Consideration in the use of antidepressant medications.

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Abbreviations: TCAs, tricyclic antidepressants; SSRIs, selec- tive serotonin-reuptake inhibitors; MAOIs, monoamine oxidase inhi- bitors; SNRI, serotonin-norepinephrine reuptake inhibitor; PMDD, premenstrual dysphoric disorder; SAD, seasonal affective disorder; PMS, premenstrual syndrome; NE, norepinephrine; 5-HT, 5-hydroxy- tryptamine; DA, dopamine; CNS, central nervous system; NRI, nora- drenalin specific reuptake inhibitor

Introduction Depression may be defined in terms of a state of feeling sad. It

may also be defined as a psychoneurotic disorder characterised by mental and functional activity, sadness, reduction in activity, difficulty in thinking, loss of concentration, perturbations in appetite, sleeping, and feelings of dejection, hopelessness and generation of suicidal tendencies.1 It is a common and recurrent disorder causing significant morbidity and mortality worldwide.2,3 Depression, a kind of mental illness, includes arousal of grief which may affect the overall thinking process, behaviour and feelings.1 Such persons suffer froman imbalanced sleep and sleeping disorders.4–6 Several workers7,8 have described the causes of depression which include genetic, heterogeneous parental behaviour to the siblings, neglect and sexual abuse. In addition, certain conditions like difficulties in job, relationships, natural disasters, finances, child birth, catastrophic injury, loss of life of loved ones and menopause.9,10 It is known that different brain regions may mediate the onset of variety of symptoms of depression as they regulate emotions, neural circuitry and mood. There is meagre information available about the underlying mechanisms of

their regulations. The malfunctioning of the hypothalamus region of the brain has been found to be associated with very less or too much sleep, disinterest in sex and other activities of enjoyment. Depression in general has three main forms such as

i. Psychotic depression characterised by severe depression,

ii. Postpartum depression characterised by perturbations in the levels of hormones and physical features after child birth and

iii. Seasonal Affective Disorder (SAD) concerning specially the win- ter months with less sunlight.11

In the women, the depression arises also due to extra work load, domestic responsibilities, child care, strained relationship, care of aged parents and poverty. In addition to all these indices, the psychological, biological and hormonal factors also significantly contribute in depression. The premenstrual dysphoric disorder (PMDD) or premenstrual syndrome (PMS) and osteoporosis in women can play important role in development of depression. Depression in men may be associated with sufferings from serious diseases such as cancer and cardiac diseases, extreme tiredness, irritation, disinterest in once- pleasurable activities, loss of balance, less sleep and getting aggressive. In older men, arteriosclerotic depression (vascular depression) has been observed. The depression which may lead to suicide in the children may be associated to the emerging sexuality and onset of puberty. The present article is an endeavour to illustrate an updated account and varied aspects of depression such as its pathophysiology, symptoms, diagnosis, treatment with drugs and their mode of actions, toxicity and use of plant products as potential antidepressants.

J Appl Biotechnol Bioeng. 2017;3(5):437‒448. 437 © 2017 Khushboo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and build upon your work non-commercially.

Antidepressants: mechanism of action, toxicity and possible amelioration

Volume 3 Issue 5 - 2017

Khushboo, Sharma B Department of Biochemistry, University of Allahabad, India

Correspondence: B Sharma, Department of Biochemistry, University of Allahabad, Allahabad 211002, UP, India, Email [email protected] Received: June 29, 2017 | Published: September 01, 2017

Abstract

Depression being a state of sadness may be defined as a psychoneurotic disorder characterised by mental and functional activity, sadness, reduction in activity, difficulty in thinking, loss of concentration, perturbations in appetite, sleeping, and feelings of dejection, hopelessness and generation of suicidal tendencies. It is a common and recurrent disorder causing significant morbidity and mortality worldwide. The antidepressant compounds used against depression are reported to be used also for treating pain, anxiety syndromes etc. They have been grouped in five different categories such as

i. Tricyclic antidepressants (TCAs)

ii. Selective serotonin-reuptake inhibitors (SSRIs)

iii. Monoamine oxidase inhibitors (MAOIs)

iv. Serotonin-norepinephrine reuptake inhibitor (SNRI) and

v. Non-TCA antidepressants based on their mode of action.

Most of the antidepressants have been reported to possess adverse effects on the health of users. The present review article focuses on an updated current of antidepressants, their mechanism of actions, pathophysiology of these compounds, their side effects and the strategies to combat the drug induced toxicity. An account of phytochemicals found to be acting as antidepressant is also included.

Keywords: depression, antidepressants, toxicity, neurotransmitters, biomarkers

Journal of Applied Biotechnology & Bioengineering

Research Article Open Access

Antidepressants: mechanism of action, toxicity and possible amelioration 438 Copyright:

©2017 Khushboo et al.

Citation: Khushboo, Sharma B. Antidepressants: mechanism of action, toxicity and possible amelioration. J Appl Biotechnol Bioeng. 2017;3(5):437‒448. DOI: 10.15406/jabb.2017.03.00082

Pathophysiology of depression

There are no useful biomarkers or imaging abnormalities to determine pathophysiology of depression during life time. The post- mortem study of brain does not reveal any consistent structural or neurochemical abnormality. Majority of the currently available medications were discovered empirically. Most current theories are based on “amine hypothesis.12” The most important hypothesis of mood disorder is related to the alterations in the levels of biogenic amines.13–15 It states that depression is caused by a functional deficiency of catecholamines, particularly norepinephrine (NE), whereas mania is caused by a functional excess of catecholamines at the critical synapses in the brain. The occurrence of depression has been found to be associated with the alterations in the levels of biogenic amines in the brain such as NE, dopamine (DA) and epinephrine, indolamine, serotonin, 5-hydroxytryptamine (5-HT) and two catecholamines.

Antidepressants

Antidepressants are those drugs which help in the reduction in symptoms of depressive disorders by altering chemical imbalances of neurotransmitters in the brain. The change in mood and behaviour is due to chemical imbalance. Neurotransmitters are the communication link between neurons in the brain. Neurotransmitters are located in vesicles found in nerve cells. The neurotransmitters such as serotonin, dopamine and noradrenaline or norepinephrine are released by the exonic end of one nerve and received by the other; the phenomenon called as reuptake. The antidepressants inhibit reuptake of neurotransmitters through selective receptors thereby increasing the concentration of specific neurotransmitter around the nerves in the brain. One of such antidepressant is selective serotonin

reuptake inhibitor (SSRI), which affects the brain serotonin level. Antidepressants may recover the signs of depression, but also exert some side-effects. They are used in the medication of a number of symptoms, including not only depression, some anxiety disorder, nervousness, OCD, manic-depressive disorders, bedwetting in childhood, major depressive disorder, diabetic peripheral neuropathic pain, social fretfulness, post-traumatic stress disorder etc. and some conclude, but not perfect in fibromyalgia, chronic hives (allergic reaction), flashes, drug induced hyperhidrosis (sweating in excess), premenstrual symptoms, pruritus (itching), nervosa, tourette, binge eating disorder etc. The medicines achieve their desired function by adversely influencing the concentrations of neurotransmitters in the brain such as NE, serotonin and dopamine and the central nervous system (CNS). Based on the mode of actions, a group of antidepressants contain 17 substances which can be further divided into subgroups. The commonly used medicines against depression are summarised in Table 1.

Antidepressants and their classification

Imipramine was discovered in 1958 as an antidepressant regimen.17 The antidepressants have been divided into five groups:

i. Tricyclic antidepressants (TCAs),

ii. Selective serotonin-reuptake inhibitors (SSRIs),

iii. Monoamine oxidase inhibitors (MAOIs),

iv. Serotonin-norepinephrine reuptake inhibitor (SNRI) and

v. Non-TCA antidepressants.

Table1 Commonly used antidepressants and their mechanisms of actions16

Sr. No. ATC-Code

Name of substance Pharmaceutical name Mechanism of action

1 N06AA04 Clomipramine Anafranil- Novartis + generics Serotonin-norepinephrine reuptake inhibitors

2 N06AA06 Trimipramine Surmontil- sanofiaventis Serotonin-norepinephrine reuptake inhibitors

3 N06AA09 Amitriptyline Saroten- lundbecktryptizol- msd Serotonin-norepinephrine reuptake inhibitors

4 N06AA10 Nortriptyline Sensaval- lundbeck Serotonin-norepinephrine reuptake inhibitors

5 N06AA21 Maprotiline Ludiomil- Novartis + generics Serotonin-norepinephrine reuptake inhibitors

6 N06AB03 Fluoxetine Fontex- lilly + generics Serotonin Reuptake inhibitors

7 N06AB04 Citalopram Cipramil- lundbeck + generics Serotonin Reuptake inhibitors

8 N06AB05 Paroxetine Seroxat- glaxosk + generics Serotonin Reuptake inhibitors

9 N06AB06 Sertraline Zoloft-Pfizer + generics Serotonin Reuptake inhibitors

10 N06AB08 Fluvoxamine Fevarin- solvaypharma Serotonin Reuptake inhibitors

11 N06AB10 Escitalopram Cipralex- lundbeck Serotonin Reuptake inhibitors

12 N06AG02 Moclobemide Aurorix- roche + generics MAO inhibitor

The TCAs block the reuptake of both norepinephrine (NE) and serotonin (5HT). This phenomenon being the primary mechanism of actions of antidepressants brings changes in the physiological behaviour of neuro-receptors. TCAs have also been reported to block muscarinic, alpha1 adrenergic and histaminic receptors. However, these molecules may lead to occurrence of different side effects in patients as summarised in Table 2.

Mourilhe20 have reported that the Selective serotonin-reuptake inhibitors (SSRIs) may block the reuptake of 5HT and increase

synaptic 5HT transmission. The SSRIs have very little or insignificant effect on the reuptake of other neurotransmitters. It has been observed that SSRIs does not display any activity at the muscarinic and histaminergic receptors which probably results into minute anti- cholinergic (ACH) and sedative effects (Table 3).

The mechanisms of actions of different antidepressants such as monoamine oxidase inhibitors (MAOIs), phenelzine (Nardil) and tranylcypromine (Parnate) associate with the inhibition of the enzymatic conversion of 5HT and NE into their corresponding

Antidepressants: mechanism of action, toxicity and possible amelioration 439 Copyright:

©2017 Khushboo et al.

Citation: Khushboo, Sharma B. Antidepressants: mechanism of action, toxicity and possible amelioration. J Appl Biotechnol Bioeng. 2017;3(5):437‒448. DOI: 10.15406/jabb.2017.03.00082

metabolites. MAOIs are generally prescribed in cases of atypical or drug resistant depression. These compounds contain a certain level of toxicity. On the contrary to it, the moclobemide (manerix) has been reported to be the first reversible inhibitor of monoamine oxidase A (RIMA). This molecule is found relatively more effective and safe.23 Another antidepressant, nefazodone (serzone) has properties of both: it acts like SSRIs which blocks the reuptake of 5HT and also act as an

antagonist of 5HT2 receptor23 thereby reducing the stimulating effects similar to SSRIs. Nefazodone has structural and pharmacological similarities to another antidepressant, trazodone (desyrel). The only difference is that nefazodone binds with α1 receptors with low affinity. All of these antidepressants do not significantly influence ACH mediated functions (Table 4).

Table 2 Antidepressants and their side effects

Sr. No.

Antidepressant substrate (Common Name)

Doses Therapeutic index (TI) Side-effects Toxicity in overdose References

1 Amitriptyline start with a dosage of up to 100 mg/day Narrow

Confusion, Numbness and Tingling In Your Arms and Legs, Headache, Constipation Or Diarrhoea, Blurred Vision, Skin Rash, Swelling Of Your Face and Tongue, Nausea, Unexpected Weight Gain Or Loss

High 18

2 Amoxapine 50 mg-100 mg maximum dose: 600 mg/day

Narrow

Dizziness or light headedness, confusion, constipation, difficulty in urinating, dry mouth

-

3 Clomipramine 25 mg, 100 mg, 250 mg/day Narrow

Dizziness or light headedness, confusion, constipation, difficulty in urinating, dry mouth

Moderate

4 Desipramine 100-300 mg/day Narrow

Dizziness or light headedness, confusion, constipation, difficulty in urinating, dry mouth

-

4 Doxepin 25-300 mg/day Narrow

Dizziness or light headedness, confusion, constipation, difficulty in urinating, dry mouth

-

5 Imipramine Hydrochloride

10-50 mg/day Narrow

Dizziness or light headedness, confusion, constipation, difficulty in urinating, dry mouth

High

6 Imipramine Pamoate 10-50 mg/day Narrow

Dizziness or light headedness, confusion, constipation, difficulty in urinating, dry mouth

High

7 Maprotiline - Narrow

Dizziness or light headedness, confusion, constipation, difficulty in urinating, dry mouth

-

8 Nortriptyline 10-25 mg/day Narrow

Dizziness or light headedness, confusion, constipation, difficulty in urinating, dry mouth

High

9 Protriptyline - Narrow

Dizziness or light headedness, confusion, constipation, difficulty in urinating, dry mouth

-

10 Trimipramine - Narrow

Dizziness or light headedness, confusion, constipation, difficulty in urinating, dry mouth

High 19

Antidepressants: mechanism of action, toxicity and possible amelioration 440 Copyright:

©2017 Khushboo et al.

Citation: Khushboo, Sharma B. Antidepressants: mechanism of action, toxicity and possible amelioration. J Appl Biotechnol Bioeng. 2017;3(5):437‒448. DOI: 10.15406/jabb.2017.03.00082

Table 3 Side effects of use of SSRIs

Sr. No.

Antidepressant substrate (Common Name)

Doses Therapeutic index Side-Effects Toxicity due to overdose References

1 Citalopram 20-40 mg/ day

Wide

Nausea, Anxiety, Insomnia Dry Mouth, Headache, Somnolence, Dizziness, Agitation, Anorexia, Diarrhoea, Constipation, Tremor, Sweating, Sexual Dysfunction

Moderate 21

2 Fluoxetine 10-20 mg and 4mg/ day

Wide

Nausea, Anxiety, Insomnia Dry Mouth, Headache, Somnolence, Dizziness, Agitation, Anorexia, Diarrhoea, Constipation, Tremor, Sweating, Sexual Dysfunction

Low 22

3 Fluvoxamine 50-100 mg/day Wide

Nausea , Anxiety, Insomnia Dry Mouth, Headache, Somnolence, Dizziness, Agitation, Anorexia, Diarrhoea, Constipation, Tremor, Sweating, Sexual Dysfunction

Low 22

4 Paroxetine 20-30 mg/day Wide

Nausea, Anxiety, Insomnia, Dry Mouth, Headache, Somnolence, Dizziness, Agitation, Anorexia, Diarrhoea, Constipation, Tremor, Sweating, Sexual Dysfunction

Low 22

5 Sertraline 25-100 mg/ day

Wide

Nausea , Anxiety, Insomnia Dry Mouth, Headache, Somnolence, Dizziness, Agitation, Anorexia, Diarrhoea, Constipation, Tremor, Sweating, Sexual Dysfunction

Low 22

6 Nefazodone 100-200mg/ day

Wide

Nausea , Anxiety, Insomnia Dry Mouth, Headache, Somnolence Dizziness Agitation Anorexia, Diarrhoea, Constipation, Tremor, Sweating, Sexual Dysfunction

- 22

7 Trazodone 50-100 mg/day Wide

Nausea , Anxiety, Insomnia Dry Mouth, Headache, Somnolence Dizziness Agitation Anorexia, Diarrhoea, Constipation, Tremor, Sweating, Sexual Dysfunction

- 22

The activity of serotonin nor-epinephrine reuptake inhibitors (SNRIs) does not exert any side effects such as sedation or hypotension but display TCAs like activity.23 Higher doses of SNRIs have been reported to mildly increase blood pressure. The above mentioned antidepressants in adequate dosages exhibit same level of effects for treatment of depression. Some of the SNRIs are duloxetine (Cymbalta), venlafaxine (Effexor XR), desvenlafaxine (Pristiq, Khedezla) and levomilnacipran (Fetzima). The first line of antidepressants is the Non-TCAs (NTCA) which includes SSRIs. These agents are relative safer with better tolerability. Those patients which do not show any response to other drugs or suffering from chronic pain or migraine are given TCAs. However, the existing reports suggest that the secondary amine TCAs (desipramine and nortriptyline) possess more side effects than tertiary amine TCAs (Table 5). A comparative estimate of antidepressants and their therapeutic properties are summarised in Table 6.

Interaction of antidepressants with the cellular recep- tors

As explained above, the MAOIs block the metabolism of neurotransmitters such as NE, DA and 5-HT and cause increase in the concentration of monoamine transmitters. The traditional MAOIs (tranylcypromine) act in irreversible and non-selective manner whereas the recently investigated MAOIs are reversible in binding and very selective for MAO-A or MAO-B. TCAs is a combo drug30 containing at least five chemical agents with different activities such as a serotonin reuptake inhibitor activity, a norepinephrine reuptake inhibitor activity, an anti-cholinergic anti-muscarinic activity, an alfa1- adrenergic antagonist activity, and an antihistamine (H1) activity.31 When taken in overdose, they cause toxicity in terms of lethal cardiac arrhythmias and seizures. The mechanism of action of TCAs relies on the inhibition of reuptake of serotonin and NE.31 The different

Antidepressants: mechanism of action, toxicity and possible amelioration 441 Copyright:

©2017 Khushboo et al.

Citation: Khushboo, Sharma B. Antidepressants: mechanism of action, toxicity and possible amelioration. J Appl Biotechnol Bioeng. 2017;3(5):437‒448. DOI: 10.15406/jabb.2017.03.00082

members of TCAs display differential inhibition activity on 5HT and NE transporters. Clomipramine has been reported to be the most potent at 5-HT reuptake pump whereas desipramine and maprotiline

were more potent at NE reuptake pump. The drug toxicity of TCAs has been explained in terms of their effects on certain receptors such as H1, M1, and alfa1.

Table 4 Doses and side effects of some other antidepressants

Sr. No.

Antidepressant substrate (Common Name)

Doses Therapeutic index Side-effects Toxicity in overdose References

1 Isocarboxazid 40-60 mg/day Wide Dizziness, Headache, Tremors Or Shaking; Constipation, Nausea; Or Dry Mouth.

High 24

2 Phenelzine 60 mg/day Wide

Dizziness, Headache, Drowsiness, Sleep Disturbances (Including Insomnia, Hypersomnia), Fatigue, Weakness, Tremors, Twitching, Myoclonic Movements, Hyperreflexia

High 25

3 Tranylcypromine 60 mg/day Wide

Scleroderma, Flare-Up Of Cystic Acne, Ataxia, Confusion, Disorientation, Memory Loss, Urinary Frequency, Urinary Incontinence, Urticaria, Fissuring In Corner Of Mouth, Akinesia

Low 26

4 Moclobemide 300 mg/day Wide Nausea, Dry Mouth, Constipation, Diarrhoea, Anxiety, Restlessness, Insomnia, Dizziness

High 27

Table 5 Doses and adverse effects of application of Non-TCA (NTCA) antidepressants

Sr. No.

Antidepressant substrate (Common Name)

Doses Therapeutic index Side-effects Toxicity in overdose References

1 Agomelatine 25-50 mg/day Narrow Dizziness Abnormal Changes In Liver Function Tests Abdominal Pain Unclear

22

2 Bupropion 150 mg/day Narrow Insomnia, Nausea, Pharyngitis, Weight Loss, Constipation, Dizziness, Headache, And Xerostomia

Moderate

3 Duloxetine 60 mg/day Wide

Asthenia, Constipation, Diarrhea, Dizziness, Drowsiness, Fatigue, Hypersomnia, Insomnia, Nausea, Sedation, Headache, and Xerostomia.

Moderate

4 Mianserin 30-200 mg/day Narrow

Drowsiness, Liver Dysfunction, Jaundice, Gynaecomastia, Convulsions, Hypomania, Hypotension, Hypertension; Coma, Arthralgia, Oedema, Tachycardia, Bradycardia, Vomiting, Dizziness and Ataxia, Anti-cholinergic Effects

Low

5 Reboxetine 8mg/Day Narrow

Urinating problem, Dry Mouth, Sweating, Tingling or Numbness of The Hands or Feet, Constipation, Increase in Blood Pressure, Increase in Heart Rate, Impotence, Insomnia, Headache, Dizziness, Nausea, Decreased Appetite

Low

Antidepressants: mechanism of action, toxicity and possible amelioration 442 Copyright:

©2017 Khushboo et al.

Citation: Khushboo, Sharma B. Antidepressants: mechanism of action, toxicity and possible amelioration. J Appl Biotechnol Bioeng. 2017;3(5):437‒448. DOI: 10.15406/jabb.2017.03.00082

Sr. No.

Antidepressant substrate (Common Name)

Doses Therapeutic index Side-effects Toxicity in overdose References

6 Trazodone 150-400 mg/day Wide

Blurred vision, Dizziness, Drowsiness, Headache, Nausea, Vomiting, and Xerostomia Syncope, Edema, Ataxia, Confusion, Diarrhea, Hypotension, Insomnia, Sedation, and Tachycardia

Low

7 Venlafaxine

75 mg/day with Food (37.5 mg/ day if Anxious or Debilitated)

Narrow

Bipolar Disorder (Manic Depression); Cirrhosis Or Other Liver Disease, Kidney Disease, Heart Disease, High Blood Pressure, High Cholesterol, Diabetes; Narrow-Angle Glaucoma, A Thyroid Disorder, A History of Seizures, A Bleeding or Blood Clotting Disorder, Low Levels of Sodium in Your Blood

Moderate

Table 6 A comparative estimate of antidepressants and their therapeutic properties.28,29

Sr. No.

Type of Anti- depressants

Name of Anti- depressant Half-life Availability

Dietary consideration Reference

1 SSRIs

Citalopram About 36 hours Tablet Contains Lactose

28

Escitalopram About 30 hours Tablets -

Fluoxetine 96-144 hours (4-6 Days)

Dispersible Tablets*/ Capsules

Contains Gelatin

Fluvoxamine 17-22 Hours Tablet -

Paroxetine About 24 Hours Tablet -

Sertraline 22-36 Hours Tablet -

2 SNRIs Duloxetine 8-17 Hours Capsules Contains Gelatin

Venlafaxine 4-7 Hours Capsules Contains Gelatin

3 Tricyclics

Amitriptyline 9-25 Hours Tablets -

Dosulepin About 50 Hours (Just Over 2 Days) 36 Hours -

Clomipramine 36 Hours Tablets -

Doxepin 33-80 Hours (1.5- 3.3 Days) Capsules Contains Lactose

Imipramine About 19 Hours Liquid Contains Lactose

Lofepramine 12-24 Hours Tablets Contains Lactose

Nortriptyline About 36 Hours Tablets Contains Lactose

Trimipramine About 23 Hours Capsules Contains Lactose

4 Tricyclic-Related Drugs

Mianserin 6-39 Hours Tablets Contains Lactose

Trazodone 5-13 Hours Tablets Contains Lactose

Table Continued..

Antidepressants: mechanism of action, toxicity and possible amelioration 443 Copyright:

©2017 Khushboo et al.

Citation: Khushboo, Sharma B. Antidepressants: mechanism of action, toxicity and possible amelioration. J Appl Biotechnol Bioeng. 2017;3(5):437‒448. DOI: 10.15406/jabb.2017.03.00082

Sr. No.

Type of Anti- depressants

Name of Anti- depressant Half-life Availability

Dietary consideration Reference

5 MAOIs

Isocarboxazid About 36 Hours Tablets Contains Lactose

Phenelzine 11-12 Hours Tablets Requires Food Restrictions

Moclobemide 2-4 Hours Tablets Requires Food Restrictions

Tranylcypromine About 2 Hours Tablets Requires Food Restrictions

6 Others

Agomelatine 1-2 Hours Tablets Contains Lactose

Mirtazapine 20-40 Hours Liquid -

Reboxetine About 13 Hours Tablets -

Triptafen N/A Tablets -

Vortioxetine About 66 Hours Tablets -

*Dispersible tablets will disintegrate quickly in the mouth or can be mixed with water, orange juice or apple juice.

*All other antidepressants currently available do not contain lactose or gelatin, and do not require any specific dietary restrictions, although caution when drinking alcohol is a recommended for all antidepressants.

Selective serotonin reuptake inhibitors (SSRIs)

SSRIs are known to selectively inhibit serotonin transport. Some of the SSRIs are fluoxetine (Prozac, Selfemra), paroxetine (Paxil, Pexeva), sertraline (Zoloft), citalopram (Celexa) and escitalopram (Lexapro). This action of SSRIs results into abrupt increase in serotonin in the somatodendritic area of serotonergic neurons which causes desensitization of the somatodendritic serotonin-1A autoreceptors.31–33 As a result, the neuronal impulse flow is increased.33 It causes increased release of serotonin from axon terminals, which culminates into desensitization of postsynaptic serotonin receptors. Desensitization of these receptors may contribute to the therapeutic actions of SSRIs or it could account for the development of tolerance to acute side effects of SSRIs. The pharmacological analysis of SSRIs suggests that these agents may cause strong but slow disinhibition of 5-HT neurotransmission in the central nervous system (CNS). In this case, the actions of antidepressants are mediated by a pathway from midbrain raphe to prefrontal cortex.34,35 The side effects generated by SSRIs include anxiety, sleep disturbances, sexual dysfunction (decreased libido, reduced pleasurability and reduction in arousal), and gastrointestinal disturbances.30 It is thought that the toxicity the 5-HT2 and 5-HT3 receptors of certain serotonergic pathways are responsible. A reciprocal relationship exists between serotonin and dopamine viz. serotonin tending to inhibit sexual functioning and dopamine tending to enhance sexual functioning. It is believed that serotonin pathway descending from brain stem down the spinal cord to spinal neurons that mediate various spinal reflexes is responsible for the sexual dysfunction in the form of ejaculation and orgasm problems. It has been reported that the enhanced serotonergic flow through this pathway inhibits sexual functioning. The serotonin’s negative effects on sexual functioning are mediated via 5-HT2 receptors. Therefore 5-HT2 antagonists can reverse SSRIs induced sexual dysfunction.36,37

The antidepressant acting as serotonin/norepinephri- ne/dopamine reuptake inhibitor (SNRI)

Stahl30 have demonstrated the pharmacologic effect of venlafaxine and found it to be dose dependent. At low doses, it essentially acts as

an SSRI and at medium to high doses, it causes additional NE reuptake inhibition and at very high doses, DA reuptake inhibition occurs.30,39 Other antidepressants such as nefazodone and trazodone act via serotonin-2 receptor antagonism with serotonin reuptake blockade. It is interesting to mention here that SSRIs stimulate 5-HT2 receptors where as nefazodone and trazodone blocks the receptor.30 This action of nefazodone and trazodone makes it safer antidepressants than the SSRIs.

Depressants as norepinephrine and dopamine reup- take inhibitor (Bupropion)

Bupropion is the only antidepressant that selectively acts on the noradrenergic and dopaminergic systems and not on the serotonin system.40 Bupropion exhibits dopaminergic and noradrenergic activity, therefore it may exert positive effect in overcoming the attention deficit disorder41 and in the treatment of smoking cessation.38 In contrary to the benefits from this drug, bupropion has been shown to induce some side effects such as overstimulation, agitation, insomnia and nausea.30,39

Antidepressants showing α-2 antagonism plus seroto- nin-2 and serotonin-3 antagonism

Mirtazapin, a noradrenergic and specific serotonergic antidepressant,43 has both pro-adrenergic and proserotonergic actions. The pro-adrenergic and proserotonergic actions of mirtazapin are due to its alpha2-antagonist properties i.e. disinhibition of both serotonin and norepinephrine neurotransmission. Similar to nefazodone, mirtazapine also does not exert any toxicity of SSRIs due to 5-HT2 stimulation. Since strong antihistamine properties are associated to mirtazapin, it has some side effects such as weight gain and sedation.30,39

The antidepressants acting as a noradrenalin specific reuptake inhibitor (NRI) (Reboxetine)

Reboxetine, a noradrenaline (norepinephrine) reuptake inhibitor, is exclusively unrelated to TCA or SSRIs. The specific properties of

Table Continued...

Antidepressants: mechanism of action, toxicity and possible amelioration 444 Copyright:

©2017 Khushboo et al.

Citation: Khushboo, Sharma B. Antidepressants: mechanism of action, toxicity and possible amelioration. J Appl Biotechnol Bioeng. 2017;3(5):437‒448. DOI: 10.15406/jabb.2017.03.00082

reboxetine includes its high affinity for the noradrenaline transporter, and little affinity for other neuro receptors including serotonin, dopamine, histamine, muscarinergic and alpha adrenergic sites.43

Antidepressants as a serotonin reuptake enhancer (Tianeptine)

Tianeptine being, a tricyclic compound of dibenzothiazepine type increases the presynaptic uptake of serotonin after single as well as repeated administration, but this action is not linked to any effects on the 5-HT post-synaptic systems.50,89 Tianeptine has no affinity for alfa1 adrenergic and H1 antihistaminic receptors. Tianeptine can be considered as the mid-position antidepressants. Defrance et al.45 have

shown that tianeptine does not show any affinity for the muscarinic receptors. Tianeptine has been reported to exert little toxicity such as gastralgia, abdominal pain, dry mouth, anorexia, nausea, vomiting, flatulence, insomnia, drowsiness, nightmares, asthenia, and tachycardia in certain patients44–46

Phytochemicals as antidepressants

Some phytochemicals are reported to act as antidepressants. These chemicals present in the plant extracts are expected to be safer and more cost effective than the existing antidepressants. Different ethno- pharmaceutical properties of various plant extracts and their effects are summarised in Table 7.

Table 7 Phytochemicals acting as natural antidepressants

Plant Extract Common name Part used from the plant

Type of extract, compound, doses Effects References

Allium macrostemon Chinese Garlic Bulb Water Extracts

Behavioural Despair

47

Allium sativum Garlic Rhizome Ethanolic Extract, dose- 25,50 and 100mg/kg

48

Aloysia polystachya Lemon Verbena Aerial Part Hydroethanolic Extract Effect on Depression

49

Apocynum venetum Dogbane Aerial Part Dose-30-125mg/kg 50

Areca catechu Betel Nut Fruit Ethanolic Extract, dose- 4-80mg/kg Effect on Motor Activity 51

Asparagus racemosus Satavari Root Methanolic Extract, dose- 100,200 and 400mg/kg

Effect on Serotonergic And Noradrenergic System And Augmentation Of Antioxidant Defences

52

Bacoba monnieri Brahmi Aerial Part Methanolic Extract, dose- 20 and 40mg/kg

Significant Antioxidant Effect, Anxiolytic Activity And Improve Memory Retention

53

Berberis aristata Indian Barberry Root Berberine, (An Alkaloid), dose-5,10 and 20mg/kg.

Effect on CNS, Inhibit Monoamine Oxidase-A

54

Bupleurum falcatum Chai Hu, Hare’s Ear Root

Root Methanolic Extract Psycho stimulant Effect 55

Cimicifuga racemosa Black Bugbane Roots And Rhizomes

Ethanolic And Isopropanolic Aqueous Extracts

Effect on heraprutical Responses In Climacteric Women

56

Clitoria ternatea Butterfly Pea Root ,Bark Ethanolic Extract, 50 or 100mg/kg

Effect on Cognitive Behaviour, Anxiety, Depression, Stress

57

Crocus sativus Saffron Stigma Ethanolic Extract Effect on Depression 58

Curcuma longa Turmeric Rhizome Aqueous Extract, dose- 140-560mg/kg for 14 days. Mao Inhibition In Brain

59

Emblica officinalis Amla Fruit - Effect on Psychiatric Disorder 60

Ginkgo biloba Ginkgo, Maidenhair Tree Leaves

Lipophilic Extract, dose- 50 and 100mg/kg

Act As Anti-Stress and Antidepressant

61

Glycyrrhiza uralensis Mulethi Root Liquiritin (Flavones)

Antidepressant Like and Antioxidant Activity By Measuring Erythrocyte Superoxide Dismutase (Sod) Activity And Plasma Malondialdehyde (MDA) Level

62

Glycyrrhiza glabra Mulethi Root Aqueous Extract, Liquorice Extract Effect on Inhibition Of Mao 63

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Citation: Khushboo, Sharma B. Antidepressants: mechanism of action, toxicity and possible amelioration. J Appl Biotechnol Bioeng. 2017;3(5):437‒448. DOI: 10.15406/jabb.2017.03.00082

Plant Extract Common name Part used from the plant

Type of extract, compound, doses Effects References

Hippeastrum vittatum Amaryllis Flower Alkaloids Effect on Neurological Disorders And Neuro degenerative Disease 64

Hypericum canariensel. And Hypericum glandulosum

Canary Island St .John Wort

Aerial Part Methanolic Extract Neuro pharmacological Effect, Helps In Muscle Relaxation, Anti- cholinergic And Sedative Properties

65

Hypericum reflexum Hypericum Aerial Part Methanolic Extract Effect on CNS 66

Kaempferia parviflora Kava Kava Kava Root/ Rhizome

Rhizome Extract Effect on Psychiatric Illness 67

Lafoensia pacari Didal Leaves - Effects on CNS 68

Magnolia bark and ginger rhizome

Magnolia, Ginger Bark, Rhizome Honokiol and Magnolol, Polysaccharides

Effect on Synergistic Interaction 69

Marsilea minuta Dwarf Water Clover Root Marsiline, Sedative And Anticonvulsant Property

Effect on Insomnia And Other Mental Disorders

70

Mimosa pudica Sensitive Plant Leave Aqueous Extract Act As Tricyclic Antidepressants 71

Mitragyna speciosa Kratom Leaves Mitragynine An Active Alkaloid Effect on Diarrhea, Diabetes And Improve Blood Circulation

72

Momordica charantia Bitter Gourd/ Bitter Melon Fruit Methanol Extract, dose- 300mg/kg

73

Morinda officinalis Indian Mulberry Root Dose- 25-50mg/kg Effective In Response Rate 74

Oscimum sanctum Tulsi Aerial Part 75

Paeonia lactiflora pall Garden Peony Root Ethanolic extract, dose- 250 and 500mg/kg

Effect on Central Monoaminergic Neurotransmitter System

76

Piper laetispicum Piper Stem And Root Amide (Alkaloid), dose- 2mg/kg

Antinociceptive Properties, Effect on Pain And Depression

77

Piper tuberculatum Black Pepper Fruit Piplartine (An Amide) , dose- 50 and 100mg/kg

Effect on Anxiolytic And Antidepressant Activities, Anxiety And Depression.

78

Polygala sabulosa Polygala Aerial Part Scopoletin, A Coumarin Effect on Serotonergic, Dopaminergic And Noradrenergic Systems

79

Rhazyastricta White Henna Leaves Aqueous Extract Effect on Monoamine Oxidase Inhibition 80

Rosmarinusofficinalis Rosemary Fresh Juice Hydro-alcoholic Extract Interaction With The Monoaminergic System

81

Salvia elegans Pineapple Sage Leave Hydroalcoholic Extract Putative Anxiolytic 82

Schinusmolle L Peruvian Pepper Tree Leaves Hexenic Extract Pharmacological Effects, atleast At A Preclinical Level

83

Siphocampylus verticillatus Siphocampylus Aerial Parts

Hydroalcoholic Extract , dose range-100-1000mg/kg

Interaction With Adrenergic, Dopaminergic, Glutamatergic And Serotonergic System

84

Sphaeranthu sindicus East Indian Globe Thistle Whole Part Hydroalcoholic Extract

Effect On Anxiety, Depression And Convulsions

85

Tabebuia avellaneda Lapacho, Taheboo Tree Bark Ethanolic Extract

Effect Of The Association Of The Extract With The Antidepressants

[86]

Table Continued..

Antidepressants: mechanism of action, toxicity and possible amelioration 446 Copyright:

©2017 Khushboo et al.

Citation: Khushboo, Sharma B. Antidepressants: mechanism of action, toxicity and possible amelioration. J Appl Biotechnol Bioeng. 2017;3(5):437‒448. DOI: 10.15406/jabb.2017.03.00082

Plant Extract Common name Part used from the plant

Type of extract, compound, doses Effects References

Tagetes lucida Marigolds Aerial Part - Effect On CNS 87

Tinospora cardifolia Guduchi Whole Part Petroleum Ether Extract, dose- 50, 100 and 200mg/ kg.

Effect on Mao-A and Mao-B 48

Valeriana officinalis Valerian Root Ethanolic Extract Effect on Mild Sleep Disorders and Nervous Tension 48

Valeriana wallichi Indian Valeriana Root Bark Methanolic and Aqueous Extract 89

Withania somnifera Ashwagandha Aerial Part Bioactive Glyco withanolides

Effect on Anxiolytic And Antidepressant Action

90

Table Continued...

Conclusion Depression is a serious psychological condition but it can

be effectively treated with available therapies. The stock of antidepressants available may be selectively used for treating depression safely without any side effects. The right medication to an individual depends on the clinico-physiological conditions of the patient such as symptoms, possible side effects, and interaction with other medications, state of pregnancy or breast feeding and the mental conditions. Different classes of antidepressants are in practice depending on the type and requirement of depression. Antidepressants include selective serotonin reuptake inhibitors (SSRIs), Serotonin and norepinephrine reuptake inhibitors (SNRIs), Norepinephrine and dopamine reuptake inhibitors (NDRIs: Bupropion (Wellbutrin, Aplenzin, Forfivo XL), Atypical antidepressants (trazodone (Oleptro), mirtazapine (Remeron) and vortioxetine (Brintellix)), Tricyclic antidepressants (imipramine (Tofranil), nortriptyline (Pamelor), amitriptyline, doxepin, trimipramine (Surmontil), desipramine (Norpramin) and protriptyline (Vivactil)), Monoamine oxidase inhibitors (MAOIs: tranylcypromine (Parnate), phenelzine (Nardil) and isocarboxazid (Marplan)) and other medications such as such as mood stabilizers or antipsychotics all as well as anti-anxiety and stimulant medications. Many of these medications have their side effects. It could be however worthwhile to investigate the plant based principles to be used as more effective and safe chemotherapeutic compared to the currently used synthetic regimen.

Acknowledgements Khushboo is grateful to UGC-New Delhi for financial support in

the form of a fellowship.

Conflict of interest The author declares no conflict of interest.

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