Case 2: Volume 2, Case #11: The figment of a man who looked upon the lady



The Case: The figment of a man who looked upon the lady

The Question: Are atypical antipsychotics anti-manic, antidepressant, anxiolytic, and hypnotic as well?

The Psychopharmacological Dilemma: How to improve insomnia that is caused by depression, anxiety, mood swings, and hallucinations

Pretest self-assessment question (answer at the end of the case)

Which of the following properties of certain atypical antipsychotics lend to their ability to promote and maintain sleep?

A. Histamine-1 receptor antagonism B. Serotonin-2A receptor antagonism C. Serotonin-7 receptor antagonism D. A and B E. All of the above

Patient evaluation on intake

• 42-year-old woman with a chief complaint of depression and interpersonal stress

Psychiatric history

• The patient states she was horribly abused as a child and had been addicted to alcohol and other substances for many years. Now has been sober for 10 years and attends AA and Narcotics Anonymous (NA) routinely with good results

• Admits moderate levels of PTSD symptoms with nightmares, flashbacks, and panic attacks

• Routinely experiences dysthymia (persistent depressive disorder) with intermittent full MDEs

• Psychiatric review of symptoms suggests symptoms of marked mood lability, affective dyscontrol, empty depression, dissociative events consistent with mild borderline personality disorder (BPDO)

• There is no history of inpatient psychiatric admissions, and rarely any suicidal gestures or self-injurious behaviors

• Denies hallucinations and delusions, but states she is paranoid that people might mean her harm and always needs to “be aware of her environment”

• She has been in legal trouble for reacting to social situations by striking out – This occurs usually when narcissistic injury occurs or if emotions

are triggered by reminders of past abuse


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• The patient has been tried on – One SSRI, paroxetine (Paxil) 40 mg/d – One TCA, nortriptyline (Pamelor) 75 mg/d

• Both monotherapies allowed for moderate improvements in her symptoms at best

• Has attended supportive psychotherapy weekly for many years • Attends AA or NA daily and has a sponsor who is supportive

Social and personal history

• Single, never married, and has no children • Has a General Education Diploma and attends college classes

sporadically now • Past alcohol and SUD, but has been in remission for 10 years • No current legal issues but has some financial hardships

Medical History

• Patient is overweight • Has CAD, DM2, chronic obstructive pulmonary disease (COPD),

hyperlipidemia, GERD, HTN, glaucoma • Compliant with her primary care clinician who collaborates well with her


Family History • MDD in mother and aunts • SUD throughout her extended family • GAD in her mother • Possible ADHD in siblings

Current psychiatric medications

• Paroxetine (Paxil) 40 mg/d (SSRI)

Current medical medications

• Exenatide (Byetta) • Metformin (Glucophage) • Glipizide (Glucotrol) • Ramipril (Altace) • Albuterol (Ventolin inhaler) • Fluticasone/salmeterol (Advair Diskus) • Latanoprost (Xalatan) • Ezetimibe (Zetia) • Pravastatin (Pravachol) • Protonix (Pantoprazole)


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Based on this patient’s history and the available evidence, what might you do next, given that she still has moderate, residual depression and PTSD symptoms?

• Try another SSRI • Switch to an SNRI • Augment with a mood stabilizer • Augment with an NDRI, like bupropion-XL (Wellbutrin-XL) • Augment with a 5-HT1A receptor partial agonist, like buspirone (BuSpar) • Augment with an atypical antipsychotic

Attending physician’s mental notes: initial evaluation

• Patient has worked hard on sobriety and even to control her personality disorder symptoms

• She is clearly depressed and agitated with PTSD • At the time, the only other approved agent for PTSDwas sertraline (Zoloft),

an SSR • Buspirone (BuSpar) and bupropion-XL (Wellbutrin-XL) are widely used,

off-label depression augmentation options, which might help her • Perhaps it is best to see what symptoms the patient deems most

important to treat first, PTSD or depression • As she is overweight with metabolic comorbidities, it may be worth

choosing medications that limit risk of weight gain

Further investigation Is there anything else you would especially like to know about this patient? • What symptoms does the patient consider critical?

– Insomnia – she does not sleep well in general and this may be caused either by depression, PTSD, or her current SSRI

– Nightmares and flashbacks – these are very problematic as they trigger in the patient other symptoms such as mood lability and potential for violence and drug use

– Depression– for her, this is secondary. Her depression is usually caused by PTSD flare-ups, their aftermath, and her interpersonal stressors

– She feels that controlling her PTSD and sobriety will mitigate her depression


Based on what you know about this patient’s history, current symptoms, and medication, what would you do now?

• Try another SSRI • Switch to an SNRI


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• Augment with a mood stabilizer • Augment with bupropion-XL (Wellbutrin-XL) • Augment with buspirone (BuSpar) • Augment with a sedating atypical antipsychotic • Augment with prazosin (Minipress) • Augment with a BZ sedative–hypnotic • Augment with a melatonin receptor agonist hypnotic • Augment with an antihistamine hypnotic

Attending physician’s mental notes: initial evaluation (continued)

• Given the higher burden of PTSD and that she is failing an SSRI that is approved for PTSD and MDD, she will need to be tapered off and switched to another medication

• Will need to make a decision to try to treat all of her symptoms at once or treat single target symptoms in order of severity

• Formal CBT, such as exposure therapy for PTSD, is not available in the community and she has good rapport with her supportive therapist and her sponsors; therefore, these treatments should continue

• The other approved medication for PTSD is sertraline (Zoloft), which makes clinical, regulatory, and guideline-based sense

• Avoiding potentially addictive products is clearly warranted

Case outcome: interim follow-ups through three months • Next, she is cross-titrated off paroxetine (Paxil) and onto paroxetine-CR

(Paxil-CR) • The patient states she has been on paroxetine (Paxil) for some time now

and is comfortable with it as it has helped partially • As informed consent is given, steering her away from continued

paroxetine use, her resistance increases • States paroxetine at higher doses in past has been problematic for her

– She is offered a newer option and she states she would like to try the slow-release CR preparation

– It is titrated to 50 mg/d – There is no clear benefit

• Is offered a switch to another SSRI, sertraline (Zoloft), or to use a combination strategy bupropion-XL (Wellbutrin-XL)

• After weighing the options and giving informed consent, knowing that sertraline (Zoloft) is mechanistically similar to her paroxetine-XR (Paxil-CR), she opts for the NDRI bupropion-XL (Wellbutrin-XL) combination in the hope of a different outcome than with her SSRI, but also that it may curb her weight and improve her energy


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• Titrated up to 450 mg/d as a combination with the SSRI, and the depression and vegetative symptoms do improve somewhat, but she continues with her usual partially treated PTSD symptoms and insomnia

Considering her current medication regimen, do you have any concerns? • Does she have a history of seizures or eating disorder, as bupropion

products may induce seizures in these patients? – She does not

• The paroxetine-CR (Paxil-CR) is a robust inhibitor of the p450 2D6 enzyme system, for which bupropion products are a substrate – Is it possible that this drug interaction might elevate her bupropion

plasma levels and induce a seizure? • She is benefitting from this combination

– Perhaps bupropion levels might be drawn, or – Perhaps augmenting her remaining PTSD symptoms with an

antiepileptic medication might be a win–win situation, where symptoms and side effects are reduced simultaneously

Attending physician’s mental notes: six months • At the time of this treatment, the CYP450 interaction was a notable

concern but this patient was significantly overweight, which likely accommodated this higher end of normal approved dosing

• Her depression appears well treated now but her PTSD residual symptoms continue to be problematic

• As she had modest gains from her first two medications, an SSRI and an NDRI, stopping them might cause relapse

• Adding another augmentation is likely warranted now, using a specific target symptom approach

Case outcome: interim follow-ups through nine months • The patient agrees to augmentation with the antiepileptic selective GABA

reuptake inhibitor (SGRI) tiagabine (Gabitril) • This agent is not addictive, and in theory should elevate GABA

availability, promote anxiolysis, and also protect against bupropion-induced seizures

• This augmentation was supported at this time by open-label trials but had no sanctioned approvals – Titrated to 16 mg/d – Sleep improves, but no other clear effects on the PTSD reliving events – It should be noted that this drug failed in controlled monotherapy

trials in the treatment of PTSD some years later, and was also given a warning that despite being an approved epilepsy treating medication, it could actually cause seizures in non-epileptics

– This patient suffered no such complications, however


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Case outcome: interim follow-ups through 12 months

• The patient gradually presents with more difficulty as random social events trigger PTSD reliving and some mood lability occurs – There are increased psychosocial stressors and a return of

depressive symptoms – Sobriety continues – PTSD symptoms increase – Outside her usual insomnia and nightmares, she now has “a little

man watching her” ◦ Upon investigation, it is determined that she has a visual

hallucination of a small man staring down at her when she is on the verge of falling asleep (hypnagogic hallucination)

◦ This hallucination is not related to any PTSD themes, but she finds it very disturbing

Clinically, what types of patients typically suffer hypnagogic hallucinations? • Narcolepsy patients • Narcoleptics also may suffer sleep paralysis, cataplexy (drop attacks),

as well as their usual REM-onset sleep attacks • In this case, these hallucinations could also be related to a relapse into

drug use or seizure activity (both of which were negative)

Case outcome: interim follow-ups through 12 months (continued)

• Evaluated for sleep disorder – Found to have OSA – Prescribed a continuous positive airway pressure (CPAP) machine

and is compliant with its use • The OSA appears to be unrelated to the hallucinations • There is no relapse into drug use to explain the hallucinations • She is not having seizures


What would you do now?

• Escalate the tiagabine (Gabitril) • Augment with a 5-HT1A receptor partial agonist • Augment with an anxiolytic or hypnotic agent that is not addictive • Add an atypical antipsychotic • Taper off the now ineffective medications and start a new regimen

Attending physician’s mental notes: 12 month follow-ups

• Despite increasing progress on her initial three medication regimen (SSRI, NDRI, SGRI), this was thwarted by social stress and exposure to PTSD-triggering stimuli


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• Given her increased mood lability, irritability, potential for violence, flashbacks, and now limited hallucinations, an antipsychotic might be warranted

• At this time, it was becoming known that the atypical antipsychotics could drive an increase in weight but it was unclear if they would increase the metabolic syndrome

• This patient already has the metabolic syndrome, but it is very well controlled and followed very closely by her PCP

Case outcome: interim follow-up, 24 months • This patient had fully relapsed • The SSRI, paroxetine-CR (Paxil-CR), is discontinued due to its

ineffectiveness • The SGRI tiagabine (Gabitril) is tapered off as it was only partially

effective, but mounting evidence suggests it may create seizures in non-epileptic patients

• Continues on bupropion (Wellbutrin-XL) as she recollects this being the most beneficial for her depressive symptoms. It also has halted her weight gain and curbed her appetite

• Next, she starts the more SERT-selective SSRI escitalopram (Lexapro) up to 20 mg/d to treat PTSD and residual depressive symptoms

• She is also given low-dose atypical antipsychotic quetiapine (Seroquel) 25–50mg at bedtime to help induce sleep, possibly improve depression, PTSD, and mood lability – It is felt to be too risky to use a potentially addictive BZ

sedative–hypnotic, given her SUD history and well-maintained sobriety

– This low-dose quetiapine is not expected to cause metabolic complications

– If she has persistent hallucinations, then the dose could be increased to full antipsychotic potential at doses greater than 400 mg/d

– Warned of low but possible TD/EPS risks – Warned of metabolic risks and primary care clinician is consulted

• Does well on this combination and gradually has very good control of depression and PTSD symptoms

• The “little man” leaves • A few weeks later, the “little man” hallucination comes back but without a

full PTSD exacerbation – The quetiapine (Seroquel) is increased to 100 mg at bedtime with

good effect once again • A few weeks later, the patient has increased problems with lability and

anger at her AA and NA meetings, which is putting her sobriety at risk


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– Now offered a daytime 25–50 mg quetiapine (Seroquel) dose, which is utilized with good effect ◦ In total, takes 150 mg daily along with the SSRI and NDRI

combination therapy • After several weeks of no hallucinations and good affect control, she

opts to lower the atypical antipsychotic slowly to avoid prolonged exposure and side effects

• This goes well clinically and she continues on her baseline SSRI plus NDRI

Attending physician’s mental notes: 36-month follow-ups • Patient now is fairly stable and doing better • The SSRI and NDRI work well together

– Symptoms are much less problematic – They appear to cancel each other’s side effects out in a win–win

scenario – Denies side effects altogether

• There is no increase in metabolic issues with the short-term, low-dose quetiapine (Seroquel) use, and an eye examination for cataracts was negative

• Patient is compliant and we can extend her visits to quarterly, short appointments while we continue her supportive psychotherapy

Case outcome and multiple interim follow-ups to 60 months

• The patient, throughout this time, has sustained months of doing very well with regard to relationships, returning to school, and being active in the community

• She has occasional mild flare-ups of PTSD and BPDO symptoms but these are less frequent and less severe, likely as a result of ongoing sobriety, supportive psychotherapy, and a consistent set of well-tolerated medications

• Occasionally, increased PTSD nightmares and the “little man” return – The patient self-titrates as-needed quetiapine (Seroquel) 50–150 mg

daily doses ◦ This treats insomnia and restores her sleep cycle ◦ This treats bedtime hallucinations ◦ This improves affective lability during the daytime

• It is also determined that she has two types of insomnia – The spells mentioned here are usually PTSD related and fairly

extreme in the patient’s point of view ◦ The rapid onset of sleep, maintenance of sleep, and possible

antipsychotic effect of her atypical antipsychotic is warranted and works well here


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– There is a second type of insomnia that is more insidious, where she has difficulty initiating sleep, increasing her fatigue and irritability with consequences next day

– Does not wish to take the atypical antipsychotic routinely as it was “quite strong” with morning fatigue and potentially more serious risks (TD/EPS/metabolic)

– For these transient bouts of insomnia that would last a few weeks at a time, she was offered the MT1/MT2 receptor agonist approved, non-addictive hypnotic (ramelteon [Rozerem] 8 mg at bedtime) with good results and no side effects

• Now reliably alternates the quetiapine (Seroquel), ramelteon (Rozerem), or no treatment, depending upon the type of sleep she is, or is not, having

Case debrief

• The patient has the common comorbidity of MDD, PTSD, and SUD • She has personality traits that leave her vulnerable to relapses • She had an uncommon hypnogogic hallucination presentation • She has been fairly stable now for many years likely due to sobriety,

sustained supportive psychotherapy, steady consistent medication management with fully dosed and rationally used polypharmacy (instead of many rapid medicine changes in reaction to new psychosocial, adjustment disorders)

• The treating team was very good about communicating about the patient’s situations, symptoms, and likely etiology (adjustment based versus syndromal based) so that systems-based care was evident and very effective

• The medication regimen continues in this fashion with continual good results

Take-home points

• The patient had a balanced biopsychosocial approach by treating team members and great support through the AA and NA communities and her primary care team – This is a win–win, textbook collaboration situation that ideally should

be emulated in these complex patient types, in that all providers were communicating and working together

• The patient had, in addition, win–win polypharmacy situations – Her SSRI and NDRI canceled out each other’s side effects while

providing additive clinical effectiveness regarding her many comorbidities

– Her quetiapine (Seroquel) low dose was able to function as a multipurpose drug in that it: (a) induced and (b) maintained


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her sleep, (c) alleviated her hallucination, and (d) provided agitation control and mood stability during the day AND it did not increase her metabolic disorder given its low dose and intermittent use

• The atypical antipsychotics likely should not be considered first- line drugs for insomnia, as they do carry risk for TD, EPS, and metabolic disorder that approved and other off-label hypnotics do not carry

Performance in practice: confessions of a psychopharmacologist • What could have been done better here?

– Hindsight is 20/20 – It likely was a bit risky, in terms of potential drug interactions,

having the patient on a full dose of paroxetine and bupropion simultaneously ◦ If she happened to be a poor CYP450 2D6 enzyme metabolizer,

then her seizure risk could increase as her bupropion levels could have elevated

◦ Use of tiagabine (Gabitril) in addition to these two medications and the 2D6 interaction risk promoted an even greater seizure risk

– Use of a more metabolically friendly atypical antipsychotic with a mild to moderate sedating profile might have been preferred to the quetiapine (Seroquel) used in this case (perhaps asenapine (Saphris))

• Possible action items for improvement in practice – Memorize drug interaction tables or use software or the internet to

screen for interactions – If more risky combinations are used, consider a blood draw

laboratory test for CYP450 isoenzyme quantification or drug levels – Be aware that atypical antipsychotics possess positive mechanisms

for inducing and maintaining sleep that are not just side effects but reasonable positive clinical effects

Tips and pearls

• Two SSRI antidepressants are approved for treating PTSD: paroxetine (Paxil) and sertraline (Zoloft)

• In recent years, prazosin (Minipress) has acquired an evidence base to support its off-label use in alleviating PTSD nightmares specifically. This would have been a reasonable option in this case

• The beta-blockers have some limited evidence that, if utilized quickly after a trauma, they blunt hyperautonomic responses and that the risk for


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developing full syndromal PTSD may be less. This would have been less helpful in this case as her trauma was not recent

• The atypical antipsychotics and antiepileptic medications also have a limited evidence base that supports their use in PTSD

• The sedatives are controversial as PTSD patients have high addiction rates

A pharmacodynamic moment

Why do some atypical antipsychotics make good hypnotic agents?

• First, using an atypical antipsychotic to treat insomnia has risks and benefits – Pros ◦ Relatively fast onset ◦ Non-addictive ◦ May induce sleep onset and improve deep sleep propensity

– Cons ◦ Risk of serious side effects that other hypnotics do not have (TD,

EPS, metabolics, cataracts [interestingly, follow-up long-term studies suggest little risk, but FDA language still suggests diligence in monitoring here for quetiapine], QTc prolongation, stroke in certain populations)

• Many atypical antipsychotics are antihistamines – H1 receptor antagonism causes sedation and somnolence as a

result of lowering wakefulness center (tuberomammillary nucleus [TMN]) activity while promoting sleep center (ventrolateral preoptic [VLPO] area) activity

– This enhances the brain’s sleep–wake switch to favor sleep – The faster acting and reliably absorbed atypical antipsychotics, each

with a shorter half-life, may be better suited as hypnotic agents as they may have more dependable sleep onset and less morning hangover effect

• Some atypical antipsychotics possess serotonin-2A (5-HT2A) receptor antagonism – This mechanism appears to help maintain patients in a sleeping state

by promoting more efficient and deeper sleep – In this way, these antihistamine effects may initiate sleep

and 5-HT2A blocking effects may maintain deeper or more efficient sleep

• At higher doses, atypical antipsychotics antagonize D2 receptors – This mechanism is known to calm agitated patients who are



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– It is possible this calming effect lowers anxiety and cortical hyperarousal at bedtime, allowing better sleep onset

• This profile of H1, 5-HT2A, and D2 antagonism is unique to the atypical antipsychotics and is not found in any approved hypnotic agent

• If approved hypnotic agents fail to aid in sleep initiation or maintenance then atypical antipsychotics may be a reasonable choice

Sleep/wake switch on and awakeA

B Sleep/wake switch off and asleep



HA neuron

HA neuron

GABA neuron

GABA neuron



Sleep/wake switch

Sleep/wake switch


TMN wake promoter

TMN wake promoter

VLPO sleep


VLPO sleep


Overactivation Normal Baseline Hypoactivation




Figure 11.1. A and B. Sleep/wake switch.


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Antihistamine and the sleep–wake switch

• The hypothalamus is a key control center for sleep and wakefulness, and the specific circuitry that regulates sleep/wake is called the sleep/wake switch

• The “off” setting, or sleep promoter, is localized within the VLPO of the hypothalamus, while “on”, wake promoter, is localized within the TMN of the hypothalamus

• Two key neurotransmitters regulate the sleep/wake switch: histamine from the TMN and GABA from the VLPO – When the TMN is active and histamine is released in the cortex and

into the VLPO, the wake promoter is on and the sleep promoter is inhibited (Figure 11.1A) ◦ H1 receptor antagonists, antihistamines, block this wakefulness

pathway whereby the released histamine transmitter cannot activate frontal lobe neurocircuitry, causing a loss of arousal and resultant fatigue

– When the VLPO is active and GABA is released into the TMN, the sleep promoter is on and the wake promoter inhibited (Figure 11.1B)

– The sleep/wake switch is also regulated by orexin/hypocretin neurons in the lateral hypothalamus (LAT), which stabilize wakefulness, and by the suprachiasmatic nucleus (SCN) of the hypothalamus, which is the body’s internal clock and is activated by melatonin, light, and activity to promote either sleep or wakefulness

Serotonin receptor antagonism and sleep

• The 5-HT2 receptor subfamily is comprised of several types with the three most commonly studied subtypes: 5-HT2A, 5-HT1A, and 5-HT2C

• 5-HT7 and 5-HT1D receptors have also been evaluated more recently for their hypnotic, circadian, and antidepressant effects

• Evidence from both clinical and preclinical studies suggests that 5-HT2A receptors modulate and improve slow wave sleep (SWS) when blocked – This is considered deep and restorative – Is often lacking in depressed or fibromyalgia (FM) patients

• 5-HT2A receptor antagonists may not induce hypnosis, or sleep onset, but once sleep occurs, there is a shift toward more efficient and improved SWS

• 5-HT2A receptor blockade may promote better sleep by a complex mechanism – Serotonin typically diminishes cortical glutamatergic arousing

neurons by agonizing 5-HT1A receptors and enhances glutamatergic excitatory arousal by stimulation of 5-HT2A receptors

– In effect, antagonizing the 5-HT2A receptor dampens cortical activity to promote some somnolence and fatigue


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