions and comments are welcomed.

All of the selected drugs are presented in the same design format in order to facilitate rapid access to information. Specifically, each drug is broken down into five sections, each designated by a unique color background: � therapeutics, � side effects, � dosing and use, � special populations, and � the art of psy- chopharmacology, followed by key references.

Therapeutics covers the brand names in major countries; the class of drug; what it is commonly prescribed and approved for by the United States Food and Drug Administration (FDA); how the drug works; how long it takes to work; what to do if it works or if it doesn’t work; the best augmenting combinations for par- tial response or treatment resistance, and the tests (if any) that are required.

Side effects explains how the drug causes side effects; gives a list of notable, life threatening or dangerous side effects; gives a specific rating for weight gain or sedation, and advice about how to handle side effects, including best augmenting agents for side effects.

Dosing and use gives the usual dosing range; dosage forms; how to dose and dosing tips; symptoms of overdose; long-term use; if habit forming, how to stop; pharmacokinetics; drug interactions, when not to use and other warnings or pre- cautions.

Special populations gives specific information about any possible renal, hepatic and cardiac impairments, and any precautions to be taken for treating the elderly, children, adolescents, and pregnant and breast-feeding women.

The art of psychopharmacology gives the author’s opinions on issues such as the potential advantages and disadvantages of any one drug, the primary target symptoms, and clinical pearls to get the best out of a drug.

Introduction

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At the back of the Guide are several indices. The first is an index by drug name, giving both generic names (uncapitalized) and trade names (capitalized and fol- lowed by the generic name in parentheses). The second is an index of common uses for the generic drugs included in the Guide and is organized by disorder/symptom. Agents that are approved by the FDA for a particular use are shown in bold. The third index is organized by drug class, and lists all the agents that fall within each particular class. In addition to these indices there is a list of abbreviations and FDA definitions for the Pregnancy Categories A, B, C, D and X. A listing of the icons used in the Guide is included on pages xiii–xv.

Readers are encouraged to consult standard references1 and comprehensive psychiatry and pharmacology textbooks for more in-depth information. They are also reminded that the art of psychopharmacology section is the author’s opinion.

It is strongly advised that readers familiarize themselves with the standard use of these drugs before attempting any of the more exotic uses discussed, such as unusual drug combinations and doses. Reading about both drugs before augment- ing one with the other is also strongly recommended. Today’s psychopharmacolo- gist should also regularly track blood pressure, weight and body mass index for most of their patients. The dutiful clinician will also check out the drug interac- tions of non-central-nervous-system (CNS) drugs with those that act in the CNS, including any prescribed by other clinicians.

Certain drugs may be for experts only and might include clozapine, thiori- dazine, pimozide, tacrine, pemoline, nefazodone, mesoridazine and MAO inhibitors, among others. Off-label uses not approved by the FDA and inade- quately studied doses or combinations of drugs may also be for the expert only, who can weigh risks and benefits in the presence of sometimes vague and conflict- ing evidence. Pregnant or nursing women, or people with two or more psychiatric illnesses, substance abuse, and/or a concomitant medical illness may be suitable patients for the expert only. Controlled substances also require expertise. Use your best judgement as to your level of expertise and realize that we are all learn- ing in this rapidly advancing field. The practice of medicine is often not so much a science as it is an art. It is important to stay within the standards of medical care for the field, and also within your personal comfort zone, while trying to help extremely ill and often difficult patients with medicines than can sometimes transform their lives and relieve their suffering.

Finally, this book is intended to be genuinely helpful for practitioners of psy- chopharmacology by providing them with the mixture of facts and opinions selected by the author. Ultimately, prescribing choices are the reader’s responsi- bility. Every effort has been made in preparing this book to provide accurate and up-to-date information in accord with accepted standards and practice at the time of publication. Nevertheless, the psychopharmacology field is evolving rapidly and the author and publisher make no warranties that the information contained herein is totally free from error, not least because clinical standards are constant- ly changing through research and regulation. Furthermore, the author and pub- lisher disclaim any responsibility for the continued currency of this information and disclaim all liability for any and all damages, including direct or consequen- tial damages, resulting from the use of information contained in this book. Doctors recommending and patients using these drugs are strongly advised to pay careful attention to, and consult information provided by the manufacturer.

xii

1 For example, Physician’s Desk Reference and Martindale’s

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alpha 2 agonist

anticonvulsant

antihistamine

benzodiazepine

cholinesterase inhibitor

conventional antipsychotic

dopamine stabilizer

lithium

modafinil (wake-promoter)

monoamine oxidase inhibitor

nefazodone (serotonin antagonist/reuptake inhibitor)

N-methyl-d-aspartate antagonist

noradrenergic and specific serotonergic antidepressant

xiii

List of icons

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norepinephrine and dopamine reuptake inhibitor

sedative hypnotic

selective norepinephrine reuptake inhibitor

selective serotonin reuptake inhibitor

serotonin-dopamine antagonist

serotonin and norepinephrine reuptake inhibitor

serotonin 1A partial agonist

stimulant

trazodone (serotonin antagonist/reuptake inhibitor)

tricyclic/tetracyclic antidepressant

How the drug works, mechanism of action

Best augmenting agents to add for partial response or treatment- resistance

Life-threatening or dangerous side effects

xiv

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Weight Gain: Degrees of weight gain associated with the drug, with unusual signifying that weight gain has been reported but is not expected; not unusual signifying that weight gain occurs in a significant minority; common signifying that many experience weight gain and/or it can be significant in amount; and problematic signifying that weight gain occurs frequently, can be significant in amount, and may be a health problem in some patients

Sedation: Degrees of sedation associated with the drug, with unusual signifying that sedation has been reported but is not expected; not unusual signifying that sedation occurs in a significant minority; common signifying that many experience sedation and/or it can be significant in amount; and problematic signifying that sedation occurs frequently, can be significant in amount, and may be a health problem in some patients

Tips for dosing based on the clinical expertise of the author

Drug interactions that may occur

Warnings and precautions regarding use of the drug

Dosing and other information specific to children and adolescents

Information regarding use of the drug during pregnancy

Clinical pearls of information based on the clinical expertise of the author

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SIDE EFFECTS

How Drug Causes Side Effects • Same mechanism for side effects as for

therapeutic effects – namely due to

ALPRAZOLAM THERAPEUTICS

Brands • Xanax, Xanax XR see index for additional brand names

Generic? Yes (not for XR)

Class • Benzodiazepine (anxiolytic)

Commonly Prescribed For (bold for FDA approved) • Generalized anxiety disorder (IR) • Panic disorder (IR and XR) • Other anxiety disorders • Anxiety associated with depression • Premenstrual dysphoric disorder • Irritable bowel syndrome and other

somatic symptoms associated with anxiety disorders

• Insomnia • Acute mania (adjunctive) • Acute psychosis (adjunctive)

How The Drug Works • Binds to benzodiazepine receptors at the

GABA-A ligand-gated chloride channel complex

• Enhances the inhibitory effects of GABA • Boosts chloride conductance through

GABA-regulated channels • Inhibits neuronal activity presumably in

amygdala-centered fear circuits to provide therapeutic benefits in anxiety disorders

How Long Until It Works • Some immediate relief with first dosing is

common; can take several weeks with daily dosing for maximal therapeutic benefit

If It Works • For short-term symptoms of anxiety – after

a few weeks, discontinue use or use on an “as-needed” basis

• For chronic anxiety disorders, the goal of treatment is complete remission of symptoms as well as prevention of future relapses

• For chronic anxiety disorders, treatment most often reduces or even eliminates symptoms, but not a cure since symptoms can recur after medicine stopped

• For long-term symptoms of anxiety, consider switching to an SSRI or SNRI for long-term maintenance

• If long-term maintenance with a benzodiazepine is necessary, continue treatment for 6 months after symptoms resolve, and then taper dose slowly

• If symptoms reemerge, consider treatment with an SSRI or SNRI, or consider restarting the benzodiazepine; sometimes benzodiazepines have to be used in combination with SSRIs or SNRIs for best results

If It Doesn’t Work • Consider switching to another agent or

adding an appropriate augmenting agent • Consider psychotherapy, especially

cognitive behavioral psychotherapy • Consider presence of concomitant

substance abuse • Consider presence of alprazolam abuse • Consider another diagnosis, such as a

comorbid medical condition

Best Augmenting Combos for Partial Response or Treatment-Resistance

• Benzodiazepines are frequently used as augmenting agents for antipsychotics and mood stabilizers in the treatment of psychotic and bipolar disorders

• Benzodiazepines are frequently used as augmenting agents for SSRIs and SNRIs in the treatment of anxiety disorders

• Not generally rational to combine with other benzodiazepines

• Caution if using as an anxiolytic concomitantly with other sedative hypnotics for sleep

Tests • In patients with seizure disorders,

concomitant medical illness, and/or those with multiple concomitant long-term medications, periodic liver tests and blood counts may be prudent

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DOSING AND USE

Usual Dosage Range • Anxiety: alprazolam IR: 1–4 mg/day • Panic: alprazolam IR: 5–6 mg/day • Panic: alprazolam XR: 3–6 mg/day

Dosage Forms • Alprazolam IR tablet 0.25 mg scored,

0.5 mg scored, 1 mg scored, 2 mg multi- scored

• Alprazolam IR solution, concentrate 1 mg/mL

• Alprazolam XR (extended-release) tablet 0.5 mg, 1 mg, 2 mg, 3 mg

How to Dose • For anxiety, alprazolam IR should be

started at 0.75–1.5 mg/day divided into 3 doses; increase dose every 3–4 days until desired efficacy is reached; maximum dose generally 4 mg/day

• For panic, alprazolam IR should be started at 1.5 mg/day divided into 3 doses; increase 1 mg or less every 3–4 days until desired efficacy is reached, increasing by smaller amounts for dosage over 4 mg/day; may require as much as 10 mg/day for desired efficacy in difficult cases

• For panic, alprazolam XR should be started at 0.5–1 mg/day once daily in the morning; dose may be increased by 1 mg/day every 3–4 days until desired efficacy is reached; maximum dose generally 10 mg/day

Dosing Tips • Use lowest possible effective dose for the

shortest possible period of time (a benzodiazepine-sparing strategy)

• Assess need for continued treatment regularly

• Risk of dependence may increase with dose and duration of treatment

• For inter-dose symptoms of anxiety, can either increase dose or maintain same total daily dose but divide into more frequent

excessive actions at benzodiazepine receptors

• Long-term adaptations in benzodiazepine receptors may explain the development of dependence, tolerance, and withdrawal

• Side effects are generally immediate, but immediate side effects often disappear in time

Notable Side Effects ✽ Sedation, fatigue, depression ✽ Dizziness, ataxia, slurred speech,

weakness ✽ Forgetfulness, confusion ✽ Hyper-excitability, nervousness • Rare hallucinations, mania • Rare hypotension • Hypersalivation, dry mouth

Life Threatening or Dangerous Side Effects

• Respiratory depression, especially when taken with CNS depressants in overdose

• Rare hepatic dysfunction, renal dysfunction, blood dyscrasias

Weight Gain

• Reported but not expected

Sedation

• Occurs in significant minority • Especially at initiation of treatment or when

dose increases • Tolerance often develops over time

What To Do About Side Effects • Wait • Wait • Wait • Lower the dose • Switch to alprazolam XR • Take largest dose at bedtime to avoid

sedative effects during the day • Switch to another agent • Administer flumazenil if side effects are

severe or life-threatening

Best Augmenting Agents for Side Effects • Many side effects cannot be improved with

an augmenting agent

ALPRAZOLAM (continued)

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(continued) ALPRAZOLAM

doses, or give as extended-release formulation

• Can also use an as-needed occasional “top up” dose for inter-dose anxiety

• Because panic disorder can require doses higher than 4 mg/day, the risk of dependence may be greater in these patients

• Some severely ill patients may require 8 mg/day or more

• Extended release formulation only needs to be taken once or twice daily

• Do not break or chew XR tablets as this will alter controlled release properties

• Frequency of dosing in practice is often greater than predicted from half-life, as duration of biological activity is often shorter than pharmacokinetic terminal half- life

• Alprazolam and alprazolam XR generally dosed about one tenth the dosage of diazepam

✽ Alprazolam and alprazolam XR generally dosed about twice the dosage of clonazepam

Overdose • Fatalities have been reported both in

monotherapy and in conjunction with alcohol; sedation, confusion, poor coordination, diminished reflexes, coma

Long-Term Use • Risk of dependence, particularly for

treatment periods longer than 12 weeks and especially in patients with past or current polysubstance abuse

Habit Forming • Alprazolam is a Schedule IV drug • Patients may develop dependence and/or

tolerance with long-term use

How to Stop • Seizures may rarely occur on withdrawal,

especially if withdrawal is abrupt; greater risk for doses above 4 mg and in those with additional risks for seizures, including those with a history of seizures

• Taper by 0.5 mg every 3 days to reduce chances of withdrawal effects

• For difficult to taper cases, consider reducing dose much more slowly after reaching 3 mg/day, perhaps by as little as 0.25 mg per week or less

• For other patients with severe problems discontinuing a benzodiazepine, dosing may need to be tapered over many months (i.e., reduce dose by 1% every 3 days by crushing tablet and suspending or dissolving in 100 ml of fruit juice and then disposing of 1 ml while drinking the rest; 3–7 days later, dispose of 2 ml, and so on). This is both a form of very slow biological tapering and a form of behavioral desensitization

• Be sure to differentiate reemergence of symptoms requiring reinstitution of treatment from withdrawal symptoms

• Benzodiazepine-dependent anxiety patients and insulin-dependent diabetics are not addicted to their medications. When benzodiazepine-dependent patients stop their medication, disease symptoms can reemerge, disease symptoms can worsen (rebound), and/or withdrawal symptoms can emerge

Pharmacokinetics • Metabolized by CYP450 3A4 • Inactive metabolites • Elimination half-life 12–15 hours

Drug Interactions • Increased depressive effects when taken

with other CNS depressants • Inhibitors of CYP450 3A, such as

nefazodone, fluvoxamine, fluoxetine, and even grapefruit juice, may decrease clearance of alprazolam and thereby raise alprazolam plasma levels and enhance sedative side effects; alprazolam dose may need to be lowered

• Thus, azole antifungal agents (such as ketoconazole and itraconazole), macrolide antibiotics, and protease inhibitors may also raise alprazolam plasma levels

• Inducers of CYP450 3A, such as carbamazepine, may increase clearance of alprazolam and lower alprazolam plasma levels and possibly reduce therapeutic effects

Other Warnings/ Precautions

• Dosage changes should be made in collaboration with prescriber

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THE ART OF PSYCHOPHARMACOLOGY

Potential Advantages • Rapid onset of action • Less sedation than some other

benzodiazepines • Availability of an XR formulation with

longer duration of action

Potential Disadvantages • Euphoria may lead to abuse • Abuse especially risky in past or present

substance abusers

Primary Target Symptoms • Panic attacks • Anxiety

SPECIAL POPULATIONS

Renal Impairment • Drug should be used with caution

Hepatic Impairment • Should begin with lower starting dose

(0.5–0.75 mg/day in 2 or 3 divided doses)

Cardiac Impairment • Benzodiazepines have been used to treat

anxiety associated with acute myocardial infarction

Elderly • Should begin with lower starting dose

(0.5–0.75 mg/day in 2 or 3 divided doses) and be monitored closely

Children and Adolescents • Safety and efficacy not established but

often used, especially short-term and at the lower end of the dosing scale

• Long-term effects of alprazolam in children/adolescents are unknown

• Use with caution in patients with pulmonary disease; rare reports of death after initiation of benzodiazepines in patients with severe pulmonary impairment

• History of drug or alcohol abuse often creates greater risk for dependency

• Hypomania and mania have occurred in depressed patients taking alprazolam

• Use only with extreme caution if patient has obstructive sleep apnea

• Some depressed patients may experience a worsening of suicidal ideation

• Some patients may exhibit abnormal thinking or behavioral changes similar to those caused by other CNS depressants (i.e., either depressant actions or disinhibiting actions)

Do Not Use • If patient has narrow angle-closure

glaucoma • If patient is taking ketoconazole or

itraconazole (azole antifungal agents) • If there is a proven allergy to alprazolam or

any benzodiazepine

• Should generally receive lower doses and be more closely monitored

Pregnancy • Risk Category D [positive evidence of risk

to human fetus; potential benefits may still justify its use during pregnancy]

• Possible increased risk of birth defects when benzodiazepines taken during pregnancy

• Because of the potential risks, alprazolam is not generally recommended as treatment for anxiety during pregnancy, especially during the first trimester

• Drug should be tapered if discontinued • Infants whose mothers received a

benzodiazepine late in pregnancy may experience withdrawal effects

• Neonatal flaccidity has been reported in infants whose mothers took a benzodiazepine during pregnancy

• Seizures, even mild seizures, may cause harm to the embryo/fetus

Breast Feeding • Some drug is found in mother’s breast milk ✽ Recommended either to discontinue drug

or bottle feed • Effects on infant have been observed and

include feeding difficulties, sedation, and weight loss

ALPRAZOLAM (continued)

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(continued) ALPRAZOLAM

Pearls ✽ One of the most popular benzodiazepines

for anxiety, especially among primary care physicians and psychiatrists

• Is a very useful adjunct to SSRIs and SNRIs in the treatment of numerous anxiety disorders

• Not effective for treating psychosis as a monotherapy, but can be used as an adjunct to antipsychotics

• Not effective for treating bipolar disorder as a monotherapy, but can be used as an adjunct to mood stabilizers and antipsychotics

• May both cause depression and treat depression in different patients

• Risk of seizure is greatest during the first 3 days after discontinuation of alprazolam, especially in those with prior seizures, head injuries, or withdrawal from drugs of abuse

• Clinical duration of action may be shorter than plasma half-life, leading to dosing more frequently than 2–3 times daily in some patients, especially for immediate release alprazolam

• Adding fluvoxamine, fluoxetine, or nefazodone can increase alprazolam levels and make the patient very sleepy unless the alprazolam dose is lowered by half or more

• When using to treat insomnia, remember that insomnia may be a symptom of some other primary disorder itself, and thus warrant evaluation for comorbid psychiatric and/or medical conditions

✽ Alprazolam XR may be less sedating than immediate release alprazolam

✽ Alprazolam XR may be dosed less frequently than immediate release alprazolam, and lead to less inter-dose breakthrough symptoms and less “clock- watching” in anxious patients

• Slower rises in plasma drug levels for alprazolam XR have the potential to reduce euphoria/abuse liability, but this has not been proven

• Slower falls in plasma drug levels for alprazolam XR have the potential to facilitate drug discontinuation by reducing withdrawal symptoms, but this has not been proven

✽ Alprozolam XR generally has longer biological duration of action than clonazepam

✽ If clonazepam can be considered a “long- acting alprazolam-like anxiolytic”, then alprazolam XR can be considered “an even longer-acting clonazepam-like anxiolytic” with the potential of improved tolerability features in terms of less euphoria, abuse, dependence, and withdrawal problems, but this has not been proven

DeVane CL, Ware MR, Lydiard RB. Pharmacokinetics, pharmacodynamics, and treatment issues of benzodiazepines: alprazolam, adinazolam, and clonazepam. Psychopharmacol Bull 1991;27:463–73.

Greenblatt DJ, Wright CE. Clinical pharmacokinetics of alprazolam. Therapeutic implications. Clin Pharmacokinet 1993; 24:453–71.

Jonas JM, Cohon MS. A comparison of the safety and efficacy of alprazolam versus other agents in the treatment of anxiety, panic, and depression: a review of the literature. J Clin Psychiatry 1993;54 (Suppl):25–45.

Klein E. The role of extended-release benzodiazepines in the treatment of anxiety: a risk-benefit evaluation with a focus on extended-release alprazolam. J Clin Psychiatry 2002;63 (Suppl 14):27–33.

Speigel DA. Efficacy studies of alprazolam in panic disorder. Psychopharmacol Bull 1998; 34:191–5.

Suggested Reading

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AMISULPRIDE THERAPEUTICS

Brands • Solian see index for additional brand names

Generic? No

Class • Atypical antipsychotic (benzamide; possibly

a dopamine stabilizer and dopamine partial agonist)

Commonly Prescribed For (bold for FDA approved) • Schizophrenia, acute and chronic (outside

of U.S., especially Europe) • Dysthymia

How The Drug Works • Theoretically blocks presynaptic dopamine

2 receptors at low doses • Theoretically blocks postsynaptic dopamine

2 receptors at higher doses ✽ May be a partial agonist at dopamine 2

receptors, which would theoretically reduce dopamine output when dopamine concentrations are high and increase dopamine output when dopamine concentrations are low

• Blocks dopamine 3 receptors, which may contribute to its clinical actions

✽ Unlike other atypical antipsychotics, amisulpride does not have potent actions at serotonin receptors

How Long Until It Works • Psychotic symptoms can improve within

1 week, but it may take several weeks for full effect on behavior as well as on cognition and affective stabilization

• Classically recommended to wait at least 4–6 weeks to determine efficacy of drug, but in practice some patients require up to 16–20 weeks to show a good response, especially on cognitive symptoms

If It Works • Most often reduces positive symptoms in

schizophrenia but does not eliminate them • Can improve negative symptoms, as well

as aggressive, cognitive, and affective symptoms in schizophrenia

• Most schizophrenic patients do not have a total remission of symptoms but rather a reduction of symptoms by about a third

• Perhaps 5–15% of schizophrenic patients can experience an overall improvement of greater than 50–60%, especially when receiving stable treatment for more than a year

• Such patients are considered super- responders or “awakeners” since they may be well enough to be employed, live independently, and sustain long-term relationships

• Continue treatment until reaching a plateau of improvement

• After reaching a satisfactory plateau, continue treatment for at least a year after first episode of psychosis

• For second and subsequent episodes of psychosis, treatment may need to be indefinite

• Even for first episodes of psychosis, it may be preferable to continue treatment indefinitely to avoid subsequent episodes

If It Doesn’t Work • Try one of the other first-line atypical

antipsychotics (risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole)

• If two or more antipsychotic monotherapies do not work, consider clozapine

• If no atypical antipsychotic is effective, consider higher doses or augmentation with valproate or lamotrigine

• Some patients may require treatment with a conventional antipsychotic

• Consider noncompliance and switch to another antipsychotic with fewer side effects or to an antipsychotic that can be given by depot injection

• Consider initiating rehabilitation and psychotherapy

• Consider presence of concomitant drug abuse

Best Augmenting Combos for Partial Response or Treatment-Resistance

• Valproic acid (valproate, divalproex, divalproex ER)

• Augmentation of amisulpride has not been systematically studied

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• Other mood stabilizing anticonvulsants (carbamazepine, oxcarbazepine, lamotrigine)

• Lithium • Benzodiazepines

Tests ✽ Although risk of diabetes and

dyslipidemia with amisulpride has not been systematically studied, monitoring as for all other atypical antipsychotics is suggested

Before starting an atypical antipsychotic ✽ Weigh all patients and track BMI during

treatment • Get baseline personal and family history of

obesity, dyslipidemia, hypertension, and cardiovascular disease

• Get waistline circumference (at umbilicus), blood pressure, fasting plasma glucose, and fasting lipid profile

• Determine if patient is • overweight (BMI 25.0–29.9) • obese (BMI ≥30) • has pre-diabetes (fasting plasma glucose

100–125 mg/dl) • has diabetes (fasting plasma glucose

>126 mg/dl) • has hypertension (BP >140/90 mm Hg) • has dyslipidemia (increased total

cholesterol, LDL cholesterol, and triglycerides; decreased HDL cholesterol)

• Treat or refer such patients for treatment, including nutrition and weight management, physical activity counseling, smoking cessation, and medical management

Monitoring after starting an atypical antipsychotic ✽ BMI monthly for 3 months, then quarterly • Blood pressure, fasting plasma glucose,

fasting lipids within 3 months and then annually, but earlier and more frequently for patients with diabetes or who have gained >5% initial weight

• Treat or refer for treatment and consider switching to another atypical antipsychotic for patients who become overweight, obese, pre-diabetic, diabetic, hypertensive, or dyslipidemic while receiving an atypical antipsychotic

✽ Even in patients without known diabetes, be vigilant for the rare but life threatening onset of diabetic ketoacidosis, which always requires immediate treatment by

monitoring for the rapid onset of polyuria, polydipsia, weight loss, nausea, vomiting, dehydration, rapid respiration, weakness and clouding of sensorium, even coma

• EKGs may be useful for selected patients (e.g., those with personal or family history of QTc prolongation; cardiac arrhythmia; recent myocardial infarction; uncompensated heart failure; or taking agents that prolong QTc interval such as pimozide, thioridazine, selected antiarrhythmics, moxifloxacin, sparfloxacin, etc.)

• Patients at risk for electrolyte disturbances (e.g., patients on diuretic therapy) should have baseline and periodic serum potassium and magnesium measurements

AMISULPRIDE (continued)

SIDE EFFECTS

How Drug Causes Side Effects • By blocking dopamine 2 receptors in the

striatum, it can cause motor side effects, especially at high doses

• By blocking dopamine 2 receptors in the pituitary, it can cause elevations in prolactin

• Mechanism of weight gain and possible increased incidence of diabetes and dyslipidemia with atypical antipsychotics is unknown

Notable Side Effects ✽ Extrapyramidal symptoms ✽ Galactorrhea, amenorrhea ✽ Atypical antipsychotics may increase the

risk for diabetes and dyslipidemia, although the specific risks associated with amisulpride are unknown

• Insomnia, sedation, agitation, anxiety • Constipation, weight gain • Rare tardive dyskinesia

Life Threatening or Dangerous Side Effects

• Rare neuroleptic malignant syndrome • Rare seizures • Dose-dependent QTc prolongation

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(continued) AMISULPRIDE

Weight Gain

• Occurs in significant minority

Sedation

• Many experience and/or can be significant in amount, especially at high doses

What To Do About Side Effects • Wait • Wait • Wait • Lower the dose • For motor symptoms, add an

anticholinergic agent • Take more of the dose at bedtime to help

reduce daytime sedation • Weight loss, exercise programs, and

medical management for high BMIs, diabetes, dyslipidemia

• Switch to another atypical antipsychotic

Best Augmenting Agents for Side Effects • Benztropine or trihexyphenidyl for motor

side effects • Many side effects cannot be improved with

an augmenting agent

Dosing Tips ✽ Efficacy for negative symptoms in

schizophrenia may be achieved at lower doses, while efficacy for positive symptoms may require higher doses

• Patients receiving low doses may only need to take the drug once daily

✽ For dysthymia and depression, use only low doses

✽ Dose-dependent QTc prolongation, so use with caution, especially at higher doses (>800 mg/day)

✽ Amisulpride may accumulate in patients with renal insufficiency, requiring lower dosing or switching to another antipsychotic to avoid QTc prolongation in these patients

Overdose • Sedation, coma, hypotension,

extrapyramidal symptoms

Long-Term Use • Amisulpride is used for both acute and

chronic schizophrenia treatment

Habit Forming • No

How to Stop • Slow down-titration (over 6 to 8 weeks),

especially when simultaneously beginning a new antipsychotic while switching (i.e., cross-titration)

• Rapid discontinuation may lead to rebound psychosis and worsening of symptoms

Pharmacokinetics • Elimination half-life approximately 12 hours • Excreted largely unchanged

Drug Interactions • Can decrease the effects of levodopa,

dopamine agonists • Can increase the effects of antihypertensive

drugs • CNS effects may be increased if used with

a CNS depressant • May enhance QTc prolongation of other

drugs capable of prolonging QTc interval

DOSING AND USE

Usual Dosage Range • Schizophrenia: 400–800 mg/day in 2 doses • Negative symptoms only: 50–300 mg/day • Dysthymia: 50 mg/day

Dosage Forms • Different formulations may be available in

different markets • Tablet 50 mg, 100 mg, 200 mg, 400 mg • Oral solution 100 mg/mL

How to Dose • Initial 400–800 mg/day in 2 doses; daily

doses above 400 mg should be divided in 2; maximum generally 1200 mg/day

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• Since amisulpride is only weakly metabolized, few drug interactions that could raise amisulpride plasma levels are expected

Other Warnings/ Precautions

• Use cautiously in patients with alcohol withdrawal or convulsive disorders because of possible lowering of seizure threshold

• If signs of neuroleptic malignant syndrome develop, treatment should be immediately discontinued

• Because amisulpride may dose- dependently prolong QTc interval, use with caution in patients who have bradycardia or who are taking drugs that can induce bradycardia (e.g., beta blockers, calcium channel blockers, clonidine, digitalis)

• Because amisulpride may dose- dependently prolong QTc interval, use with caution in patients who have hypokalemia and/or hypomagnesemia or who are taking drugs that can induce hypokalemia and/or magnesemia (e.g., diuretics, stimulant laxatives, intravenous amphotericin B, glucocorticoids, tetracosactide)

• Use only with caution if at all in Parkinson’s disease or Lewy Body dementia, especially at high doses

Do Not Use • If patient has pheochromocytoma • If patient has prolactin-dependent tumor • If patient is pregnant or nursing • If patient is taking agents capable of

significantly prolonging QTc interval (e.g., pimozide; thioridazine; selected antiarrhythmics such as quinidine, disopyramide, amiodarone, and sotalol; selected antibiotics such as moxifloxacin and sparfloxacin)

• If there is a history of QTc prolongation or cardiac arrhythmia, recent acute myocardial infarction, uncompensated heart failure

• If patient is taking cisapride, intravenous erythromycin, or pentamidine

• In children • If there is a proven allergy to amisulpride

SPECIAL POPULATIONS

Renal Impairment • Use with caution; drug may accumulate • Amisulpride is eliminated by the renal

route; in cases of severe renal insufficiency, the dose should be decreased and intermittent treatment or switching to another antipsychotic should be considered

Hepatic Impairment • Use with caution, but dose adjustment not

generally necessary

Cardiac Impairment • Amisulpride produces a dose-dependent

prolongation of QTc interval, which may be enhanced by the existence of bradycardia, hypokalemia, congenital or acquired long QTc interval, which should be evaluated prior to administering amisulpride

• Use with caution if treating concomitantly with a medication likely to produce prolonged bradycardia, hypokalemia, slowing of intracardiac conduction, or prolongation of the QTc interval

• Avoid amisulpride in patients with a known history of QTc prolongation, recent acute myocardial infarction, and uncompensated heart failure

Elderly • Some patients may be more susceptible to

sedative and hypotensive effects

Children and Adolescents • Efficacy and safety not established under

age 18

Pregnancy • Although animal studies have not shown

teratogenic effect, amisulpride is not recommended for use during pregnancy

• Psychotic symptoms may worsen during pregnancy and some form of treatment may be necessary

• Amisulpride may be preferable to anticonvulsant mood stabilizers if treatment is required during pregnancy

AMISULPRIDE (continued)

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(continued) AMISULPRIDE

Breast Feeding • Unknown if amisulpride is secreted in

human breast milk, but all psychotropics assumed to be secreted in breast milk

✽ Recommended either to discontinue drug or bottle feed

• Mediates its atypical antipsychotic properties via novel actions on dopamine receptors, perhaps dopamine stabilizing partial agonist actions on dopamine 2 receptors

• May be more of a dopamine 2 antagonist than aripiprazole, but less of a dopamine 2 antagonist than other atypical or conventional antipsychotics

• Low dose activating actions may be beneficial for negative symptoms in schizophrenia

• Very low doses may be useful in dysthymia • Compared to sulpiride, amisulpride has

better oral bioavailability and more potency, thus allowing lower dosing, less weight gain, and fewer extrapyramidal symptoms

• Compared to other atypical antipsychotics with potent serotonin 2A antagonism, amisulpride may have more extrapyramidal symptoms and prolactin elevation, but may still be classified as an atypical antipsychotic, particularly at low doses

• Patients have very similar antipsychotic responses to any conventional antipsychotic, which is different from atypical antipsychotics where antipsychotic responses of individual patients can occasionally vary greatly from one atypical antipsychotic to another

• Patients with inadequate responses to atypical antipsychotics may benefit from a trial of augmentation with a conventional antipsychotic or switching to a conventional antipsychotic

• However, long-term polypharmacy with a combination of a conventional antipsychotic with an atypical antipsychotic may combine their side effects without clearly augmenting the efficacy of either

• Although a frequent practice by some prescribers, adding two conventional antipsychotics together has little rationale and may reduce tolerability without clearly enhancing efficacy

THE ART OF PSYCHOPHARMACOLOGY

Potential Advantages • Not as clearly associated with weight gain

as some other atypical antipsychotics • For patients who are responsive to low

dose activation effects that reduce negative symptoms and depression

Potential Disadvantages • Patients who have difficulty being

compliant with twice daily dosing • Patients for whom elevated prolactin may

not be desired (e.g., possibly pregnant patients; pubescent girls with amenorrhea; postmenopausal women with low estrogen who do not take estrogen replacement therapy)

• Patients with severe renal impairment

Primary Target Symptoms • Positive symptoms of psychosis • Negative symptoms of psychosis • Depressive symptoms

Pearls ✽ Efficacy has been particularly well

demonstrated in patients with predominantly negative symptoms

✽ The increase in prolactin caused by amisulpride may cause menstruation to stop

• Some treatment-resistant patients with inadequate responses to clozapine may benefit from amisulpride augmentation of clozapine

• Risks of diabetes and dyslipidemia not well studied, but does not seem to cause as much weight gain as some other atypical antipsychotics

• Has atypical antipsychotic properties (i.e., antipsychotic action without a high incidence of extrapyramidal symptoms), especially at low doses, but not a serotonin dopamine antagonist

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AMISULPRIDE (continued)

Burns T, Bale R. Clinical advantages of amisulpride in the treatment of acute schizophrenia. J Int Med Res 2001; 29 (6): 451–66.

Curran MP, Perry CM. Spotlight on amisulpride in schizophrenia. CNS Drugs 2002; 16 (3): 207–11.

Leucht S, Pitschel-Walz G, Engel RR, Kissling W. Amisulpride, an unusual “atypical” antipsychotic: a meta-analysis of randomized controlled trials. Am J Psychiatry 2002; 159 (2): 180–90.

Suggested Reading

0521011698s01.qxd 9/2/04 2:26 PM Page 12

AMITRIPTYLINE THERAPEUTICS

Brands • Elavil see index for additional brand names

Generic? Yes

Class • Tricyclic antidepressant (TCA) • Serotonin and norepinephrine/

noradrenaline reuptake inhibitor

Commonly Prescribed For (bold for FDA approved) • Depression • Endogenous depression ✽ Neuropathic pain/chronic pain ✽ Fibromyalgia ✽ Headache ✽ Low back pain/neck pain • Anxiety • Insomnia • Treatment-resistant depression

How The Drug Works • Boosts neurotransmitters serotonin and

norepinephrine/noradrenaline • Blocks serotonin reuptake pump (serotonin

transporter), presumably increasing serotonergic neurotransmission

• Blocks norepinephrine reuptake pump (norepinephrine transporter), presumably increasing noradrenergic neurotransmission

• Presumably desensitizes both serotonin 1A receptors and beta adrenergic receptors

• Since dopamine is inactivated by norepinephrine reuptake in frontal cortex, which largely lacks dopamine transporters, amitriptyline can increase dopamine neurotransmission in this part of the brain

How Long Until It Works • May have immediate effects in treating

insomnia or anxiety • Onset of therapeutic actions usually not

immediate, but often delayed 2 to 4 weeks • If it is not working within 6 to 8 weeks for

depression, it may require a dosage increase or it may not work at all

• May continue to work for many years to prevent relapse of symptoms

If It Works • The goal of treatment of depression is

complete remission of current symptoms as well as prevention of future relapses

• The goal of treatment of chronic pain conditions such as neuropathic pain, fibromyalgia, headaches, low back pain, and neck pain is to reduce symptoms as much as possible, especially in combination with other treatments

• Treatment of depression most often reduces or even eliminates symptoms, but not a cure since symptoms can recur after medicine stopped

• Treatment of chronic pain conditions such as neuropathic pain, fibromyalgia, headache, low back pain, and neck pain may reduce symptoms, but rarely eliminates them completely, and is not a cure since symptoms can recur after medicine is stopped

• Continue treatment of depression until all symptoms are gone (remission)

• Once symptoms of depression are gone, continue treating for 1 year for the first episode of depression

• For second and subsequent episodes of depression, treatment may need to be indefinite

• Use in anxiety disorders and chronic pain conditions such as neuropathic pain, fibromyalgia, headache, low back pain, and neck pain may also need to be indefinite, but long-term treatment is not well studied in these conditions

If It Doesn’t Work • Many depressed patients only have a

partial response where some symptoms are improved but others persist (especially insomnia, fatigue, and problems concentrating)

• Other depressed patients may be nonresponders, sometimes called treatment-resistant or treatment-refractory

• Consider increasing dose, switching to another agent or adding an appropriate augmenting agent

• Consider psychotherapy • Consider evaluation for another diagnosis

or for a comorbid condition (e.g., medical illness, substance abuse, etc.)

• Some patients may experience apparent lack of consistent efficacy due to activation of latent or underlying bipolar disorder, and

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require antidepressant discontinuation and a switch to a mood stabilizer

Best Augmenting Combos for Partial Response or Treatment-Resistance

• Lithium, buspirone, thyroid hormone (for depression)

• Gabapentin, tiagabine, other anticonvulsants, even opiates if done by experts while monitoring carefully in difficult cases (for chronic pain)

Tests • None for healthy individuals ✽ Since tricyclic and tetracyclic

antidepressants are frequently associated with weight gain, before starting treatment, weigh all patients and determine if the patient is already overweight (BMI 25.0–29.9) or obese (BMI ≥30)

• Before giving a drug that can cause weight gain to an overweight or obese patient, consider determining whether the patient already has pre-diabetes (fasting plasma glucose 100–125 mg/dl), diabetes (fasting plasma glucose >126 mg/dl), or dyslipidemia (increased total cholesterol, LDL cholesterol and triglycerides; decreased HDL cholesterol), and treat or refer such patients for treatment, including nutrition and weight management, physical activity counseling, smoking cessation, and medical management

✽ Monitor weight and BMI during treatment ✽ While giving a drug to a patient who has

gained >5% of initial weight, consider evaluating for the presence of pre-diabetes, diabetes, or dyslipidemia, or consider switching to a different antidepressant

• Patients at risk for electrolyte disturbances (e.g., patients on diuretic therapy) should have baseline and periodic serum potassium and magnesium measurements

SIDE EFFECTS

How Drug Causes Side Effects • Anticholinergic activity may explain

sedative effects, dry mouth, constipation, and blurred vision

• Sedative effects and weight gain may be due to antihistamine properties

• Blockade of alpha adrenergic 1 receptors may explain dizziness, sedation, and hypotension

• Cardiac arrhythmias and seizures, especially in overdose, may be caused by blockade of ion channels

Notable Side Effects • Blurred vision, constipation, urinary

retention, increased appetite, dry mouth, nausea, diarrhea, heartburn, unusual taste in mouth, weight gain

• Fatigue, weakness, dizziness, sedation, headache, anxiety, nervousness, restlessness

• Sexual dysfunction (impotence, change in libido)

• Sweating, rash, itching

Life Threatening or Dangerous Side Effects

• Paralytic ileus, hyperthermia (TCAs + anticholinergic agents)

• Lowered seizure threshold and rare seizures

• Orthostatic hypotension, sudden death, arrhythmias, tachycardia

• QTc prolongation • Hepatic failure, extrapyramidal symptoms • Increased intraocular pressure • Rare induction of mania and activation of

suicidal ideation

Weight Gain

• Many experience and/or can be significant in amount

• Can increase appetite and carbohydrate craving

Sedation

• Many experience and/or can be significant in amount

AMITRIPTYLINE (continued)

0521011698s01.qxd 9/2/04 2:26 PM Page 14

DOSING AND USE

Usual Dosage Range • 50–150 mg/day

Dosage Forms • Capsule 25 mg, 50 mg, 100 mg

How to Dose • Initial 25 mg/day at bedtime; increase by

25 mg every 3–7 days • 75 mg/day in divided doses; increase to

150 mg/day; maximum 300 mg/day

Dosing Tips • If given in a single dose, should generally

be administered at bedtime because of its sedative properties

• If given in split doses, largest dose should generally be given at bedtime because of its sedative properties

• If patients experience nightmares, split dose and do not give large dose at bedtime

• Patients treated for chronic pain may only require lower doses

• If intolerable anxiety, insomnia, agitation, akathisia, or activation occur either upon dosing initiation or discontinuation, consider the possibility of activated bipolar disorder, and switch to a mood stabilizer or an atypical antipsychotic

Overdose • Death may occur; CNS depression,

convulsions, cardiac dysrhythmias, severe hypotension, ECG changes, coma

(continued) AMITRIPTYLINE

• Tolerance to sedative effects may develop with long-term use

What To Do About Side Effects • Wait • Wait • Wait • Lower the dose • Switch to an SSRI or newer antidepressant

Best Augmenting Agents for Side Effects • Many side effects cannot be improved with

an augmenting agent

Long-Term Use • Safe

Habit Forming • No

How to Stop • Taper to avoid withdrawal effects • Even with gradual dose reduction, some

withdrawal symptoms may appear within the first 2 weeks

• Many patients tolerate 50% dose reduction for 3 days, then another 50% reduction for 3 days, then discontinuation

• If withdrawal symptoms emerge during discontinuation, raise dose to stop symptoms and then restart withdrawal much more slowly

Pharmacokinetics • Substrate for CYP450 2D6 and 1A2 • Plasma half-life 10–28 hours • Metabolized to an active metabolite,

nortriptyline, which is predominantly a norepinephrine reuptake inhibitor, by demethylation via CYP450 1A2

Drug Interactions • Tramadol increases the risk of seizures in

patients taking TCAs • Use of TCAs with anticholinergic drugs

may result in paralytic ileus or hyperthermia

• Fluoxetine, paroxetine, bupropion, duloxetine, and other CYP450 2D6 inhibitors may increase TCA concentrations

• Fluvoxamine, a CYP450 1A2 inhibitor, can decrease the conversion of amitriptyline to nortriptyline and increase amitriptyline plasma concentrations

• Cimetidine may increase plasma concentrations of TCAs and cause anticholinergic symptoms

• Phenothiazines or haloperidol may raise TCA blood concentrations

• May alter effects of antihypertensive drugs; may inhibit hypotensive effects of clonidine

• Use of TCAs with sympathomimetic agents may increase sympathetic activity

• Methylphenidate may inhibit metabolism of TCAs

• Activation and agitation, especially following switching or adding

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SPECIAL POPULATIONS

Renal Impairment • Use with caution; may need to lower dose

Hepatic Impairment • Use with caution; may need to lower dose

Cardiac Impairment • TCAs have been reported to cause

arrhythmias, prolongation of conduction time, orthostatic hypotension, sinus tachycardia, and heart failure, especially in the diseased heart

• Myocardial infarction and stroke have been reported with TCAs

• TCAs produce QTc prolongation, which may be enhanced by the existence of bradycardia, hypokalemia, congenital or acquired long QTc interval, which should be evaluated prior to administering amitriptyline

• Use with caution if treating concomitantly with a medication likely to produce prolonged bradycardia, hypokalemia, slowing of intracardiac conduction, or prolongation of the QTc interval

• Avoid TCAs in patients with a known history of QTc prolongation, recent acute myocardial infarction, and uncompensated heart failure

• TCAs may cause a sustained increase in heart rate in patients with ischemic heart disease and may worsen (decrease) heart rate variability, an independent risk of mortality in cardiac populations

• Since SSRIs may improve (increase) heart rate variability in patients following a myocardial infarct and may improve survival as well as mood in patients with acute angina or following a myocardial infarction, these are more appropriate

antidepressants, may represent the induction of a bipolar state, especially a mixed dysphoric bipolar II condition sometimes associated with suicidal ideation, and require the addition of lithium, a mood stabilizer or an atypical antipsychotic, and/or discontinuation of amitriptyline

Other Warnings/ Precautions

• Add or initiate other antidepressants with caution for up to 2 weeks after discontinuing amitriptyline

• Generally, do not use with MAO inhibitors, including 14 days after MAOIs are stopped; do not start an MAOI until 2 weeks after discontinuing amitriptyline, but see Pearls

• Use with caution in patients with history of seizures, urinary retention, narrow angle- closure glaucoma, hyperthyroidism

• TCAs can increase QTc interval, especially at toxic doses, which can be attained not only by overdose but also by combining with drugs that inhibit TCA metabolism via CYP450 2D6, potentially causing torsade de pointes-type arrhythmia or sudden death

• Because TCAs can prolong QTc interval, use with caution in patients who have bradycardia or who are taking drugs that can induce bradycardia (e.g., beta blockers, calcium channel blockers, clonidine, digitalis)

• Because TCAs can prolong QTc interval, use with caution in patients who have hypokalemia and/or hypomagnesemia, or who are taking drugs that can induce hypokalemia and/or magnesemia (e.g., diuretics, stimulant laxatives, intravenous amphotericin B, glucocorticoids, tetracosactide)

Do Not Use • If patient is recovering from myocardial

infarction • If patient is taking agents capable of

significantly prolonging QTc interval (e.g., pimozide, thioridazine, selected antiarrhythmics, moxifloxacin, sparfloxacin)

• If there is a history of QTc prolongation or cardiac arrhythmia, recent acute

myocardial infarction, uncompensated heart failure

• If patient is taking drugs that inhibit TCA metabolism, including CYP450 2D6 inhibitors, except by an expert

• If there is reduced CYP450 2D6 function, such as patients who are poor 2D6 metabolizers, except by an expert and at low doses

• If there is a proven allergy to amitriptyline or nortriptyline

AMITRIPTYLINE (continued)

0521011698s01.qxd 9/2/04 2:26 PM Page 16

THE ART OF PSYCHOPHARMACOLOGY

Potential Advantages • Patients with insomnia • Severe or treatment-resistant depression • Patients with a wide variety of chronic pain

syndromes

Potential Disadvantages • Pediatric and geriatric patients • Patients concerned with weight gain • Cardiac patients

Primary Target Symptoms • Depressed mood • Symptoms of anxiety • Somatic symptoms • Chronic pain • Insomnia

Pearls • Was once one of the most widely

prescribed agents for depression • Remains one of the most favored TCAs for

treating headache and a wide variety of chronic pain syndromes, including neuropathic pain, fibromyalgia, migraine, neck pain, and low back pain

✽ Preference of some prescribers for amitriptyline over other tricyclic/tetracyclic antidepressants for the treatment of chronic pain syndromes is based more upon art and anecdote rather than controlled clinical trials, since many TCAs/tetracylics may be effective for chronic pain syndromes

• Tricyclic antidepressants are no longer generally considered a first-line treatment

(continued) AMITRIPTYLINE

agents for cardiac population than tricyclic/tetracyclic antidepressants

✽ Risk/benefit ratio may not justify use of TCAs in cardiac impairment

Elderly • May be more sensitive to anticholinergic,

cardiovascular, hypotensive, and sedative effects

• Initial dose 50 mg/day; increase gradually up to 100 mg/day

Children and Adolescents • Use with caution, observing for activation

of known or unknown bipolar disorder and/or suicidal ideation, and strongly consider informing parents or guardian of this risk so they can help observe child or adolescent patients

• Not generally recommended for use under age 12

• Several studies show lack of efficacy of TCAs for depression

• May be used to treat enuresis or hyperactive/impulsive behaviors

• Some cases of sudden death have occurred in children taking TCAs

• Adolescents: initial dose 50 mg/day; increase gradually up to 100 mg/day

Pregnancy • Risk Category C [some animal studies

show adverse effects, no controlled studies in humans]

• Crosses the placenta • Adverse effects have been reported in

infants whose mothers took a TCA (lethargy, withdrawal symptoms, fetal malformations)

• Must weigh the risk of treatment (first trimester fetal development, third trimester newborn delivery) to the child against the risk of no treatment (recurrence of depression, maternal health, infant bonding) to the mother and child

• For many patients this may mean continuing treatment during pregnancy

Breast Feeding • Some drug is found in mother’s breast milk ✽ Recommended either to discontinue drug

or bottle feed

• Immediate postpartum period is a high-risk time for depression, especially in women who have had prior depressive episodes, so drug may need to be reinstituted late in the third trimester or shortly after childbirth to prevent a recurrence during the postpartum period

• Must weigh benefits of breast feeding with risks and benefits of antidepressant treatment versus non-treatment to both the infant and the mother

• For many patients this may mean continuing treatment during breast feeding

0521011698s01.qxd 9/2/04 2:26 PM Page 17

option for depression because of their side effect profile

✽ Amitriptyline has been shown to be effective in primary insomnia

• TCAs may aggravate psychotic symptoms • Alcohol should be avoided because of

additive CNS effects • Underweight patients may be more

susceptible to adverse cardiovascular effects

• Children, patients with inadequate hydration, and patients with cardiac disease may be more susceptible to TCA- induced cardiotoxicity than healthy adults

• For the expert only: although generally prohibited, a heroic but potentially dangerous treatment for severely treatment-resistant patients is to give a tricyclic/tetracyclic antidepressant other than clomipramine simultaneously with an MAO inhibitor for patients who fail to respond to numerous other antidepressants

• If this option is elected, start the MAOI with the tricyclic/tetracyclic antidepressant simultaneously at low doses after appropriate drug washout, then alternately increase doses of these agents every few days to a week as tolerated

• Although very strict dietary and concomitant drug restrictions must be

observed to prevent hypertensive crises and serotonin syndrome, the most common side effects of MAOI/tricyclic or tetracyclic combinations may be weight gain and orthostatic hypotension

• Patients on TCAs should be aware that they may experience symptoms such as photosensitivity or blue-green urine

• SSRIs may be more effective than TCAs in women, and TCAs may be more effective than SSRIs in men

• Since tricyclic/tetracyclic antidepressants are substrates for CYP450 2D6, and 7% of the population (especially Caucasians) may have a genetic variant leading to reduced activity of 2D6, such patients may not safely tolerate normal doses of tricyclic/tetracyclic antidepressants and may require dose reduction

• Phenotypic testing may be necessary to detect this genetic variant prior to dosing with a tricyclic/tetracyclic antidepressant, especially in vulnerable populations such as children, elderly, cardiac populations, and those on concomitant medications

• Patients who seem to have extraordinarily severe side effects at normal or low doses may have this phenotypic CYP450 2D6 variant and require low doses or switching to another antidepressant not metabolized by 2D6

AMITRIPTYLINE (continued)

Anderson IM. Meta-analytical studies on new antidepressants. Br Med Bull 2001; 57:161–178.

Anderson IM. Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and tolerability. J Aff Disorders 2000;58:19–36.

Barbui C, Hotopf M. Amitriptyline v. the rest: still the leading antidepressant after 40 years of randomised controlled trials. Br J Psychiatry 2001;178:129–144.

Bryson HM, Wilde MI. Amitriptyline. A review of its pharmacological properties and therapeutic use in chronic pain states. Drugs Aging 1996;8:459–76.

Suggested Reading

0521011698s01.qxd 9/2/04 2:26 PM Page 18

AMOXAPINE THERAPEUTICS

Brands • Asendin see index for additional brand names

Generic? Yes

Class • Tricyclic antidepressant (TCA), sometimes

classified as a tetracyclic antidepressant • Norepinephrine/noradrenaline reuptake

inhibitor • Serotonin 2A antagonist • Parent drug and especially an active

metabolite are dopamine 2 antagonists

Commonly Prescribed For (bold for FDA approved) • Neurotic or reactive depressive disorder • Endogenous and psychotic depressions • Depression accompanied by anxiety or

agitation • Depressive phase of bipolar disorder • Anxiety • Insomnia • Neuropathic pain/chronic pain • Treatment-resistant depression

How The Drug Works • Boosts neurotransmitter

norepinephrine/noradrenaline • Blocks norepinephrine reuptake pump

(norepinephrine transporter), presumably increasing noradrenergic neurotransmission

• Since dopamine is inactivated by norepinephrine reuptake in frontal cortex, which largely lacks dopamine transporters, amoxapine can thus increase dopamine neurotransmission in this part of the brain

• A more potent inhibitor of norepinephrine reuptake pump than serotonin reuptake pump (serotonin transporter)

• At high doses may also boost neurotransmitter serotonin and presumably increase serotonergic neurotransmission

• Blocks dopamine 2 receptors, reducing positive symptoms of psychosis

How Long Until It Works • Onset of therapeutic actions usually not

immediate, but often delayed 2 to 4 weeks

• If it is not working within 6 to 8 weeks for depression, it may require a dosage increase or it may not work at all

• May continue to work for many years to prevent relapse of symptoms

If It Works • The goal of treatment is complete

remission of current symptoms as well as prevention of future relapses

• Treatment most often reduces or even eliminates symptoms, but not a cure since symptoms can recur after medicine stopped

• Continue treatment until all symptoms are gone (remission)

• Once symptoms gone, continue treating for 1 year for the first episode of depression

• For second and subsequent episodes of depression, treatment may need to be indefinite

• Use in anxiety disorders may also need to be indefinite

If It Doesn’t Work • Many patients only have a partial response

where some symptoms are improved but others persist (especially insomnia, fatigue, and problems concentrating)

• Other patients may be nonresponders, sometimes called treatment-resistant or treatment-refractory

• Consider increasing dose, switching to another agent or adding an appropriate augmenting agent

• Consider psychotherapy • Consider evaluation for another diagnosis

or for a comorbid condition (e.g., medical illness, substance abuse, etc.)

Best Augmenting Combos for Partial Response or Treatment-Resistance

• Lithium, buspirone, thyroid hormone

Tests • None for healthy individuals ✽ Since tricyclic and tetracyclic

antidepressants are frequently associated with weight gain, before starting treatment,

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SIDE EFFECTS

How Drug Causes Side Effects • Anticholinergic activity may explain

sedative effects, dry mouth, constipation, and blurred vision

• Sedative effects and weight gain may be due to antihistamine properties

• Blockade of alpha adrenergic 1 receptors may explain dizziness, sedation, and hypotension

• Cardiac arrhythmias and seizures, especially in overdose, may be caused by blockade of ion channels

weigh all patients and determine if the patient is already overweight (BMI 25.0–29.9) or obese (BMI ≥30)

✽ Monitor weight and BMI during treatment ✽ While giving a drug to a patient who has

gained >5% of initial weight, consider evaluating for the presence of pre-diabetes, diabetes, or dyslipidemia, or consider switching to a different antidepressant

• Patients at risk for electrolyte disturbances (e.g., patients on diuretic therapy) should have baseline and periodic serum potassium and magnesium measurements

Notable Side Effects • Blurred vision, constipation, urinary

retention, increased appetite, dry mouth, nausea, diarrhea, heartburn, unusual taste in mouth, weight gain

• Fatigue, weakness, dizziness, sedation, headache, anxiety, nervousness, restlessness

• Sexual dysfunction, sweating ✽ Can cause extrapyramidal symptoms,

akathisia, and theoretically, tardive dyskinesia

Life Threatening or Dangerous Side Effects

• Paralytic ileus, hyperthermia (TCAs/tetracyclics + anticholinergic agents)

• Lowered seizure threshold and rare seizures

• Orthostatic hypotension, sudden death, arrhythmias, tachycardia

• QTc prolongation • Hepatic failure, extrapyramidal symptoms • Increased intraocular pressure • Rare induction of mania and activation of

suicidal ideation

Weight Gain

• Many experience and/or can be significant in amount

• Can increase appetite and carbohydrate craving

Sedation

• Many experience and/or can be significant in amount

• Tolerance to sedative effect may develop with long-term use

What To Do About Side Effects • Wait • Wait • Wait • Lower the dose • Switch to an SSRI or newer antidepressant

AMOXAPINE (continued)

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DOSING AND USE

Usual Dosage Range • 200–300 mg/day

Dosage Forms • Tablets 25 mg, 50 mg, 100 mg, 150 mg

How to Dose • Initial 25 mg 2–3 times/day; increase

gradually to 100 mg 2–3 times/day or a single dose at bedtime; maximum 400 mg/day (may dose up to 600 mg/day in inpatients)

Dosing Tips • If given in a single dose, should generally

be administered at bedtime because of its sedative properties

• If given in split doses, largest dose should generally be given at bedtime because of its sedative properties

• If patients experience nightmares, split dose and do not give large dose at bedtime

Overdose • Death may occur; convulsions, cardiac

dysrhythmias, severe hypotension, CNS depression, coma, changes in ECG

Long-Term Use • Generally safe • Some patients may develop withdrawal

dyskinesias when discontinuing amoxapine after long-term use

Habit Forming • Some patients may develop tolerance

(continued) AMOXAPINE

Best Augmenting Agents for Side Effects • Many side effects cannot be improved with

an augmenting agent • May use anticholinergics for

extrapyramidal symptoms, or switch to another antidepressant

How to Stop • Taper to avoid withdrawal effects • Even with gradual dose reduction some

withdrawal symptoms may appear within the first 2 weeks

• Many patients tolerate 50% dose reduction for 3 days, then another 50% reduction for 3 days, then discontinuation

• If withdrawal symptoms emerge during discontinuation, raise dose to stop symptoms and then restart withdrawal much more slowly

Pharmacokinetics • Substrate for CYP450 2D6 • Half-life of parent drug approximately 8

hours ✽ 7- and 8-hydroxymetabolites are active

and possess serotonin 2A and dopamine 2 antagonist properties, similar to atypical antipsychotics

✽ Amoxapine is the N-desmethyl metabolite of the conventional antipsychotic loxapine

• Half-life of the active metabolites approximately 24 hours

Drug Interactions • Tramadol increases the risk of seizures in

patients taking TCAs • Use of TCAs/tetracyclics with

anticholinergic drugs may result in paralytic ileus or hyperthermia

• Fluoxetine, paroxetine, bupropion, duloxetine, and other CYP450 2D6 inhibitors may increase TCA/tetracyclic concentrations

• Cimetidine may increase plasma concentrations of TCAs/tetracyclics and cause anticholinergic symptoms

• Phenothiazines or haloperidol may raise TCA/tetracyclic blood concentrations

• May alter effects of antihypertensive drugs; may inhibit hypotensive effects of clonidine

• Use of TCAs/tetracyclics with sympathomimetic agents may increase sympathetic activity

• Methylphenidate may inhibit metabolism of TCAs/tetracyclics

• Activation and agitation, especially following switching or adding antidepressants, may represent the induction of a bipolar state, especially a mixed dysphoric bipolar II condition

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SPECIAL POPULATIONS

Renal Impairment • Use with caution – may require lower than

usual adult dose

Hepatic Impairment • Use with caution – may require lower than

usual adult dose

Cardiac Impairment • TCAs/tetracyclics have been reported to

cause arrhythmias, prolongation of conduction time, orthostatic hypotension, sinus tachycardia, and heart failure, especially in the diseased heart

• Myocardial infarction and stroke have been reported with TCAs/tetracyclics

• TCAs/tetracyclics produce QTc prolongation, which may be enhanced by the existence of bradycardia, hypokalemia, congenital or acquired long QTc interval, which should be evaluated prior to administering amoxapine

• Use with caution if treating concomitantly with a medication likely to produce prolonged bradycardia, hypokalemia, slowing of intracardiac conduction, or prolongation of the QTc interval

• Avoid TCAs/tetracyclics in patients with a known history of QTc prolongation, recent acute myocardial infarction, and uncompensated heart failure

• TCAs/tetracyclics may cause a sustained increase in heart rate in patients with ischemic heart disease and may worsen (decrease) heart rate variability, an independent risk of mortality in cardiac populations

sometimes associated with suicidal ideation, and require the addition of lithium, a mood stabilizer or an atypical antipsychotic, and/or discontinuation of amoxapine

Other Warnings/ Precautions

• Add or initiate other antidepressants with caution for up to 2 weeks after discontinuing amoxapine

• Generally, do not use with MAO inhibitors, including 14 days after MAOIs are stopped; do not start an MAOI until 2 weeks after discontinuing amoxapine, but see Pearls

• Use with caution in patients with history of seizure, urinary retention, narrow angle- closure glaucoma, hyperthyroidism

• TCAs/tetracyclics can increase QTc interval, especially at toxic doses, which can be attained not only by overdose but also by combining with drugs that inhibit its metabolism via CYP450 2D6, potentially causing torsade de pointes-type arrhythmia or sudden death

• Because TCAs/tetracyclics can prolong QTc interval, use with caution in patients who have bradycardia or who are taking drugs that can induce bradycardia (e.g., beta blockers, calcium channel blockers, clonidine, digitalis)

• Because TCAs/tetracyclics can prolong QTc interval, use with caution in patients who have hypokalemia and/or hypomagnesemia, or who are taking drugs that can induce hypokalemia and/or magnesemia (e.g., diuretics, stimulant laxatives, intravenous amphotericin B, glucocorticoids, tetracosactide)

Do Not Use • If patient is recovering from myocardial

infarction • If patient is taking agents capable of

significantly prolonging QTc interval (e.g., pimozide, thioridazine, selected antiarrhythmics, moxifloxacin, sparfloxacin)

• If there is a history of QTc prolongation or cardiac arrhythmia, recent acute myocardial infarction, uncompensated heart failure

• If patient is taking drugs that inhibit TCA/tetracyclic metabolism, including CYP450 2D6 inhibitors, except by an expert

• If there is reduced CYP450 2D6 function, such as patients who are poor 2D6 metabolizers, except by an expert and at low doses

• If there is a proven allergy to amoxapine or loxapine

AMOXAPINE (continued)

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THE ART OF PSYCHOPHARMACOLOGY

Potential Advantages • Severe or treatment-resistant depression • Treatment-resistant psychotic depression

Potential Disadvantages • Pediatric and geriatric patients • Patients concerned with weight gain • Cardiac patients • Patients with Parkinson’s disease or tardive

dyskinesia

Primary Target Symptoms • Depressed mood

Pearls • Tricyclic/tetracyclic antidepressants are no

longer generally considered a first-line treatment option for depression because of their side effect profile

• Tricyclic/tetracyclic antidepressants continue to be useful for severe or treatment-resistant depression

✽ Because of potential extrapyramidal symptoms, akathisia, and theoretical risk of tardive dyskinesia, first consider other TCAs/tetracyclics for long-term use in general and for treatment of chronic patients

• TCAs may aggravate psychotic symptoms • Alcohol should be avoided because of

additive CNS effects • Underweight patients may be more

susceptible to adverse cardiovascular effects

• Children, patients with inadequate hydration, and patients with cardiac disease may be more susceptible to TCA- induced cardiotoxicity than healthy adults

(continued) AMOXAPINE

infarction, these are more appropriate agents for cardiac population than tricyclic/tetracyclic antidepressants

✽ Risk/benefit ratio may not justify use of TCAs/tetracyclics in cardiac impairment

Elderly • May be more sensitive to anticholinergic,

cardiovascular, hypotensive, and sedative effects

• Initial dose 25 mg/day at bedtime; increase by 25 mg/day each week; maximum dose 300 mg/day

Children and Adolescents • Use with caution, observing for activation

of known or unknown bipolar disorder and/or suicidal ideation, and strongly consider informing parents or guardian of this risk so they can help observe child or adolescent patients

• Not generally recommended for use under age 16

• Several studies show lack of efficacy of TCAs/tetracyclics for depression

• May be used to treat enuresis or hyperactive/impulsive behaviors

• Some cases of sudden death have occurred in children taking TCAs/tetracyclics

• Adolescents: initial 25–50 mg/day; increase gradually to 100 mg/day in divided doses or single dose at bedtime

Pregnancy • Risk Category C [some animal studies

show adverse effects, no controlled studies in humans]

• Amoxapine crosses the placenta • Adverse effects have been reported in

infants whose mothers took a TCA (lethargy, withdrawal symptoms, fetal malformations)

• Evaluate for treatment with an antidepressant with a better risk/benefit ratio

Breast Feeding • Some drug is found in mother’s breast milk ✽ Recommended either to discontinue drug

or bottle feed

• Evaluate for treatment with an antidepressant with a better risk/benefit ratio

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• Use of MAOIs with clomipramine is always prohibited because of the risk of serotonin syndrome and death

• Amoxapine may be the preferred trycyclic/tetracyclic antidepressant to combine with an MAOI in heroic cases due to its theoretically protective 5HT2A antagonist properties

• Although very strict dietary and concomitant drug restrictions must be observed to prevent hypertensive crises and serotonin syndrome, the most common side effects of MAOI/tricyclic or tetracyclic combinations may be weight gain and orthostatic hypotention

• Patients on TCAs/tetracyclics should be aware that they may experience symptoms such as photosensitivity or blue-green urine

• SSRIs may be more effective than TCAs/tetracyclics in women, and

TCAs/tetracyclics may be more effective than SSRIs in men

✽ May cause some motor effects, possibly due to effects on dopamine receptors

✽ Amoxapine may have a faster onset of action than some other antidepressants

✽ May be pharmacologically similar to an atypical antipsychotic in some patients

✽ At high doses, patients who form high concentrations of active metabolites may have akathisia, extrapyramidal symptoms, and possibly develop tardive dyskinesia

✽ Structurally and pharmacologically related to the antipsychotic loxapine

AMOXAPINE (continued)

Anderson IM. Meta-analytical studies on new antidepressants. Br Med Bull 2001; 57:161–178.

Anderson IM. Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and tolerability. J Aff Disorders 2000;58:19–36.

Hayes PE, Kristoff CA. Adverse reactions to five new antidepressants. Clin Pharm 1986; 5:471–80.

Jue SG, Dawson GW, Brogden RN. Amoxapine: a review of its pharmacology and efficacy in depressed states. Drugs 1982; 24:1–23.

Suggested Reading

0521011698s01.qxd 9/2/04 2:26 PM Page 24

ARIPIPRAZOLE THERAPEUTICS

Brands • Abilify see index for additional brand names

Generic? Not in U.S., Europe, or Japan

Class • Dopamine partial agonist (dopamine

stabilizer, atypical antipsychotic, third generation antipsychotic; sometimes included as a second generation antipsychotic; also a mood stabilizer)

Commonly Prescribed For (bold for FDA approved) • Schizophrenia • Maintaining stability in schizophrenia • Other psychotic disorders • Acute mania • Bipolar maintenance • Bipolar depression • Behavioral disturbances in dementias • Behavioral disturbances in children and

adolescents • Disorders associated with problems with

impulse control

How The Drug Works ✽ Partial agonism at dopamine 2 receptors • Theoretically reduces dopamine output

when dopamine concentrations are high, thus improving positive symptoms and mediating antipsychotic actions

• Theoretically increases dopamine output when dopamine concentrations are low, thus improving cognitive, negative, and mood symptoms

• Actions at dopamine 3 receptors could theoretically contribute to aripiprazole’s efficacy

• Partial agonism at 5HT1A receptors may be relevant at clinical doses

• Blockade of serotonin type 2A receptors may contribute at clinical doses to cause enhancement of dopamine release in certain brain regions, thus reducing motor side effects and possibly improving cognitive and affective symptoms

How Long Until It Works • Psychotic symptoms can improve within

1 week, but it may take several weeks for

full effect on behavior as well as on cognition and affective stabilization

If It Works • Most often reduces positive symptoms in

schizophrenia but does not eliminate them • Can improve negative symptoms, as well

as aggressive, cognitive, and affective symptoms in schizophrenia

• Most schizophrenic patients do not have a total remission of symptoms but rather a reduction of symptoms by about a third

• Perhaps 5–15% of schizophrenic patients can experience an overall improvement of greater than 50–60%, especially when receiving stable treatment for more than a year

• Such patients are considered super- responders or “awakeners” since they may be well enough to be employed, live independently, and sustain long-term relationships

• Many bipolar patients may experience a reduction of symptoms by half or more

• Continue treatment until reaching a plateau of improvement

• After reaching a satisfactory plateau, continue treatment for at least a year after first episode of psychosis

• For second and subsequent episodes of psychosis, treatment may need to be indefinite

• Even for first episodes of psychosis, it may be preferable to continue treatment indefinitely to avoid subsequent episodes

• Treatment may not only reduce mania but also prevent recurrences of mania in bipolar disorder

If It Doesn’t Work • Try one of the other atypical antipsychotics

(risperidone, olanzapine, quetiapine, ziprasidone, amisulpride)

• If two or more antipsychotic monotherapies do not work, consider clozapine

• If no first-line atypical antipsychotic is effective, consider higher doses or augmentation with valproate or lamotrigine

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SIDE EFFECTS

How Drug Causes Side Effects • By blocking alpha 1 adrenergic receptors, it

can cause dizziness, sedation, and hypotension

• Partial agonist actions at dopamine 2 receptors in the striatum can cause motor side effects, such as akathisia (occasionally)

• Partial agonist actions at dopamine 2 receptors can also cause nausea, occasional vomiting, and activating side effects

✽ Mechanism of any possible weight gain is unknown; weight gain is not common with aripiprazole and may thus have a different mechanism from atypical antipsychotics for which weight gain is common or problematic

✽ Mechanism of any possible increased incidence of diabetes or dyslipidemia is unknown; early experience suggests these complications are not clearly associated with aripiprazole and if present may therefore have a different mechanism from that of atypical antipsychotics associated with an increased incidence of diabetes and dyslipidemia

Notable Side Effects ✽ Dizziness, insomnia, akathisia, activation ✽ Nausea, vomiting • Orthostatic hypotension, occasionally

during initial dosing • Constipation

• Some patients may require treatment with a conventional antipsychotic

• Consider noncompliance and switch to another antipsychotic with fewer side effects or to an antipsychotic that can be given by depot injection

• Consider initiating rehabilitation and psychotherapy

• Consider presence of concomitant drug abuse

Best Augmenting Combos for Partial Response or Treatment-Resistance

• Valproic acid (valproate, divalproex, divalproex ER)

• Other mood stabilizing anticonvulsants (carbamazepine, oxcarbazepine, lamotrigine)

• Lithium • Benzodiazepines

Tests Before starting an atypical antipsychotic ✽ Weigh all patients and track BMI during

treatment • Get baseline personal and family history of

obesity, dyslipidemia, hypertension, and cardiovascular disease

✽ Get waist circumference (at umbilicus), blood pressure, fasting plasma glucose, and fasting lipid profile

• Determine if the patient is • overweight (BMI 25.0–29.9) • obese (BMI ≥30) • has pre-diabetes (fasting plasma glucose

100–125 mg/dl) • has diabetes (fasting plasma glucose

>126 mg/dl) • has hypertension (BP >140/90 mm Hg) • has dyslipidemia (increased total

cholesterol, LDL cholesterol, and triglycerides; decreased HDL cholesterol)

• Treat or refer such patients for treatment, including nutrition and weight management, physical activity counseling, smoking cessation, and medical management

Monitoring after starting an atypical antipsychotic ✽ BMI monthly for 3 months, then quarterly ✽ Blood pressure, fasting plasma glucose,

fasting lipids within 3 months and then annually, but earlier and more frequently

for patients with diabetes or who have gained >5% of initial weight

✽ Even in patients without known diabetes, be vigilant for the rare but life threatening onset of diabetic ketoacidosis, which always requires immediate treatment, by monitoring for the rapid onset of polyuria, polydipsia, weight loss, nausea, vomiting, dehydration, rapid respiration, weakness and clouding of sensorium, even coma

ARIPIPRAZOLE (continued)

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(continued) ARIPIPRAZOLE

• Headache, asthenia, sedation • Theoretical risk of tardive dyskinesia

Life Threatening or Dangerous Side Effects

• Rare neuroleptic malignant syndrome (much reduced risk compared to conventional antipsychotics)

• Rare seizures

Weight Gain

• Reported in a few patients, especially those with low BMIs, but not expected

• Less frequent and less severe than for most other antipsychotics

Sedation

• Reported in a few patients but not expected • May be less than for some other

antipsychotics, but never say never • Can be activating at moderate to high

doses

What To Do About Side Effects • Wait • Wait • Wait • Reduce the dose • Anticholinergics may reduce akathisia

when present • Weight loss, exercise programs, and

medical management for high BMIs, diabetes, dyslipidemia

• Switch to another atypical antipsychotic

Best Augmenting Agents for Side Effects • Benztropine or trihexyphenidyl for motor

side effects and akathisia • Many side effects cannot be improved with

an augmenting agent

DOSING AND USE

Usual Dosage Range • 15–30 mg/day

Dosage Forms • Tablet 5 mg, 10 mg, 15 mg, 20 mg, 30 mg

How to Dose • Initial approved recommendation is

15 mg/day; maximum approved dose 30 mg/day

Dosing Tips ✽ For some, less may be more: frequently,

patients not acutely psychotic may need to be dosed lower (e.g., 5–10 mg/day) in order to avoid akathisia and activation and for maximum tolerability

• For others, more may be more: rarely, patients may need to be dosed higher than 30 mg/day for optimum efficacy

• Consider cutting 5 mg tablet in half (tablets not scored) for children and adolescents, as well as for adults very sensitive to side effects

✽ Although studies suggest patients switching to aripiprazole from another antipsychotic can do well with rapid switch or with cross-titration, clinical experience suggests many patients may do best by adding a full dose of aripiprazole to the maintenance dose of the first antipsychotic for several days prior to slow down- titration of the first antipsychotic

• Rather than raise the dose above these levels in acutely agitated patients requiring acute antipsychotic actions, consider augmentation with a benzodiazepine or conventional antipsychotic, either orally or intramuscularly

• Rather than raise the dose above these levels in partial responders, consider augmentation with a mood stabilizing anticonvulsant, such as valproate or lamotrigine

• Children and elderly should generally be dosed at the lower end of the dosage spectrum

• Less expensive than some antipsychotics, more expensive than others depending on dose administered

• Due to its very long half-life, aripiprazole will take longer to reach steady state when

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SPECIAL POPULATIONS

Renal Impairment • Dose adjustment not necessary

Hepatic Impairment • Dose adjustment not necessary

Cardiac Impairment • Use in patients with cardiac impairment

has not been studied, so use with caution because of risk of orthostatic hypotension

Elderly • Dose adjustment generally not necessary,

but some elderly patients may tolerate lower doses better

Children and Adolescents • Not officially recommended for patients

under age 18 • Clinical experience and early data suggest

aripiprazole may be safe and effective for behavioral disturbances in children and adolescents, especially at lower doses

• Children and adolescents using aripiprazole may need to be monitored more often than adults and may tolerate lower doses better

Pregnancy • Risk Category C [some animal studies

show adverse effects, no controlled studies in humans]

• Psychotic symptoms may worsen during pregnancy and some form of treatment may be necessary

initiating dosing, and longer to wash out when stopping dosing, than other atypical antipsychotics

Overdose • No fatalities have been reported; sedation,

vomiting

Long-Term Use • Approved to delay relapse in long-term

treatment of schizophrenia • Often used for long-term maintenance in

bipolar disorder and various behavioral disorders

Habit Forming • No

How to Stop • Slow down-titration (over 6 to 8 weeks),

especially when simultaneously beginning a new antipsychotic while switching (i.e., cross-titration)

• Rapid discontinuation could theoretically lead to rebound psychosis and worsening of symptoms

Pharmacokinetics • Metabolized primarily by CYP450 2D6 and

CYP450 3A4 • Mean elimination half-life 75 hours

(aripiprazole) and 94 hours (major metabolite dehydro-aripiprazole)

Drug Interactions • Ketaconazole and possibly other CYP450

3A4 inhibitors such as nefazodone, fluvoxamine, and fluoxetine may increase plasma levels of aripiprazole

• Carbamazepine and possibly other inducers of CYP450 3A4 may decrease plasma levels of aripiprazole

• Quinidine and possibly other inhibitors of CYP450 2D6 such as paroxetine, fluoxetine, and duloxetine may increase plasma levels of aripiprazole

• Aripiprazole may enhance the effects of antihypertensive drugs

• Aripiprazole may antagonize levodopa, dopamine agonists

Other Warnings/ Precautions

• Use with caution in patients with conditions that predispose to hypotension (dehydration, overheating)

• Dysphagia has been associated with antipsychotic use, and aripiprazole should be used cautiously in patients at risk for aspiration pneumonia

Do Not Use • If there is a proven allergy to aripiprazole

ARIPIPRAZOLE (continued)

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THE ART OF PSYCHOPHARMACOLOGY

Potential Advantages • Some cases of psychosis and bipolar

disorder refractory to treatment with other antipsychotics

✽ Patients concerned about gaining weight ✽ Patients with diabetes • Patients requiring rapid onset of

antipsychotic action without dosage titration

Potential Disadvantages • Patients in whom sedation is desired • May be more difficult to dose for children,

elderly, or “off label” uses

Primary Target Symptoms • Positive symptoms of psychosis • Negative symptoms of psychosis

(continued) ARIPIPRAZOLE

• Aripiprazole may be preferable to anticonvulsant mood stabilizers if treatment is required during pregnancy

Breast Feeding • Unknown if aripiprazole is secreted in

human breast milk, but all psychotropics assumed to be secreted in breast milk

✽ Recommended either to discontinue drug or bottle feed

• Infants of women who choose to breast feed while on aripiprazole should be monitored for possible adverse effects

• Cognitive symptoms • Unstable mood • Aggressive symptoms

Pearls ✽ Well accepted in clinical practice when

wanting to avoid weight gain because less weight gain than most other antipsychotics

✽ Well accepted in clinical practice when wanting to avoid sedation because less sedation than most other antipsychotics at all doses

✽ Can even be activating, which can be reduced by lowering the dose or starting at a lower dose

• A moderately priced atypical antipsychotic within the therapeutic dosing range

✽ May not have diabetes or dyslipidemia risk, but monitoring is still indicated

• Anecdotal reports of utility in treatment- resistant cases

• Has a very favorable tolerability profile in clinical practice

• Favorable tolerability profile leading to “off- label” uses for many indications other than schizophrenia (e.g., acute bipolar mania; bipolar II disorder, including hypomanic, mixed, rapid cycling, and depressed phases; treatment-resistant depression; anxiety disorders)

Marder SR, McQuade RD, Stock E, Kaplita S, Marcus R, Safferman AZ, Saha A, Ali M, Iwamoto T. Aripiprazole in the treatment of schizophrenia: safety and tolerability in short- term, placebo-controlled trials. Schizophr Res 2003;61(2–3):123–36.

Sajatovic M. Treatment for mood and anxiety disorders: quetiapine and aripiprazole. Curr Psychiatry Rep 2003;5:320–6.

Shapiro DA, Renock S, Arrington E, Chiodo LA, Liu LX, Sibley DR, Roth BL, Mailman R. Aripiprazole, a novel atypical antipsychotic

drug with a unique and robust pharmacology. Neuropsychopharmacology 2003;28:1400–11.

Stahl SM. Dopamine system stabilizers, aripiprazole, and the next generation of antipsychotics, part 1: “Goldilocks” actions at dopamine receptors. J Clin Psychiatry 2001;62:841–2.

Stahl SM. Dopamine system stabilizers, aripiprazole, and the next generation of antipsychotics, part 2: illustrating their mechanism of action. J Clin Psychiatry 2001;62 (12):923–4.

Suggested Reading

0521011698s01.qxd 9/2/04 2:26 PM Page 29

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SIDE EFFECTS

How Drug Causes Side Effects • Norepinephrine increases in parts of the

brain and body and at receptors other than those that cause therapeutic actions (e.g., unwanted actions of norepinephrine on acetylcholine release causing decreased appetite, increased heart rate and blood pressure, dry mouth, urinary retention, etc.)

ATOMOXETINE THERAPEUTICS

Brands • Strattera see index for additional brand names

Generic? No

Class • Selective norepinephrine reuptake inhibitor

(NRI)

Commonly Prescribed For (bold for FDA approved) • Attention deficit hyperactivity disorder

(ADHD) in adults and children over 6 • Treatment-resistant depression

How The Drug Works • Boosts neurotransmitters

norepinephrine/noradrenaline and dopamine

• Blocks norepinephrine reuptake pumps, also known as norepinephrine transporters

• Presumably this increases noradrenergic neurotransmission

• Since dopamine is inactivated by norepinephrine reuptake in frontal cortex, which largely lacks dopamine transporters, atomoxetine can also increase dopamine neurotransmission in this part of the brain

How Long Until It Works ✽ Onset of therapeutic actions in ADHD can

be seen as early as the first day of dosing • Therapeutic actions may continue to

improve for 4 to 8 weeks • If it is not working within 6 to 8 weeks, it

may not work at all

If It Works • The goal of treatment of ADHD is reduction

of symptoms of inattentiveness, motor hyperactivity, and/or impulsiveness that disrupt social, school, and/or occupational functioning

• Continue treatment until all symptoms are under control or improvement is stable and then continue treatment indefinitely as long as improvement persists

• Reevaluate the need for treatment periodically

• Treatment for ADHD begun in childhood may need to be continued into adolescence

and adulthood if continued benefit is documented

If It Doesn’t Work • Consider adjusting dose or switching to

another agent • Consider behavioral therapy • Consider the presence of noncompliance

and counsel patient and parents • Consider evaluation for another diagnosis

or for a comorbid condition (e.g., bipolar disorder, substance abuse, medical illness, etc.)

• Some patients may experience apparent lack of consistent efficacy due to activation of latent or underlying bipolar disorder, and require atomoxetine discontinuation and a switch to a mood stabilizer

Best Augmenting Combos for Partial Response or Treatment-Resistance

✽ Best to attempt other monotherapies prior to augmenting

• SSRIs, SNRIs, or mirtazapine for treatment-resistant depression (use combinations of antidepressants with atomoxetine with caution as this may theoretically activate bipolar disorder and suicidal ideation)

• Mood stabilizers or atypical antipsychotics for comorbid bipolar disorder

• For the expert, can combine with modafinil, methylphenidate, or amphetamine for ADHD

Tests • None recommended for healthy patients • May be prudent to monitor blood pressure

and pulse when initiating treatment and until dosage increments have stabilized

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DOSING AND USE

Usual Dosage Range • 90 mg/day, 1.2 mg/kg/day

Dosage Forms • Capsule 10 mg, 18 mg, 25 mg, 40 mg,

60 mg

How to Dose • For children 70 kg or less: initial dose

0.5 mg/kg/day; after 3 days can increase to 1.2 mg/kg/day either once in the morning or divided; maximum dose 1.4 mg/kg/day or 100 mg/day, whichever is less

• For adults and children over 70 kg: initial dose 40 mg/day; after 3 days can increase to 80 mg/day once in the morning or divided; after 2–4 weeks can increase to 100 mg/day if necessary; maximum daily dose 100 mg

Dosing Tips • Can be given once a day in the morning ✽ Efficacy with once-daily dosing despite a

half-life of 5 hours suggests therapeutic effects persist beyond direct pharmacologic effects, unlike stimulants

• Most side effects are immediate but often go away with time

• Lack of enhancing dopamine activity in limbic areas theoretically explains atomoxetine’s lack of abuse potential

Notable Side Effects ✽ Sedation, fatigue ✽ Decreased appetite • Increased heart rate (6–9 beats/min) • Increased blood pressure (2–4 mm Hg) • Insomnia, dizziness, anxiety, agitation,

aggression, irritability • Dry mouth, constipation, nausea, vomiting,

abdominal pain, dyspepsia • Urinary hesitancy, urinary retention (older

men) • Dysmenorrhea, sweating • Sexual dysfunction (men: decreased libido,

erectile disturbance, impotence, ejaculatory dysfunction, abnormal orgasm; women: decreased libido, abnormal orgasm)

Life Threatening or Dangerous Side Effects

• Increased heart rate and hypertension • Orthostatic hypotension • Hypomania and, theoretically, rare

induction of mania and activation of suicidal ideation

Weight Gain

• Reported but not expected • Patients may experience weight loss

Sedation

• Occurs in significant minority

What To Do About Side Effects • Wait • Wait • Wait • Lower the dose • If giving once daily, can change to split

dose twice daily • In a few weeks, switch or add other drugs

Best Augmenting Agents for Side Effects • For urinary hesitancy, give an alpha 1

blocker such as tamsulosin • Often best to try another monotherapy

prior to resorting to augmentation strategies to treat side effects

• Many side effects are dose-dependent (i.e., they increase as dose increases, or they reemerge until tolerance re-develops)

• Many side effects are time-dependent (i.e., they start immediately upon dosing and upon each dose increase, but go away with time)

• Activation and agitation may represent the induction of a bipolar state, especially a mixed dysphoric bipolar II condition sometimes associated with suicidal ideation, and require the addition of lithium, a mood stabilizer or an atypical antipsychotic, and/or discontinuation of atomoxetine

ATOMOXETINE (continued)

0521011698s01.qxd 9/2/04 2:26 PM Page 32

SPECIAL POPULATIONS

Renal Impairment • Dose adjustment not generally necessary

Hepatic Impairment • For patients with moderate liver

impairment, dose should be reduced to 50% of normal dose

• For patients with severe liver impairment, dose should be reduced to 25% of normal dose

Cardiac Impairment • Use with caution because atomoxetine can

increase heart rate and blood pressure

Elderly • Some patients may tolerate lower doses

better

Children and Adolescents • Approved to treat ADHD in children over

age 6 • Recommended dose is 1.2 mg/kg/day

(continued) ATOMOXETINE

whose effects are generally closely correlated with plasma drug levels

• Once-daily dosing may increase gastrointestinal side effects

• Starting dose is half of therapeutic dose • Lower starting dose allows detection of

those patients who may be especially sensitive to side effects such as tachycardia and increased blood pressure

• Patients especially sensitive to the side effects of atomoxetine may include those individuals deficient in the enzyme that metabolizes atomoxetine, CYP450 2D6 (i.e., 7% of the population, especially Caucasians)

• In such individuals, use half the usual dose of atomoxetine if tolerated

• Other individuals may require up to 1.8 mg/kg total daily dose

Overdose • No fatalities have been reported; sedation,

agitation, hyperactivity, abnormal behavior, gastrointestinal symptoms

Long-Term Use • Safe

Habit Forming • No

How to Stop • Taper not necessary

Pharmacokinetics • Metabolized by CYP450 2D6 • Half-life approximately 5 hours

Drug Interactions • Tramadol increases the risk of seizures in

patients taking an antidepressant • Plasma concentrations of atomoxetine may

be increased by drugs that inhibit CYP450 2D6 (e.g., paroxetine, fluoxetine), so atomoxetine dose may need to be reduced if co-administered

• Co-administration of atomoxetine and albuterol may lead to increases in heart rate and blood pressure

• Co-administration with methylphenidate does not increase cardiovascular side effects beyond those seen with methylphenidate alone

• Do not use with MAO inhibitors, including 14 days after MAOIs are stopped

Other Warnings/ Precautions

• Growth (height and weight) should be monitored during treatment with atomoxetine; for patients who are not growing or gaining weight satisfactorily, interruption of treatment should be considered

• Use with caution in patients with hypertension, tachycardia, cardiovascular disease, or cerebrovascular disease

• Use with caution in patients with bipolar disorder

• Use with caution in patients with urinary retention, benign prostatic hypertrophy

• Use with caution with antihypertensive drugs

Do Not Use • If patient is taking an MAO inhibitor • If patient has narrow angle-closure

glaucoma • If there is a proven allergy to atomoxetine

0521011698s01.qxd 9/2/04 2:26 PM Page 33

Pregnancy • Risk Category C [some animal studies

show adverse effects, no controlled studies in humans]

• Use in women of childbearing potential requires weighing potential benefits to the mother against potential risks to the fetus

✽ For ADHD patients, atomoxetine should generally be discontinued before anticipated pregnancies

Breast Feeding • Unknown if atomoxetine is secreted in

human breast milk, but all psychotropics assumed to be secreted in breast milk

✽ Recommend either to discontinue drug or bottle feed

• Since dopamine is inactivated by norepinephrine reuptake in frontal cortex, which largely lacks dopamine transporters, atomoxetine can increase dopamine as well as norepinephrine in this part of the brain, presumably causing therapeutic actions in ADHD

• Since dopamine is inactivated by dopamine reuptake in nucleus accumbens, which largely lacks norepinephrine transporters, atomoxetine does not increase dopamine in this part of the brain, presumably explaining why atomoxetine lacks abuse potential

• Preliminary studies and atomoxetine’s known mechanism of action as a selective norepinephrine reuptake inhibitor suggest its efficacy as an antidepressant

• Pro-noradrenergic actions may be theoretically useful for the treatment of chronic pain

• Atomoxetine’s mechanism of action and its potential antidepressant actions suggest it has the potential to de-stabilize latent or undiagnosed bipolar disorder, similar to the known actions of proven antidepressants

• Thus, administer with caution to ADHD patients who may also have bipolar disorder

• Unlike stimulants, atomoxetine may not exacerbate tics in Tourette’s Syndrome patients with comorbid ADHD

• Urinary retention in men over 50 with borderline urine flow has been observed with other agents with potent norepinephrine reuptake blocking properties (e.g., reboxetine, milnacipran), so administer atomoxetine with caution to these patients

• Atomoxetine was originally called tomoxetine but the name was changed to avoid potential confusion with tamoxifen, which might lead to errors in drug dispensing

ATOMOXETINE (continued)

THE ART OF PSYCHOPHARMACOLOGY

Potential Advantages • No known abuse potential

Potential Disadvantages • May not act as rapidly as stimulants when

initiating treatment in some patients

Primary Target Symptoms • Concentration, attention span • Motor hyperactivity • Depressed mood

Pearls ✽ Unlike other agents approved for ADHD,

atomoxetine does not have abuse potential and is not a scheduled substance

✽ Despite its name as a selective norepinephrine reuptake inhibitor, atomoxetine enhances both dopamine and norepinephrine in frontal cortex, presumably accounting for its therapeutic actions on attention and concentration

0521011698s01.qxd 9/2/04 2:26 PM Page 34

(continued) ATOMOXETINE

Kratochvil CJ, Vaughan BS, Harrington MJ, Burke WJ. Atomoxetine: a selective noradrenaline reuptake inhibitor for the treatment of attention-deficit/hyperactivity disorder. Expert Opin Pharmacother 2003;4(7):1165–74.

Michelson D, Adler L, Spencer T, Reimherr FW, West SA, Allen AJ, Kelsey D, Wernicke J, Dietrich A, Milton D. Atomoxetine in adults with ADHD: two randomized, placebo- controlled studies. Biol Psychiatry 2003;53(2):112–20.

Simpson D, Perry CM. Atomoxetine. Paediatr Drugs 2003;5(6):407–15.

Wernicke JF, Kratochvil CJ. Safety profile of atomoxetine in the treatment of children and adolescents with ADHD. J Clin Psychiatry 2002;63 Suppl 12:50–5.

Suggested Reading

0521011698s01.qxd 9/2/04 2:26 PM Page 35

0521011698s01.qxd 9/2/04 2:26 PM Page 36

BUPROPION THERAPEUTICS

Brands • Wellbutrin, Wellbutrin SR, Wellbutrin XL

• Zyban see index for additional brand names

Generic? Yes (bupropion and bupropion SR)

Class • NDRI (norepinephrine dopamine reuptake

inhibitor); antidepressant; smoking cessation treatment

Commonly Prescribed For (bold for FDA approved) • Major depressive disorder (bupropion,

bupropion SR, and bupropion XL) • Nicotine addiction (bupropion SR) • Bipolar depression • Attention deficit / hyperactivity disorder • Sexual dysfunction

How The Drug Works • Boosts neurotransmitters

norepinephrine/noradrenaline and dopamine

• Blocks norepinephrine reuptake pump (norepinephrine transporter), presumably increasing norepinephrine neurotransmission

• Since dopamine is inactivated by norepinephrine reuptake in frontal cortex, which largely lacks dopamine transporters, bupropion can increase dopamine neurotransmission in this part of the brain

• Blocks dopamine reuptake pump (dopamine transporter), presumably increasing dopaminergic neurotransmission

How Long Until It Works • Onset of therapeutic actions usually not

immediate, but often delayed 2 to 4 weeks • If it is not working within 6 to 8 weeks for

depression, it may require a dosage increase or it may not work at all

• May continue to work for many years to prevent relapse of symptoms

If It Works • The goal of treatment of depression is

complete remission of current symptoms as well as prevention of future relapses

• Treatment of depression most often reduces or even eliminates symptoms, but is not a cure since symptoms can recur after medicine stopped

• Continue treatment of depression until all symptoms are gone (remission)

• Once symptoms of depression are gone, continue treating for 1 year for the first episode of depression

• For second and subsequent episodes of depression, treatment may need to be indefinite

• Treatment for nicotine addiction should consist of a single treatment for 6 weeks

If It Doesn’t Work • Many patients only have a partial response

where some symptoms are improved but others persist (especially insomnia, fatigue, and problems concentrating)

• Other patients may be nonresponders, sometimes called treatment-resistant or treatment-refractory

• Some patients who have an initial response may relapse even though they continue treatment, sometimes called “poop-out”

• Consider increasing dose, switching to another agent or adding an appropriate augmenting agent

• Consider psychotherapy • Consider evaluation for another diagnosis

or for a comorbid condition (e.g., medical illness, substance abuse, etc.)

• Some patients may experience apparent lack of consistent efficacy due to activation of latent or underlying bipolar disorder, and require antidepressant discontinuation and a switch to a mood stabilizer, although this may be a less frequent problem with bupropion than with other antidepressants

Best Augmenting Combos for Partial Response or Treatment-Resistance

• Trazodone for residual insomnia • Benzodiazepines for residual anxiety ✽ Can be added to SSRIs to reverse SSRI-

induced sexual dysfunction, SSRI-induced apathy (use combinations of antidepressants with caution as this may

0521011698s01.qxd 9/2/04 2:26 PM Page 37

SIDE EFFECTS

How Drug Causes Side Effects • Side effects are probably caused in part by

actions of norepinephrine and dopamine in brain areas with undesired effects (e.g., insomnia, tremor, agitation, headache, dizziness)

• Side effects are probably also caused in part by actions of norepinephrine in the periphery with undesired effects (e.g., sympathetic and parasympathetic effects such as dry mouth, constipation, nausea, anorexia, sweating)

• Most side effects are immediate but often go away with time

Notable Side Effects • Dry mouth, constipation, nausea, weight

loss, anorexia • Insomnia, dizziness, headache, agitation,

tremor, abdominal pain, tinnitus • Sweating • Hypertension (rare)

Life Threatening or Dangerous Side Effects

• Rare seizures (higher incidence for immediate release than for sustained release; risk increases with doses above the recommended maximums; risk

activate bipolar disorder and suicidal ideation)

✽ Can be added to SSRIs to treat partial responders

✽ Often used as an augmenting agent to mood stabilizers and/or atypical antipsychotics in bipolar depression

• Mood stabilizers or atypical antipsychotics can also be added to bupropion for psychotic depression or treatment-resistant depression

• Hypnotics for insomnia • Mirtazapine, modafinil, atomoxetine (add

with caution and at lower doses since bupropion could theoretically raise atomoxetine levels) both for residual symptoms of depression and attention deficit disorder

Tests • None for healthy individuals

increases for patients with predisposing factors)

• Hypomania (more likely in bipolar patients but perhaps less common than with some other antidepressants)

• Rare induction of mania and activation of suicidal ideation

Weight Gain

• Reported but not expected

Sedation

• Reported but not expected

What To Do About Side Effects • Wait • Wait • Wait • Keep dose as low as possible • Take no later than mid-afternoon to avoid

insomnia • Switch to another drug

Best Augmenting Agents for Side Effects • Often best to try another antidepressant

monotherapy prior to resorting to augmentation strategies to treat side effects

• Trazodone or a hypnotic for drug-induced insomnia

• Mirtazapine for insomnia, agitation, and gastrointestinal side effects

• Benzodiazepines or buspirone for drug- induced anxiety, agitation

• Many side effects are dose-dependent (i.e., they increase as dose increases, or they reemerge until tolerance re-develops)

• Many side effects are time-dependent (i.e., they start immediately upon dosing and upon each dose increase, but go away with time)

BUPROPION (continued)

0521011698s01.qxd 9/2/04 2:26 PM Page 38

(continued) BUPROPION

DOSING AND USE

Usual Dosage Range • Bupropion: 225–450 mg in 3 divided doses

(maximum single dose 150 mg) • Bupropion SR: 200–450 mg in 2 divided

doses (maximum single dose 200 mg) • Bupropion XL: 150–450 mg once daily

Dosage Forms • Bupropion: tablet 75 mg, 100 mg • Bupropion SR (sustained release): tablet

100 mg, 150 mg, 200 mg • Bupropion XL (extended release): tablet

150 mg, 300 mg

How to Dose • Depression: for bupropion immediate

release, dosing should be in divided doses, starting at 75 mg twice daily, increasing to 100 mg twice daily, then to 100 mg 3 times daily; maximum dose 450 mg per day

• Depression: for bupropion SR, initial dose 100 mg twice a day, increase to 150 mg twice a day after at least 3 days; wait 4 weeks or longer to ensure drug effects before increasing dose; maximum dose 400 mg total per day

• Depression: for bupropion XL, initial dose 150 mg once daily in the morning; can increase to 300 mg QD after 4 days; maximum dose 450 mg once daily

• Nicotine addiction [for bupropion SR]: Initial dose 150 mg/day once a day, increase to 150 mg twice a day after at least 3 days; maximum dose 300 mg/day; bupropion treatment should begin 1–2 weeks before smoking is discontinued

Dosing Tips • XL formulation has replaced immediate

release and SR formulations as the preferred option

• XL is best dosed once a day, whereas SR is best dosed twice daily, and immediate release is best dosed 3 times daily

• Dosing higher than 450 mg/day (400 mg/day SR) increases seizure risk

• Patients who do not respond to 450 mg/day should discontinue use or get blood levels of bupropion and its major active metabolite 6-hydroxy-bupropion

• If levels of parent drug and active metabolite are low despite dosing at

450 mg/day, experts can prudently increase dosing beyond the therapeutic range while monitoring closely, informing the patient of the potential risk of seizures and weighing risk benefit ratios in difficult-to-treat patients

• When used for bipolar depression, it is usually as an augmenting agent to mood stabilizers, lithium, and/or atypical antipsychotics

• For smoking cessation, may be used in conjunction with nicotine replacement therapy

• Do not break or chew SR or XL tablets as this will alter controlled release properties

• The more anxious and agitated the patient, the lower the starting dose, the slower the titration, and the more likely the need for a concomitant agent such as trazodone or a benzodiazepine

• If intolerable anxiety, insomnia, agitation, akathisia, or activation occur either upon dosing initiation or discontinuation, consider the possibility of activated bipolar disorder and switch to a mood stabilizer or an atypical antipsychotic

Overdose • Rarely lethal; seizures, cardiac

disturbances, hallucinations, loss of consciousness

Long-Term Use • For smoking cessation, treatment for up to

6 months has been found effective

Habit Forming • No

How to Stop • Tapering is prudent to avoid withdrawal

effects, but no well-documented tolerance, dependence, or withdrawal reactions

Pharmacokinetics • Inhibits CYP450 2D6 • Parent half-life 10–14 hours • Metabolite half-life 20–27 hours

Drug Interactions • Tramadol increases the risk of seizures in

patients taking an antidepressant • Can increase tricyclic antidepressant levels;

use with caution with tricyclic

0521011698s01.qxd 9/2/04 2:26 PM Page 39

antidepressants or when switching from a TCA to bupropion

• Can be fatal when combined with MAO inhibitors, so do not use with MAO inhibitors or for at least 14 days after MAOIs are stopped

• Do not start an MAO inhibitor for at least two weeks after discontinuing bupropion

• Via CYP450 2D6 inhibition, bupropion could theoretically interfere with the analgesic actions of codeine, and increase the plasma levels of some beta blockers and of atomoxetine

• Via CYP450 2D6 inhibition, bupropion could theoretically increase concentrations of thioridazine and cause dangerous cardiac arrhythmias

Other Warnings/ Precautions

• Use cautiously with other drugs that increase seizure risk (TCAs, lithium, phenothiazines, thioxanthenes, some antipsychotics)

• Bupropion should be used with caution in patients taking levodopa or amantadine, as these agents can potentially enhance dopamine neurotransmission and be activating

• Do not use if patient has severe insomnia • Use with caution in patients with bipolar

disorder unless treated with concomitant mood stabilizing agent

• Monitor patients for activation of suicidal ideation, especially children and adolescents

Do Not Use • Zyban in combination with any formulation

of Wellbutrin • If patient has history of seizures • If patient is anorexic or bulimic, either

currently or in the past, but see Pearls • If patient is abruptly discontinuing alcohol

or sedative use • If patient has had recent head injury • If patient has a nervous system tumor • If patient is taking an MAO inhibitor • If patient is taking thioridazine • If there is a proven allergy to bupropion

SPECIAL POPULATIONS

Renal Impairment • Lower initial dose, perhaps give less

frequently • Drug concentration may be increased • Patient should be monitored closely

Hepatic Impairment • Lower initial dose, perhaps give less

frequently • Patient should be monitored closely • In severe hepatic cirrhosis, bupropion XL

should be administered at no more than 150 mg every other day

Cardiac Impairment • Limited available data • Evidence of rise in supine blood pressure • Use with caution

Elderly • Some patients may tolerate lower doses

better

Children and Adolescents • Use with caution, observing for activation

of known or unknown bipolar disorder and/or suicidal ideation, and strongly consider informing parents or guardian of this risk so they can help observe child or adolescent patients

• Safety and efficacy have not been established

• May be used for ADHD in children or adolescents

• May be used for smoking cessation in adolescents

• Preliminary research suggests efficacy in comorbid depression and ADHD

• Dosage may follow adult pattern for adolescents

• Children may require lower doses initially, with a maximum dose of 300 mg/day

Pregnancy • Risk Category B [animal studies do not

show adverse effects; no controlled studies in humans]

• Pregnant women wishing to stop smoking may consider behavioral therapy before pharmacotherapy

BUPROPION (continued)

0521011698s01.qxd 9/2/04 2:26 PM Page 40

THE ART OF PSYCHOPHARMACOLOGY

Potential Advantages • Retarded depression • Atypical depression • Bipolar depression • Patients concerned about sexual

dysfunction • Patients concerned about weight gain

Potential Disadvantages • Patients experiencing weight loss

associated with their depression • Patients who are excessively activated

Primary Target Symptoms • Depressed mood • Sleep disturbance, especially hypersomnia • Cravings associated with nicotine

withdrawal • Cognitive functioning

(continued) BUPROPION

• Not generally recommended for use during pregnancy, especially during first trimester

• For many patients this may mean continuing treatment during pregnancy

Breast Feeding • Some drug is found in mother’s breast milk • If child becomes irritable or sedated, breast

feeding or drug may need to be discontinued

• Must weigh benefits of breast feeding with risks and benefits of antidepressant treatment versus non-treatment to both the infant and the mother

• For many patients, this may mean continuing treatment during breast feeding

Pearls ✽ May be effective if SSRIs have failed or

for SSRI “poop-out” • Less likely to produce hypomania than

some other antidepressants ✽ May improve cognitive

slowing/pseudodementia ✽ Reduces hypersomnia and fatigue • Approved to help reduce craving during

smoking cessation • Anecdotal use in attention deficit disorder • May cause sexual dysfunction only

infrequently • May exacerbate tics • Bupropion may not be as effective in

anxiety disorders as many other antidepressants

• Prohibition for use in eating disorders is related to past observations when bupropion immediate release was dosed at especially high levels to low body weight patients with active anorexia nervosa

• Current practice suggests that patients of normal BMI without additional risk factors for seizures can benefit from bupropion, especially if given prudent doses of the XL formulation; such treatment should be administered by experts, and patients should be monitored closely and informed of the potential risks

• The active enantiomer of the principle active metabolite (+6-hydroxy-bupropion) is in clinical development as a novel antidepressant

0521011698s01.qxd 9/2/04 2:26 PM Page 41

BUPROPION (continued)

Ferry L, Johnston JA. Efficacy and safety of bupropion SR for smoking cessation: data from clinical trials and five years of postmarketing experience. Int J Clin Pract 2003;57(3):224–30.

Hirschfeld RM. Efficacy of SSRIs and newer antidepressants in severe depression: comparison with TCAs. Journal of Clinical Psychiatry 1999;60:326–335.

Horst WD, Preskorn SH. Mechanisms of action and clinical characteristics of three atypical antidepressants: venlafaxine, nefazodone, bupropion. Journal of Affective Disorders 1998;51:237–254.

Masand PS, Gupta S. Long-term side effects of newer-generation antidepressants: SSRIs, venlafaxine, nefazodone, bupropion, and mirtazapine. Ann Clin Psychiatry 2002;14(3):175–82.

Nieuwstraten CE, Dolovich LR. Bupropion versus selective serotonin-reuptake inhibitors for treatment of depression. Ann Pharmacother 2001;35(12):1608–13.

Suggested Reading

0521011698s01.qxd 9/2/04 2:26 PM Page 42

SIDE EFFECTS

How Drug Causes Side Effects • Serotonin partial agonist actions in parts of

the brain and body and at receptors other than those that cause therapeutic actions

Notable Side Effects ✽ Dizziness, headache, nervousness,

sedation, excitement • Nausea • Restlessness

Life Threatening or Dangerous Side Effects

• Rare cardiac symptoms

Weight Gain

• Reported but not expected

Sedation

• Occurs in significant minority

What To Do About Side Effects • Wait • Wait • Wait • Lower the dose • Give total daily dose divided into 3, 4, or

more doses • Switch to another agent

Best Augmenting Agents for Side Effects • Many side effects cannot be improved with

an augmenting agent

BUSPIRONE THERAPEUTICS

Brands • BuSpar see index for additional brand names

Generic? Yes

Class • Anxiolytic (azapirone; serotonin 1A partial

agonist; serotonin stabilizer)

Commonly Prescribed For (bold for FDA approved) • Management of anxiety disorders • Short-term treatment of symptoms of

anxiety • Mixed anxiety and depression • Treatment-resistant depression (adjunctive)

How The Drug Works • Binds to serotonin type 1A receptors • Partial agonist actions post-synaptically

may theoretically diminish serotonergic activity and contribute to anxiolytic actions

• Partial agonist actions at presynaptic somatodendritic serotonin autoreceptors may theoretically enhance serotonergic activity and contribute to antidepressant actions

How Long Until It Works • Generally takes within 2–4 weeks to

achieve efficacy • If it is not working within 6 to 8 weeks, it

may require a dosage increase or it may not work at all

If It Works • The goal of treatment is complete

remission of symptoms as well as prevention of future relapses

• Treatment most often reduces or even eliminates symptoms, but not a cure since symptoms can recur after medicine stopped

• Chronic anxiety disorders may require long-term maintenance with buspirone to control symptoms

If It Doesn’t Work • Consider switching to another agent (a

benzodiazepine or antidepressant)

Best Augmenting Combos for Partial Response or Treatment-Resistance

• Sedative hypnotic for insomnia • Buspirone is often given as an augmenting

agent to SSRIs or SNRIs

Tests • None for healthy individuals

0521011698s01.qxd 9/2/04 2:27 PM Page 43

SPECIAL POPULATIONS

Renal Impairment • Use with caution • Not recommended for patients with severe

renal impairment

Hepatic Impairment • Use with caution • Not recommended for patients with severe

hepatic impairment

Cardiac Impairment • Buspirone has been used to treat hostility

in patients with cardiac impairment

Elderly • Some patients may tolerate lower doses

better

Children and Adolescents • Studies in children 6–17 do not show

significant reduction in anxiety symptoms in GAD

• Safety profile in children encourages use

Pregnancy • Risk Category B [animal studies do not

show adverse effects, no controlled studies in humans]

• Not generally recommended in pregnancy, but may be safer than some other options

Breast Feeding • Some drug is found in mother’s breast milk • Trace amounts may be present in nursing

children whose mothers are on buspirone

DOSING AND USE

Usual Dosage Range • 20–30 mg/day

Dosage Forms • Tablet 5 mg scored, 10 mg scored, 15 mg

multi-scored, 30 mg multi-scored

How to Dose • Initial 15 mg twice a day; increase in

5 mg/day increments every 2–3 days until desired efficacy is reached; maximum dose generally 60 mg/day

Dosing Tips • Requires dosing 2–3 times a day for full

effect

Overdose • No deaths reported in monotherapy;

sedation, dizziness, small pupils, nausea, vomiting

Long-Term Use • Limited data suggest that it is safe

Habit Forming • No

How to Stop • Taper generally not necessary

Pharmacokinetics • Metabolized primarily by CYP450 3A4 • Elimination half-life approximately

2–3 hours

Drug Interactions • Do not use with MAO inhibitors, including

14 days after MAOIs are stopped • CYP450 3A4 inhibitors (e.g., fluxotine,

fluvoxamine, nefazodone) may reduce clearance of buspirone and raise its plasma levels, so the dose of buspirone may need to be lowered when given concomitantly with these agents

• CYP450 3A4 inducers (e.g., carbamazepine) may increase clearance of buspirone, so the dose of buspirone may need to be raised

• Buspirone may increase plasma concentrations of haloperidol

• Buspirone may raise levels of nordiazepam, the active metabolite of diazepam, which may result in increased symptoms of dizziness, headache, or nausea

Other Warnings/ Precautions

• None

Do Not Use • If patient is taking an MAO inhibitor • If there is a proven allergy to buspirone

BUSPIRONE (continued)

0521011698s01.qxd 9/2/04 2:27 PM Page 44

(continued) BUSPIRONE

• If child becomes irritable or sedated, breast feeding or drug may need to be discontinued

• May have less severe side effects than benzodiazepines

✽ Buspirone generally lacks sexual dysfunction

• Buspirone may reduce sexual dysfunction associated with generalized anxiety disorder and with serotonergic antidepressants

• Sedative effects may be more likely at doses above 20 mg/day

• May have less anxiolytic efficacy than benzodiazepines for some patients

• Buspirone is generally reserved as an augmenting agent to treat anxiety

• A new controlled-release azapirone related to buspirone is in late clinical testing as an antidepressant (gepirone ER)

THE ART OF PSYCHOPHARMACOLOGY

Potential Advantages • Safety profile • Lack of dependence, withdrawal • Lack of sexual dysfunction or weight gain

Potential Disadvantages • Takes 4 weeks for results, whereas

benzodiazepines have immediate effects

Primary Target Symptoms • Anxiety

Pearls ✽ Buspirone does not appear to cause

dependence and shows virtually no withdrawal symptoms

Apter JT, Allen LA. Buspirone: future directions. J Clin Psychopharmacol 1999; 19:86–93.

Mahmood I, Sahaiwalla C. Clinical pharmacokinetics and pharmacodynamics of buspirone, an anxiolytic drug. Clin Pharmacokinet 1999;36:277–87.

Pecknold JC. A risk-benefit assessment of buspirone in the treatment of anxiety disorders. Drug Saf 1997;16:118–32.

Sramek JJ, Hong WW, Hamid S, Nape B, Cutler NR. Meta-analysis of the safety and tolerability of two dose regimens of buspirone in patients with persistent anxiety. Depress Anxiety 1999;9:131–4.

Suggested Reading

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CARBAMAZEPINE THERAPEUTICS

Brands • Tegretol • Carbatrol

see index for additional brand names

Generic? Yes (not for extended release formulation)

Class • Anticonvulsant, antineuralgic for chronic

pain, voltage-sensitive sodium channel antagonist

Commonly Prescribed For (bold for FDA approved) • Partial seizures with complex

symptomatology • Generalized tonic-clonic seizures (grand

mal) • Mixed seizure patterns • Pain associated with true trigeminal

neuralgia • Glossopharyngeal neuralgia • Bipolar disorder • Psychosis, schizophrenia (adjunctive)

How The Drug Works ✽ Acts as a use-dependent blocker of

voltage-sensitive sodium channels ✽ Interacts with the open channel

conformation of voltage-sensitive sodium channels

✽ Interacts at a specific site of the alpha pore-forming subunit of voltage-sensitive sodium channels

• Inhibits release of glutamate

How Long Until It Works • For acute mania, effects should occur

within a few weeks • May take several weeks to months to

optimize an effect on mood stabilization • Should reduce seizures by 2 weeks

If It Works • The goal of treatment is complete

remission of symptoms (e.g., seizures, mania, pain)

• Continue treatment until all symptoms are gone or until improvement is stable and then continue treating indefinitely as long as improvement persists

• Continue treatment indefinitely to avoid recurrence of mania and seizures

• Treatment of chronic neuropathic pain most often reduces but does not eliminate pain and is not a cure since symptoms usually recur after medicine stopped

If It Doesn’t Work (for bipolar disorder) ✽ Many patients only have a partial

response where some symptoms are improved but others persist or continue to wax and wane without stabilization of mood

• Other patients may be nonresponders, sometimes called treatment-resistant or treatment-refractory

• Consider increasing dose, switching to another agent or adding an appropriate augmenting agent

• Consider adding psychotherapy • Consider biofeedback or hypnosis for pain • For bipolar disorder, consider the presence

of noncompliance and counsel patient • Switch to another mood stabilizer with

fewer side effects or to extended release carbamazepine

• Consider evaluation for another diagnosis or for a comorbid condition (e.g., medical illness, substance abuse, etc.)

Best Augmenting Combos for Partial Response or Treatment-Resistance

• Carbamazepine is itself a second-line augmenting agent for numerous other anticonvulsants, lithium, and atypical antipsychotics in treating bipolar disorder

• Carbamazepine is itself a second or third- line augmenting agent for atypical antipsychotics in treating schizophrenia

Tests ✽ Before starting: blood count, liver, kidney,

and thyroid function tests • During treatment: blood count every

2 weeks for 2 months, then every 3 months throughout treatment

• During treatment: liver, kidney, and thyroid function tests every 6–12 months

• Consider monitoring sodium levels because of possibility of hyponatremia

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DOSING AND USE

Usual Dosage Range • 400–1200 mg/day • Under age 6: 10–20 mg/kg/day

Dosage Forms • Tablet 100 mg chewable, 200 mg • Extended release tablet 100 mg, 200 mg,

400 mg • Extended release capsule 200 mg, 300 mg • Oral suspension 100 mg/5mL (450 mL)

How to Dose • For bipolar disorder and seizures (ages 13

and older): initial 200 mg twice daily (tablet) or 1 teaspoon (100 mg) 4 times a day (suspension); each week increase by up to 200 mg/day in divided doses (2 doses for extended release formulation, 3–4 doses for other tablets); maximum dose generally 1200 mg/day for adults and 1000 mg/day for children under age 15; maintenance dose generally 800–1200 mg/day for adults; some patients may require up to 1600 mg/day

• Seizures (under age 13): see Children and Adolescents

• Trigeminal neuralgia: initial 100 mg twice daily (tablet) or 0.5 teaspoon (50 mg) 4 times a day; each week increase by up to 200 mg/day in divided doses (100 mg every 12 hours for tablet formulations, 50 mg 4 times a day for suspension formulation); maximum dose generally 1200 mg/day

• Lower initial dose and slower titration should be used for carbamazepine suspension

SIDE EFFECTS

How Drug Causes Side Effects • CNS side effects theoretically due to

excessive actions at voltage-sensitive sodium channels

• Major metabolite (carbamazepine-10, 11 epoxide) may be the cause of many side effects

• Mild anticholinergic effects may contribute to sedation, blurred vision

Notable Side Effects ✽ Sedation, dizziness, confusion,

unsteadiness, headache ✽ Nausea, vomiting, diarrhea • Blurred vision ✽ Benign leukopenia (transient; in up to 10%) ✽ Rash

Life Threatening or Dangerous Side Effects

✽ Rare aplastic anemia, agranulocytosis (unusual bleeding or bruising, mouth sores, infections, fever, sore throat)

✽ Rare severe dermatologic reactions (Stevens Johnson syndrome)

• Rare cardiac problems • Rare induction of psychosis or mania ✽ SIADH (syndrome of inappropriate

antidiuretic hormone secretion) with hyponatremia

• Increased frequency of generalized convulsions (in patients with atypical absence seizures)

Weight Gain

• Occurs in significant minority

Sedation

• Frequent and can be significant in amount • Some patients may not tolerate it • Dose-related • Can wear off with time, but commonly

does not wear off at high doses

What To Do About Side Effects • Wait • Wait • Wait

• Take with food or split dose to avoid gastrointestinal effects

• Extended release carbamazepine can be sprinkled on soft food

• Take at night to reduce daytime sedation • Switch to another agent or to extended

release carbamazepine

Best Augmenting Agents for Side Effects • Many side effects cannot be improved with

an augmenting agent

CARBAMAZEPINE (continued)

0521011698s01.qxd 9/2/04 2:27 PM Page 48

(continued) CARBAMAZEPINE

Dosing Tips • Higher peak levels occur with the

suspension formulation than with the same dose of the tablet formulation, so suspension should generally be started at a lower dose and titrated slowly

• Take carbamazepine with food to avoid gastrointestinal effects

✽ Slow dose titration may delay onset of therapeutic action but enhance tolerability to sedating side effects

• Should titrate slowly in the presence of other sedating agents, such as other anticonvulsants, in order to best tolerate additive sedative side effects

✽ Can sometimes minimize the impact of carbamazepine upon the bone marrow by dosing slowly and monitoring closely when initiating treatment; initial trend to leukopenia/neutropenia may reverse with continued conservative dosing over time and allow subsequent dosage increases with careful monitoring

✽ Carbamazepine often requires a dosage adjustment upward with time, as the drug induces its own metabolism, thus lowering its own plasma levels over the first several weeks to months of treatment

• Do not break or chew carbamazepine extended release tablets as this will alter controlled release properties

Overdose • Can be fatal (lowest known fatal dose in

adults is 3.2 g, in adolescents is 4 g, and in children is 1.6 g); nausea, vomiting, involuntary movements, irregular heartbeat, urinary retention, trouble breathing, sedation, coma

Long-Term Use • May lower sex drive • Monitoring of liver, kidney, thyroid

functions, blood counts and sodium may be required

Habit Forming • No

How to Stop • Taper; may need to adjust dosage of

concurrent medications as carbamazepine is being discontinued

✽ Rapid discontinuation may increase the risk of relapse in bipolar disorder

• Epilepsy patients may seize upon withdrawal, especially if withdrawal is abrupt

• Discontinuation symptoms uncommon

Pharmacokinetics • Metabolized in the liver, primarily by

CYP450 3A4 • Renally excreted • Active metabolite (carbamazepine-

10,11 epoxide) • Initial half-life 26–65 hours (35–40 hours

for extended release formulation); half-life 12–17 hours with repeated doses

• Half-life of active metabolite is approximately 34 hours

✽ Is not only a substrate for CYP450 3A4, but also an inducer of CYP450 3A4

✽ Thus, carbamazepine induces its own metabolism, often requiring an upward dosage adjustment

Drug Interactions • Enzyme-inducing antiepileptic drugs

(carbamazepine itself as well as phenobarbital, phenytoin, and primidone) may increase the clearance of carbamazepine and lower its plasma levels

• CYP450 3A4 inducers, such as carbamazepine itself, can lower the plasma levels of carbamazepine

• CYP450 3A4 inhibitors, such as nefazodone, fluvoxamine, and fluoxetine, can increase plasma levels of carbamazepine

• Carbamazepine can increase plasma levels of clomipramine, phenytoin, primidone

• Carbamazepine can decrease plasma levels of acetaminophen, clozapine, benzodiazepines, dicumarol, doxycycline, theophylline, warfarin, and haloperidol as well as other anticonvulsants such as phensuximide, methsuximide, ethosuximide, phenytoin, tiagabine, topiramate, lamotrigine, and valproate

• Carbamazepine can decrease plasma levels of hormonal contraceptives and adversely affect their efficacy

• Combined use of carbamazepine with other anticonvulsants may lead to altered thyroid function

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SPECIAL POPULATIONS

Renal Impairment • Carbamazepine is renally secreted, so the

dose may need to be lowered

Hepatic Impairment • Drug should be used with caution • Rare cases of hepatic failure have occurred

Cardiac Impairment • Drug should be used with caution

Elderly • Some patients may tolerate lower doses

better • Elderly patients may be more susceptible

to adverse effects

Children and Adolescents • Approved use for epilepsy; therapeutic

range of total carbamazepine in plasma is considered the same for children and adults

• Ages 6–12: initial dose 100 mg twice daily (tablets) or 0.5 teaspoon (50 mg) 4 times a day (suspension); each week increase by up to 100 mg/day in divided doses (2 doses for extended release formulation, 3–4 doses for all other formulations); maximum dose generally 1000 mg/day; maintenance dose generally 400–800 mg/day

• Ages 5 and younger: initial 10–20 mg/kg/day in divided doses (2–3 doses for tablet formulations, 4 doses for suspension); increase weekly as needed; maximum dose generally 35 mg/kg/day

Pregnancy • Risk category D [positive evidence of risk

to human fetus; potential benefits may still justify its use during pregnancy]

✽ Use during first trimester may raise risk of neural tube defects (e.g., spina bifida) or other congenital anomalies

• Combined use of carbamazepine and lithium may increase risk of neurotoxic effects

• Depressive effects are increased by other CNS depressants (alcohol, MAOIs, other anticonvulsants, etc.)

• Combined use of carbamazepine suspension with liquid formulations of chlorpromazine has been shown to result in excretion of an orange rubbery precipitate; because of this, combined use of carbamazepine suspension with any liquid medicine is not recommended

Other Warnings/ Precautions

✽ Patients should be monitored carefully for signs of unusual bleeding or bruising, mouth sores, infections, fever, or sore throat, as the risk of aplastic anemia and agranulocytosis with carbamazepine use is 5–8 times greater than in the general population (risk in the untreated general population is 6 patients per one million per year for agranulocytosis and 2 patients per one million per year for aplastic anemia)

• Because carbamazepine has a tricyclic chemical structure, it is not recommended to be taken with MAOIs, including 14 days after MAOIs are stopped; do not start an MAOI until 2 weeks after discontinuing carbamazepine

• May exacerbate narrow angle-closure glaucoma

• Because carbamazepine can lower plasma levels of hormonal contraceptives, it may also reduce their effectiveness

• May need to restrict fluid intake because of risk of developing syndrome of inappropriate antidiuretic hormone secretion, hyponatremia and its complications

• Use with caution in patients with mixed seizure disorders that include atypical absence seizures because carbamazepine has been associated with increased frequency of generalized convulsions in such patients

Do Not Use • If patient is taking an MAOI • If patient has history of bone marrow

suppression

• If there is a proven allergy to any tricyclic compound

• If there is a proven allergy to carbamazepine

CARBAMAZEPINE (continued)

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THE ART OF PSYCHOPHARMACOLOGY

Potential Advantages • Treatment-resistant bipolar and psychotic

disorders

Potential Disadvantages • Patients who do not wish to or cannot

comply with blood testing and close monitoring

• Patients who cannot tolerate sedation • Pregnant patients

Primary Target Symptoms • Incidence of seizures • Unstable mood, especially mania • Pain

Pearls • Carbamazepine is the first anticonvulsant

widely used for the treatment of bipolar disorder

✽ Due to the emergence of anticonvulsants with better documentation of efficacy and better tolerability, use in bipolar disorder is declining

✽ An extended release formulation has better evidence of efficacy and improved tolerability in bipolar disorder than does immediate release carbamazepine

• Dosage frequency as well as sedation, diplopia, confusion, and ataxia may be reduced with extended release carbamazepine

• Risk of serious side effects is greatest in the first few months of treatment

• Common side effects such as sedation often abate after a few months

✽ May be effective in patients who fail to respond to lithium or other mood stabilizers

✽ Especially preferred as a second or third- line treatment for mania

(continued) CARBAMAZEPINE

• Use in women of childbearing potential requires weighing potential benefits to the mother against the risks to the fetus

✽ If drug is continued, perform tests to detect birth defects

✽ If drug is continued, start on folate 1 mg/day early in pregnancy to reduce risk of neural tube defects

• Use of anticonvulsants in combination may cause a higher prevalence of teratogenic effects than anticonvulsant monotherapy

• Taper drug if discontinuing • Seizures, even mild seizures, may cause

harm to the embryo/fetus ✽ For bipolar patients, carbamazepine

should generally be discontinued before anticipated pregnancies

• Recurrent bipolar illness during pregnancy can be quite disruptive

• For bipolar patients, given the risk of relapse in the postpartum period, some form of mood stabilizer treatment may need to be restarted immediately after delivery if patient is unmedicated during pregnancy

✽ Atypical antipsychotics may be preferable to lithium or anticonvulsants such as carbamazepine if treatment of bipolar disorder is required during pregnancy

• Bipolar symptoms may recur or worsen during pregnancy and some form of treatment may be necessary

Breast Feeding • Some drug is found in mother’s breast milk ✽ Recommended either to discontinue drug

or bottle feed • If drug is continued while breast feeding,

infant should be monitored for possible adverse effects, including hematological effects

• If infant shows signs of irritability or sedation, drug may need to be discontinued

• Some cases of neonatal seizures, respiratory depression, vomiting, and diarrhea have been reported in infants whose mothers received carbamazepine during pregnancy

✽ Bipolar disorder may recur during the postpartum period, particularly if there is a history of prior postpartum episodes of either depression or psychosis

• Relapse rates may be lower in women who receive prophylactic treatment for postpartum episodes of bipolar disorder

• Atypical antipsychotics and anticonvulsants such as valproate may be safer than carbamazepine during the postpartum period when breast feeding

0521011698s01.qxd 9/2/04 2:27 PM Page 51

• Not clearly effective for the depressed phase of bipolar disorder

• Can be complicated to dose • Can be complicated to use with

concomitant medications

• Although less well investigated in bipolar disorder, oxcarbazepine, a structural analog of carbamazepine, may be better tolerated and thus an appropriate alternative to carbamazepine

CARBAMAZEPINE (continued)

Brambilla P, Barale F, Soares JC. Perspectives on the use of anticonvulsants in the treatment of bipolar disorder. Int J Neuropsychopharmacol. 2001; 4: 421–46.

Leucht S, McGrath J, White P, Kissling W. Carbamazepine for schizophrenia and schizoaffective psychoses. Cochrane Database Syst Rev. 2002;(3):CD001258.

Marson AG, Williamson PR, Hutton JL, Clough HE, Chadwick DW. Carbamazepine versus valproate monotherapy for epilepsy. Cochrane Database Syst Rev. 2000; (3): CD001030.

Weisler RH, Kalali AH, Ketter TA. A multicenter, randomized, double-blind, placebo-controlled trial of extended-release carbamazepine capsules as monotherapy for bipolar disorder patients with manic or mixed episodes. J Clin Psychiatry 2004; 65: 478–84.

Suggested Reading

0521011698s01.qxd 9/2/04 2:27 PM Page 52

SIDE EFFECTS

How Drug Causes Side Effects • Same mechanism for side effects as for

therapeutic effects – namely due to excessive actions at benzodiazepine receptors

• Long-term adaptations in benzodiazepine receptors may explain the development of dependence, tolerance, and withdrawal

CHLORDIAZEPOXIDE THERAPEUTICS

Brands • Limbitrol • Librium • Librax

see index for additional brand names

Generic? Yes

Class • Benzodiazepine (anxiolytic)

Commonly Prescribed For (bold for FDA approved) • Anxiety disorders • Symptoms of anxiety • Preoperative apprehension and anxiety • Withdrawal symptoms of acute alcoholism

How The Drug Works • Binds to benzodiazepine receptors at the

GABA-A ligand-gated chloride channel complex

• Enhances the inhibitory effects of GABA • Boosts chloride conductance through

GABA-regulated channels • Inhibits neuronal activity presumably in

amygdala-centered fear circuits to provide therapeutic benefits in anxiety disorders

How Long Until It Works • Some immediate relief with first dosing is

common; can take several weeks with daily dosing for maximal therapeutic benefit

If It Works • For short-term symptoms of anxiety – after

a few weeks, discontinue use or use on an “as-needed” basis

• For chronic anxiety disorders, the goal of treatment is complete remission of symptoms as well as prevention of future relapses

• For chronic anxiety disorders, treatment most often reduces or even eliminates symptoms, but not a cure since symptoms can recur after medicine stopped

• For long-term symptoms of anxiety, consider switching to an SSRI or SNRI for long-term maintenance

• If long-term maintenance with a benzodiazepine is necessary, continue

treatment for 6 months after symptoms resolve, and then taper dose slowly

If It Doesn’t Work • Consider switching to another agent or

adding an appropriate augmenting agent • Consider psychotherapy, especially

cognitive behavioral psychotherapy • Consider presence of concomitant

substance abuse • Consider presence of chlordiazepoxide

abuse • Consider another diagnosis, such as a

comorbid medical condition

Best Augmenting Combos for Partial Response or Treatment-Resistance

• Benzodiazepines are frequently used as augmenting agents for antipsychotics and mood stabilizers in the treatment of psychotic and bipolar disorders

• Benzodiazepines are frequently used as augmenting agents for SSRIs and SNRIs in the treatment of anxiety disorders

• Not generally rational to combine with other benzodiazepines

• Caution if using as an anxiolytic concomitantly with other sedative hypnotics for sleep

Tests • In patients with seizure disorders,

concomitant medical illness, and/or those with multiple concomitant long-term medications, periodic liver tests and blood counts may be prudent

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• Side effects are generally immediate, but immediate side effects often disappear in time

Notable Side Effects ✽ Sedation, fatigue, depression ✽ Dizziness, ataxia, slurred speech,

weakness ✽ Forgetfulness, confusion ✽ Hyper-excitability, nervousness ✽ Pain at injection site • Rare hallucinations, mania • Rare hypotension • Hypersalivation, dry mouth

Life Threatening or Dangerous Side Effects

• Respiratory depression, especially when taken with CNS depressants in overdose

• Rare hepatic dysfunction, renal dysfunction, blood dyscrasias

Weight Gain

• Reported but not expected

Sedation

• Many experience and/or can be significant in amount

• Especially at initiation of treatment or when dose increases

• Tolerance often develops over time

What To Do About Side Effects • Wait • Wait • Wait • Lower the dose • Take largest dose at bedtime to avoid

sedative effects during the day • Switch to another agent • Administer flumazenil if side effects are

severe or life-threatening

Best Augmenting Agents for Side Effects • Many side effects cannot be improved with

an augmenting agent

DOSING AND USE

Usual Dosage Range • Oral: mild to moderate anxiety:

15–40 mg/day in 3–4 doses • Oral: severe anxiety: 60–100 mg/day in

3–4 doses

Dosage Forms • Capsule 5 mg, 10 mg, 25 mg • Injectable 100 mg/5 mL

How to Dose • Injectable: acute/severe anxiety: initial

50–100 mg; 25–50 mg 3–4 times/day if necessary

• Injectable: alcohol withdrawal: initial 50–100 mg; repeat after 2 hours if necessary

• Injectable: preoperative: 50–100 mg 1 hour before surgery

• Patients who receive injectable chlordiazepoxide should be observed for up to 3 hours

Dosing Tips ✽ One of the few benzodiazepines available

in an injectable formulation • Chlordiazepoxide injection is intended for

acute use; patients who require longer treatment should be switched to the oral formulation

• Use lowest possible effective dose for the shortest possible period of time (a benzodiazepine-sparing strategy)

• Assess need for continued treatment regularly

• Risk of dependence may increase with dose and duration of treatment

• For inter-dose symptoms of anxiety, can either increase dose or maintain same total daily dose but divide into more frequent doses

• Can also use an as-needed occasional “top up” dose for inter-dose anxiety

• Because anxiety disorders can require higher doses, the risk of dependence may be greater in these patients

• Some severely ill patients may require doses higher than the generally recommended maximum dose

• Frequency of dosing in practice is often greater than predicted from half-life, as duration of biological activity is often shorter than pharmacokinetic terminal half-life

CHLORDIAZEPOXIDE (continued)

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SPECIAL POPULATIONS

Renal Impairment • Oral: Initial 10–20 mg/day in 2–4 doses;

increase as needed • Injectable: 25–50 mg

Hepatic Impairment • Oral: Initial 10–20 mg/day in 2–4 doses;

increase as needed • Injectable: 25–50 mg

Cardiac Impairment • Benzodiazepines have been used to treat

anxiety associated with acute myocardial infarction

Elderly • Oral: Initial 10–20 mg/day in 2–4 doses;

increase as needed • Injectable: 25–50 mg • Elderly patients may be more sensitive to

sedative effects

Children and Adolescents • Oral: Not recommended under age 6

(continued) CHLORDIAZEPOXIDE

Overdose • Fatalities can occur; hypotension,

tiredness, ataxia, confusion, coma

Long-Term Use • Evidence of efficacy for up to 16 weeks • Risk of dependence, particularly for

treatment periods longer than 12 weeks, and especially in patients with past or current polysubstance abuse

Habit Forming • Chlordiazepoxide is a Schedule IV drug • Patients may develop dependence and/or

tolerance with long-term use

How to Stop • Patients with history of seizure may seize

upon withdrawal, especially if withdrawal is abrupt

• Taper by 10 mg every 3 days to reduce chances of withdrawal effects

• For difficult to taper patients, consider reducing dose much more slowly after reaching 20 mg/day, perhaps by as little as 5 mg per week or less

• Be sure to differentiate reemergence of symptoms requiring reinstitution of treatment from withdrawal symptoms

Pharmacokinetics • Elimination half-life 24–48 hours

Drug Interactions • Increased depressive effects when taken

with other CNS depressants

Other Warnings/ Precautions

• Dosage changes should be made in collaboration with prescriber

• Use with caution in patients with pulmonary disease; rare reports of death after initiation of benzodiazepines in patients with severe pulmonary impairment

• History of drug or alcohol abuse often creates greater risk for dependency

• Some depressed patients may experience a worsening of suicidal ideation

• Some patients may exhibit abnormal thinking or behavioral changes similar to those caused by other CNS depressants (i.e., either depressant actions or disinhibiting actions)

Do Not Use • If patient has narrow angle-closure

glaucoma • If there is a proven allergy to

chlordiazepoxide or any benzodiazepine

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• Oral: Initial 10–20 mg/day in 2–4 doses; may increase to 20–30 mg/day in 2–3 doses if ineffective

• Injectable: Not recommended under age 12 • Injectable: 25–50 mg • Hyperactive children should be monitored

for paradoxical effects • Long-term effects of chlordiazepoxide in

children/adolescents are unknown • Should generally receive lower doses and

be more closely monitored

Pregnancy • Risk Category D [positive evidence of risk

to human fetus; potential benefits may still justify its use during pregnancy]

• Possible increased risk of birth defects when benzodiazepines taken during pregnancy

• Because of the potential risks, chlordiazepoxide is not generally recommended as treatment for anxiety during pregnancy, especially during the first trimester

• Drug should be tapered if discontinued • Infants whose mothers received a

benzodiazepine late in pregnancy may experience withdrawal effects

• Neonatal flaccidity has been reported in infants whose mothers took a benzodiazepine during pregnancy

• Seizures, even mild seizures, may cause harm to the embryo/fetus

Breast Feeding • Unknown if chlordiazepoxide is secreted in

human breast milk, but all psychotropics assumed to be secreted in breast milk

✽ Recommended either to discontinue drug or bottle feed

• Effects of benzodiazepines on nursing infants have been reported and include feeding difficulties, sedation, and weight loss

CHLORDIAZEPOXIDE (continued)

THE ART OF PSYCHOPHARMACOLOGY

Potential Advantages • Rapid onset of action

Potential Disadvantages • Euphoria may lead to abuse • Abuse especially risky in past or present

substance abusers

Primary Target Symptoms • Panic attacks • Anxiety

Pearls • Can be a useful adjunct to SSRIs and

SNRIs in the treatment of numerous anxiety disorders, but not used as frequently as some other benzodiazepines

• Not effective for treating psychosis as a monotherapy, but can be used as an adjunct to antipsychotics

• Not effective for treating bipolar disorder as a monotherapy, but can be used as an adjunct to mood stabilizers and antipsychotics

• Can both cause depression and treat depression in different patients

• When using to treat insomnia, remember that insomnia may be a symptom of some other primary disorder itself, and thus warrant evaluation for comorbid psychiatric and/or medical conditions

✽ Remains a viable treatment option for alcohol withdrawal

Baskin SI, Esdale A. Is chlordiazepoxide the rational choice among benzodiazepines? Pharmacotherapy 1982;2:110–9.

Erstad BL, Cotugno CL. Management of alcohol withdrawal. Am J Health Syst Pharm 1995;52:697–709.

Fraser AD. Use and abuse of the benzodiazepines. Ther Drug Monit 1998; 20:481–9.

Murray JB. Effects of valium and librium on human psychomotor and cognitive functions. Genet Psychol Monogr 1984;109(2D Half):167–97.

Suggested Reading

0521011698s01.qxd 9/2/04 2:27 PM Page 56

CHLORPROMAZINE THERAPEUTICS

Brands • Thorazine see index for additional brand names

Generic? Yes

Class • Conventional antipsychotic (neuroleptic,

phenothiazine, dopamine 2 antagonist, antiemetic)

Commonly Prescribed For (bold for FDA approved) • Schizophrenia • Nausea, vomiting • Restlessness and apprehension before

surgery • Acute intermittent porphyria • Manifestations of manic type of manic-

depressive illness • Tetanus (adjunct) • Intractable hiccups • Combativeness and/or explosive

hyperexcitable behavior (in children) • Hyperactive children who show excessive

motor activity with accompanying conduct disorders consisting of some or all of the following symptoms: impulsivity, difficulty sustaining attention, aggressivity, mood lability, and poor frustration tolerance

• Psychosis • Bipolar disorder

How The Drug Works • Blocks dopamine 2 receptors, reducing

positive symptoms of psychosis and improving other behaviors

• Combination of dopamine D2, histamine H1, and cholinergic M1 blockade in the vomiting center may reduce nausea and vomiting

How Long Until It Works • Psychotic symptoms can improve within 1

week, but it may take several weeks for full effect on behavior

• Actions on nausea and vomiting are immediate

If It Works • Most often reduces positive symptoms in

schizophrenia but does not eliminate them • Most schizophrenic patients do not have a

total remission of symptoms but rather a reduction of symptoms by about a third

• Continue treatment in schizophrenia until reaching a plateau of improvement

• After reaching a satisfactory plateau, continue treatment for at least a year after first episode of psychosis in schizophrenia

• For second and subsequent episodes of psychosis in schizophrenia, treatment may need to be indefinite

• Reduces symptoms of acute psychotic mania but not proven as a mood stabilizer or as an effective maintenance treatment in bipolar disorder

• After reducing acute psychotic symptoms in mania, switch to a mood stabilizer and/or an atypical antipsychotic for mood stabilization and maintenance

If It Doesn’t Work • Consider trying one of the first-line atypical

antipsychotics (risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, amisulpride)

• Consider trying another conventional antipsychotic

• If 2 or more antipsychotic monotherapies do not work, consider clozapine

Best Augmenting Combos for Partial Response or Treatment-Resistance

• Augmentation of conventional antipsychotics has not been systematically studied

• Addition of a mood stabilizing anticonvulsant such as valproate, carbamazepine, or lamotrigine may be helpful in both schizophrenia and bipolar mania

• Augmentation with lithium in bipolar mania may be helpful

• Addition of a benzodiazepine, especially short-term for agitation

Tests ✽ Since conventional antipsychotics are

frequently associated with weight gain, before starting treatment, weigh all patients and determine if the patient is already

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SIDE EFFECTS

How Drug Causes Side Effects • By blocking dopamine 2 receptors in the

striatum, it can cause motor side effects • By blocking dopamine 2 receptors in the

pituitary, it can cause elevations in prolactin

• By blocking dopamine 2 receptors excessively in the mesocortical and mesolimbic dopamine pathways, especially at high doses, it can cause worsening of negative and cognitive symptoms (neuroleptic-induced deficit syndrome)

• Anticholinergic actions may cause sedation, blurred vision, constipation, dry mouth

• Antihistaminic actions may cause sedation, weight gain

• By blocking alpha 1 adrenergic receptors, it can cause dizziness, sedation, and hypotension

• Mechanism of weight gain and any possible increased incidence of diabetes or

overweight (BMI 25.0–29.9) or obese (BMI ≥30)

✽ Monitor weight and BMI during treatment ✽ While giving a drug to a patient who has

gained >5% of initial weight, consider evaluating for the presence of pre-diabetes, diabetes, or dyslipidemia, or consider switching to a different antipsychotic

• Should check blood pressure in the elderly before starting and for the first few weeks of treatment

• Monitoring elevated prolactin levels of dubious clinical benefit

• Phenothiazines may cause false positive phenylketonuria results

dyslipidemia with conventional antipsychotics is unknown

Notable Side Effects ✽ Neuroleptic-induced deficit syndrome ✽ Akathisia ✽ Priapism ✽ Extrapyramidal symptoms, Parkinsonism,

tardive dyskinesia ✽ Galactorrhea, amenorrhea • Dizziness, sedation, impaired memory • Dry mouth, constipation, urinary retention,

blurred vision • Decreased sweating • Sexual dysfunction • Hypotension, tachycardia, syncope • Weight gain

Life Threatening or Dangerous Side Effects

• Rare neuroleptic malignant syndrome • Rare jaundice, agranulocytosis • Rare seizures

Weight Gain

• Many experience and/or can be significant in amount

Sedation

• Tolerance to sedation can develop over time

What To Do About Side Effects • Wait • Wait • Wait • For motor symptoms, add an

anticholinergic agent • Reduce the dose • For sedation, give at night • Switch to an atypical antipsychotic • Weight loss, exercise programs, and

medical management for high BMIs, diabetes dyslipidemia

Best Augmenting Agents for Side Effects • Benztropine or trihexyphenidyl for motor

side effects

CHLORPROMAZINE (continued)

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DOSING AND USE

Usual Dosage Range • 200–800 mg/day

Dosage Forms • Tablet 10 mg, 25 mg, 50 mg, 100 mg,

200 mg • Capsule 30 mg, 75 mg, 150 mg • Ampul 25 mg/mL; 1 mL, 2 mL • Vial 25 mg/mL; 10 mL • Liquid 10 mg/5 mL • Suppository 25 mg, 100 mg

How to Dose • Psychosis: increase dose until symptoms

are controlled; after 2 weeks reduce to lowest effective dose

• Psychosis (intramuscular): varies by severity of symptoms and inpatient/outpatient status

Dosing Tips • Low doses may have more sedative actions

than antipsychotic actions • Low doses have been used to provide

short-term relief of daytime agitation and anxiety and to enhance sedative hypnotic actions in non-psychotic patients, but other treatment options such as atypical antipsychotics are now preferred

• Higher doses may induce or worsen negative symptoms of schizophrenia

• Ampuls and vials contain sulfites that may cause allergic reactions, particularly in patients with asthma

• One of the few antipsychotics available as a suppository

Overdose • Extrapyramidal symptoms, sedation,

hypotension, coma, respiratory depression

(continued) CHLORPROMAZINE

• Sometimes amantadine can be helpful for motor side effects

• Benzodiazepines may be helpful for akathisia

• Many side effects cannot be improved with an augmenting agent

Long-Term Use • Some side effects may be irreversible (e.g.,

tardive dyskinesia)

Habit Forming • No

How to Stop • Slow down-titration of oral formulation

(over 6 to 8 weeks), especially when simultaneously beginning a new antipsychotic while switching (i.e., cross- titration)

• Rapid oral discontinuation may lead to rebound psychosis and worsening of symptoms

• If antiparkinson agents are being used, they should be continued for a few weeks after chlorpromazine is discontinued

Pharmacokinetics • Half-life approximately 8–33 hours

Drug Interactions • May decrease the effects of levodopa,

dopamine agonists • May increase the effects of

antihypertensive drugs except for guanethidine, whose antihypertensive actions chlorpromazine may antagonize

• Additive effects may occur if used with CNS depressants

• Some pressor agents (e.g., epinephrine) may interact with chlorpromazine to lower blood pressure

• Alcohol and diuretics may increase the risk of hypotension

• Reduces effects of anticoagulants • May reduce phenytoin metabolism and

increase phenytoin levels • Plasma levels of chlorpromazine and

propranolol may increase if used concomitantly

• Some patients taking a neuroleptic and lithium have developed an encephalopathic syndrome similar to neuroleptic malignant syndrome

Other Warnings/ Precautions

• If signs of neuroleptic malignant syndrome develop, treatment should be immediately discontinued

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THE ART OF PSYCHOPHARMACOLOGY

Potential Advantages • Intramuscular formulation for emergency

use • Patients who require sedation for

behavioral control

Potential Disadvantages • Patients with tardive dyskinesia • Children • Elderly • Patients who wish to avoid sedation

Primary Target Symptoms • Positive symptoms of psychosis • Motor and autonomic hyperactivity • Violent or aggressive behavior

SPECIAL POPULATIONS

Renal Impairment • Use with caution

Hepatic Impairment • Use with caution

Cardiac Impairment • Cardiovascular toxicity can occur,

especially orthostatic hypotension

Elderly • Lower doses should be used and patient

should be monitored closely • Often do not tolerate sedating actions of

chlorpromazine

Children and Adolescents • Can be used cautiously in children or

adolescents over 1 with severe behavioral problems

• Oral – 0.25 mg/lb every 4–6 hours as needed; rectal – 0.5 mg/lb every 6–8 hours as needed; IM – 0.25 mg/lb every

• Use cautiously in patients with alcohol withdrawal or convulsive disorders because of possible lowering of seizure threshold

• Use with caution in patients with respiratory disorders, glaucoma, or urinary retention

• Avoid extreme heat exposure • Avoid undue exposure to sunlight • Antiemetic effect of chlorpromazine may

mask signs of other disorders or overdose; suppression of cough reflex may cause asphyxia

• Use only with caution if at all in Parkinson’s disease or Lewy Body dementia

Do Not Use • If patient is in a comatose state • If patient is taking metrizamide or large

doses of CNS depressants • If there is a proven allergy to

chlorpromazine • If there is a known sensitivity to any

phenothiazine

6–8 hours as needed; maximum 40 mg/day (under 5), 75 mg/day (5–12)

• Do not use if patient shows signs of Reye’s syndrome

• Generally consider second-line after atypical antipsychotics

Pregnancy • Risk Category C [some animal studies

show adverse effects, no controlled studies in humans]

• Reports of extrapyramidal symptoms, jaundice, hyperreflexia, hyporeflexia in infants whose mothers took a phenothiazine during pregnancy

• Chlorpromazine should generally not be used during the first trimester

• Chlorpromazine should only be used during pregnancy if clearly needed

• Psychotic symptoms may worsen during pregnancy and some form of treatment may be necessary

• Atypical antipsychotics may be preferable to conventional antipsychotics or anticonvulsant mood stabilizers if treatment is required during pregnancy

Breast Feeding • Some drug is found in mother’s breast milk • Effects on infant have been observed

(dystonia, tardive dyskinesia, sedation) ✽ Recommended either to discontinue drug

or bottle feed

CHLORPROMAZINE (continued)

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(continued) CHLORPROMAZINE

Pearls • Chlorpromazine is one of the earliest

classical conventional antipsychotics • Chlorpromazine has a broad spectrum of

efficacy, but risk of tardive dyskinesia and the availability of alternative treatments make its utilization outside of psychosis a short-term and second-line treatment option

• Chlorpromazine is a low potency phenothiazine

• Sedative actions of low potency phenothiazines are an important aspect of their therapeutic actions in some patients and side effect profile in others

• Conventional antipsychotics are much less expensive than atypical antipsychotics

• Low potency phenothiazines like chlorpromazine have a greater risk of cardiovascular side effects

• Patients with inadequate responses to atypical antipsychotics may benefit from a trial of augmentation with a conventional antipsychotic such as chlorpromazine or from switching to a conventional antipsychotic such as chlorpromazine

• However, long-term polypharmacy with a combination of a conventional antipsychotic such as chlorpromazine with an atypical antipsychotic may combine their side effects without clearly augmenting the efficacy of either

Davis JM, Chen N, Glick ID. A meta-analysis of the efficacy of second-generation antipsychotics. Arch Gen Psychiatry 2003;60:553–64.

Frankenburg FR. Choices in antipsychotic therapy in schizophrenia. Harv Rev Psychiatry 1999;6:241–9.

Gocke E. Review of the genotoxic properties of chlorpromazine and related phenothiazines. Mutat Res 1996;366:9–21.

Leucht S, Wahlbeck K, Hamann J, Kissling W. New generation antipsychotics versus low-

potency conventional antipsychotics: a systematic review and meta-analysis. The Lancet 2003;361:1581–9.

Thomley B, Adams CE, Awad G. Chlorpromazine versus placebo for schizophrenia. Cochrane Database Syst Rev 2000;(2):CD000284.

Tohen M, Jacobs TG, Feldman PD. Onset of action of antipsychotics in the treatment of mania. Bipolar Disord 2000;2(3 Pt 2):261–8.

Suggested Reading

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CITALOPRAM THERAPEUTICS

Brands • Celexa see index for additional brand names

Generic? In Australia and some European countries, but not in U.S.

Class • SSRI (selective serotonin reuptake

inhibitor); often classified as an antidepressant, but it is not just an antidepressant

Commonly Prescribed For (bold for FDA approved) • Depression • Premenstrual dysphoric disorder (PMDD) • Obsessive-compulsive disorder (OCD) • Panic disorder • Generalized anxiety disorder • Posttraumatic stress disorder (PTSD) • Social anxiety disorder (social phobia)

How The Drug Works • Boosts neurotransmitter serotonin • Blocks serotonin reuptake pump (serotonin

transporter) • Desensitizes serotonin receptors, especially

serotonin 1A autoreceptors • Presumably increases serotonergic

neurotransmission ✽ Citalopram also has mild antagonist

actions at H1 histamine receptors ✽ Citalopram’s inactive R enantiomer may

interfere with the therapeutic actions of the active S enantiomer at serotonin reuptake pumps

How Long Until It Works • Onset of therapeutic actions usually not

immediate, but often delayed 2 to 4 weeks • If it is not working within 6 to 8 weeks, it

may require a dosage increase or it may not work at all

• May continue to work for many years to prevent relapse of symptoms

If It Works • The goal of treatment is complete

remission of current symptoms as well as prevention of future relapses

• Treatment most often reduces or even eliminates symptoms, but not a cure since symptoms can recur after medicine stopped

• Continue treatment until all symptoms are gone (remission) or significantly reduced (e.g., OCD, PTSD)

• Once symptoms are gone, continue treating for 1 year for the first episode of depression

• For second and subsequent episodes of depression, treatment may need to be indefinite

• Use in anxiety disorders may also need to be indefinite

If It Doesn’t Work • Many patients only have a partial response

where some symptoms are improved but others persist (especially insomnia, fatigue, and problems concentrating in depression)

• Other patients may be nonresponders, sometimes called treatment-resistant or treatment-refractory

• Some patients who have an initial response may relapse even though they continue treatment, sometimes called “poop-out”

• Consider increasing dose, switching to another agent or adding an appropriate augmenting agent

• Consider psychotherapy • Consider evaluation for another diagnosis

or for a comorbid condition (e.g., medical illness, substance abuse, etc.)

Best Augmenting Combos for Partial Response or Treatment-Resistance

• Trazodone, especially for insomnia • Bupropion, mirtazapine, reboxetine, or

atomoxetine (add with caution and at lower doses since citalopram could theoretically raise atomoxetine levels); use combinations of antidepressants with caution as this may activate bipolar disorder and suicidal ideation

• Modafinil, especially for fatigue, sleepiness, and lack of concentration

• Mood stabilizers or atypical antipsychotics for bipolar depression, psychotic

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SIDE EFFECTS

How Drug Causes Side Effects • Theoretically due to increases in serotonin

concentrations at serotonin receptors in parts of the brain and body other than those that cause therapeutic actions (e.g., unwanted actions of serotonin in sleep centers causing insomnia, unwanted actions of serotonin in the gut causing diarrhea, etc.)

• Increasing serotonin can cause diminished dopamine release and might contribute to emotional flattening, cognitive slowing, and apathy in some patients

• Most side effects are immediate but often go away with time, in contrast to most therapeutic effects which are delayed and are enhanced over time

✽ Citalopram’s unique mild antihistamine properties may contribute to sedation and fatigue in some patients

Notable Side Effects • Sexual dysfunction (men: delayed

ejaculation, erectile dysfunction; men and women: decreased sexual desire, anorgasmia)

• Gastrointestinal (decreased appetite, nausea, diarrhea, constipation, dry mouth)

• Mostly central nervous system (insomnia but also sedation, agitation, tremors, headache, dizziness)

• Note: patients with diagnosed or undiagnosed bipolar or psychotic disorders may be more vulnerable to CNS-activating actions of SSRIs

• Autonomic (sweating) • Bruising and rare bleeding • Rare hyponatremia (mostly in elderly

patients and generally reversible on discontinuation of citalopram)

depression, treatment-resistant depression, or treatment-resistant anxiety disorders

• Benzodiazepines • If all else fails for anxiety disorders,

consider gabapentin or tiagabine • Hypnotics for insomnia • Classically, lithium, buspirone, or thyroid

hormone

Tests • None for healthy individuals

• SIADH (syndrome of inappropriate antidiuretic hormone secretion)

Life Threatening or Dangerous Side Effects

• Rare seizures • Rare induction of mania and activation of

suicidal ideation

Weight Gain

• Reported but not expected • Citalopram has been associated with both

weight gain and weight loss in various studies, but is relatively weight neutral overall

Sedation

• Occurs in significant minority

What To Do About Side Effects • Wait • Wait • Wait • Take in the morning if nighttime insomnia • Take at night if daytime sedation • In a few weeks, switch to another agent or

add other drugs

Best Augmenting Agents for Side Effects • Often best to try another SSRI or another

antidepressant monotherapy prior to resorting to augmentation strategies to treat side effects

• Trazodone or a hypnotic for insomnia • Bupropion, sildenafil, vardenafil, or tadalafil

for sexual dysfunction • Bupropion for emotional flattening,

cognitive slowing, or apathy • Mirtazapine for insomnia, agitation, and

gastrointestinal side effects • Benzodiazepines for jitteriness and anxiety,

especially at initiation of treatment and especially for anxious patients

• Many side effects are dose-dependent (i.e., they increase as dose increases, or they reemerge until tolerance re-develops)

• Many side effects are time-dependent (i.e., they start immediately upon dosing and

CITALOPRAM (continued)

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DOSING AND USE

Usual Dosage Range • 20–60 mg/day

Dosage Forms • Tablets 10 mg, 20 mg scored, 40 mg

scored

How to Dose • Initial 20 mg/day; increase by 20 mg/day

after 1 or more weeks until desired efficacy is reached; maximum usually 60 mg/day; single dose administration, morning or evening

Dosing Tips • Tablets are scored, so to save costs, give

10 mg as half of 20 mg tablet or 20 mg as half of 40 mg tablet, since the tablets cost about the same in many markets

• Many patients respond better to 40 mg than to 20 mg

• Given once daily, any time of day when best tolerated by the individual

• If intolerable anxiety, insomnia, agitation, akathisia, or activation occur either upon dosing initiation or discontinuation, consider the possibility of activated bipolar disorder and switch to a mood stabilizer or an atypical antipsychotic

Overdose • Rare fatalities have been reported with

citalopram overdose, both alone and in combination with other drugs

• Vomiting, sedation, heart rhythm disturbances, dizziness, sweating, nausea, tremor

• Rarely amnesia, confusion, coma, convulsions

(continued) CITALOPRAM

upon each dose increase, but go away with time)

Long-Term Use • Safe

Habit Forming • No

How to Stop • Taper not usually necessary • However, tapering to avoid potential

withdrawal reactions generally prudent • Many patients tolerate 50% dose reduction

for 3 days, then another 50% reduction for 3 days, then discontinuation

• If withdrawal symptoms emerge during discontinuation, raise dose to stop symptoms and then restart withdrawal much more slowly

Pharmacokinetics • Parent drug has 23–45 hour half-life • Weak inhibitor of CYP450 2D6

Drug Interactions • Tramadol increases the risk of seizures in

patients taking an antidepressant • Can increase tricyclic antidepressant levels;

use with caution with tricyclic antidepressants

• Can cause a fatal “serotonin syndrome” when combined with MAO inhibitors, so do not use with MAO inhibitors or at least for 14 days after MAOIs are stopped

• Do not start an MAO inhibitor for at least 2 weeks after discontinuing citalopram

• May displace highly protein bound drugs (e.g., warfarin)

• Can rarely cause weakness, hyperreflexia, and incoordination when combined with sumatriptan or possibly other triptans, requiring careful monitoring of patient

• Via CYP450 2D6 inhibition, citalopram could theoretically interfere with the analgesic actions of codeine, and increase the plasma levels of some beta blockers and of atomoxetine

• Via CYP450 2D6 inhibition, citalopram could theoretically increase concentrations of thioridazine and cause dangerous cardiac arrhythmias

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SPECIAL POPULATIONS

Renal Impairment • No dose adjustment for mild to moderate

impairment • Use cautiously in patients with severe

impairment

Hepatic Impairment • Recommended dose 20 mg/day; can be

raised to 40 mg/day for nonresponders • May need to dose cautiously at the lower

end of the dose range in some patients for maximal tolerability

Cardiac Impairment • Clinical experience suggests that

citalopram is safe in these patients • Treating depression with SSRIs in patients

with acute angina or following myocardial infarction may reduce cardiac events and improve survival as well as mood

Elderly • 20 mg/day; 40 mg/day for nonresponders • May need to dose at the lower end of the

dose range in some patients for maximal tolerability

• Citalopram may be an especially well- tolerated SSRI in the elderly

Children and Adolescents • Use with caution, observing for activation

of known or unknown bipolar disorder and/or suicidal ideation, and strongly

Other Warnings/ Precautions

• Use with caution in patients with history of seizures

• Use with caution in patients with bipolar disorder unless treated with concomitant mood stabilizing agent

• Monitor patients for activation of suicidal ideation, especially children and adolescents

Do Not Use • If patient is taking an MAO inhibitor • If patient is taking thioridazine • If there is a proven allergy to citalopram or

escitalopram

consider informing parents or guardian of this risk so they can help observe child or adolescent patients

• Not specifically approved, but preliminary data suggest citalopram is safe and effective in children and adolescents with OCD and with depression

Pregnancy • Risk Category C [some animal studies

show adverse effects, no controlled studies in humans]

• Not generally recommended for use during pregnancy, especially during first trimester

• Nonetheless, continuous treatment during pregnancy may be necessary and has not been proven to be harmful to the fetus

• At delivery there may be more bleeding in the mother and transient irritability or sedation in the newborn

• For many patients, this may mean continuing treatment during pregnancy

• Neonates exposed to SSRIs or SNRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding; reported symptoms are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome, and include respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying

Breast Feeding • Some drug is found in mother’s breast milk • Trace amounts may be present in nursing

children whose mothers are on citalopram • If child becomes irritable or sedated, breast

feeding or drug may need to be discontinued

• Immediate postpartum period is a high-risk time for depression, especially in women who have had prior depressive episodes,

CITALOPRAM (continued)

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(continued) CITALOPRAM

THE ART OF PSYCHOPHARMACOLOGY

Potential Advantages • Elderly patients • Patients excessively activated or sedated

by other SSRIs

Potential Disadvantages • May require dosage titration to attain

optimal efficacy • Can be sedating in some patients

Primary Target Symptoms • Depressed mood • Anxiety • Panic attacks, avoidant behavior, re-

experiencing, hyperarousal • Sleep disturbance, both insomnia and

hypersomnia

Pearls ✽ May be more tolerable than some other

antidepressants • May have less sexual dysfunction than

some other SSRIs • May be especially well tolerated in the

elderly ✽ May be less well tolerated than

escitalopram • Documentation of efficacy in anxiety

disorders is less comprehensive than for escitalopram and other SSRIs

• Can cause cognitive and affective “flattening”

• Some evidence suggests that citalopram treatment during only the luteal phase may be more effective than continuous treatment for patients with PMDD

• SSRIs may be less effective in women over 50, especially if they are not taking estrogen

• SSRIs may be useful for hot flushes in perimenopausal women

• Nonresponse to citalopram in elderly may require consideration of mild cognitive impairment or Alzheimer disease

Bezchlibnyk-Butler K, Aleksic I, Kennedy SH. Citalopram – a review of pharmacological and clinical effects. Journal of Psychiatry and Neuroscience 2000;25:241–254.

Edwards JG, Anderson I. Systematic review and guide to selection of selective serotonin reuptake inhibitors. Drugs 1999;57:507–533.

Keller MB. Citalopram therapy for depression: a review of 10 years of European experience and data from U.S. clinical trials. Journal of Clinical Psychiatry 2000;61:896–908.

Pollock BG. Citalopram: a comprehensive review. Expert Opin Pharmacother 2001;2:681–98.

Stahl SM. Placebo-controlled comparison of the selective serotonin reuptake inhibitors citalopram and sertraline. Biol Psychiatry 2000;48:894–901.

Suggested Reading

so drug may need to be reinstituted late in the third trimester or shortly after childbirth to prevent a recurrence during the postpartum period

• Must weigh benefits of breast feeding with risks and benefits of antidepressant treatment versus non-treatment to both the infant and the mother

• For many patients, this may mean continuing treatment during breast feeding

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CLOMIPRAMINE THERAPEUTICS

Brands • Anafranil see index for additional brand names

Generic? Yes

Class • Tricyclic antidepressant (TCA) • Parent drug is a potent serotonin reuptake

inhibitor • Active metabolite is a potent

norepinephrine/noradrenaline reuptake inhibitor

Commonly Prescribed For (bold for FDA approved) ✽ Obsessive-compulsive disorder • Depression ✽ Severe and treatment-resistant

depression ✽ Cataplexy syndrome • Anxiety • Insomnia • Neuropathic pain/chronic pain

How The Drug Works • Boosts neurotransmitters serotonin and

norepinephrine/noradrenaline • Blocks serotonin reuptake pump (serotonin

transporter), presumably increasing serotonergic neurotransmission

• Blocks norepinephrine reuptake pump (norepinephrine transporter), presumably increasing noradrenergic neurotransmission

• Presumably desensitizes both serotonin 1A receptors and beta adrenergic receptors

• Since dopamine is inactivated by norepinephrine reuptake in frontal cortex, which largely lacks dopamine transporters, clomipramine can increase dopamine neurotransmission in this part of the brain

How Long Until It Works • May have immediate effects in treating

insomnia or anxiety • Onset of therapeutic actions in depression

usually not immediate, but often delayed 2 to 4 weeks

• Onset of therapeutic action in OCD can be delayed 6 to 12 weeks

• If it is not working within 6 to 8 weeks for depression, it may require a dosage increase or it may not work at all

• If it is not working within 12 weeks for OCD, it may not work at all

• May continue to work for many years to prevent relapse of symptoms

If It Works • The goal of treatment of depression is

complete remission of current symptoms as well as prevention of future relapses

• Treatment most often reduces or even eliminates symptoms, but not a cure since symptoms can recur after medicine stopped

• Although the goal of treatment of OCD is also complete remission of symptoms, this may be less likely than in depression

• The goal of treatment of chronic neuropathic pain is to reduce symptoms as much as possible, especially in combination with other treatments

• Continue treatment of depression until all symptoms are gone (remission)

• Once symptoms of depression are gone, continue treating for 1 year for the first episode of depression

• For second and subsequent episodes of depression, treatment may need to be indefinite

• Use in OCD may also need to be indefinite, starting from the time of initial treatment

• Use in other anxiety disorders and chronic pain may also need to be indefinite, but long-term treatment is not well studied in these conditions

If It Doesn’t Work • Many patients only have a partial response

where some symptoms are improved but others persist (especially insomnia, fatigue, and problems concentrating)

• Other patients may be nonresponders, sometimes called treatment-resistant or treatment-refractory

• Consider increasing dose, switching to another agent or adding an appropriate augmenting agent

• Consider psychotherapy, especially behavioral therapy in OCD

• Consider evaluation for another diagnosis or for a comorbid condition (e.g., medical illness, substance abuse, etc.)

• Some patients may experience apparent lack of consistent efficacy due to activation

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