Consideration in the use of antidepressant medications.

Antidepressant medications can also be classified as monoamine agonists (serotonergic, noradrenergic, and dopaminergic). Identify the classes of antidepressants and outline common considerations for each.

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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 sharmabi@yahoo.com

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

https://creativecommons.org/licenses/by-nc/4.0/

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

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

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Antidepressants: mechanism of action, toxicity and possible amelioration 439
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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

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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

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

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Antidepressants: mechanism of action, toxicity and possible amelioration 441
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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

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

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

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..

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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…

https://doi.org/10.15406/jabb.2017.03.00082

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

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

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

Aloysia polystachya Lemon Verbena Aerial Part Hydroethanolic Extract
Effect on Depression

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

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

Significant Antioxidant Effect,
Anxiolytic Activity And Improve
Memory Retention

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

Effect on CNS, Inhibit Monoamine
Oxidase-A

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

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

Effect on Cognitive Behaviour,
Anxiety, Depression, Stress

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

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

Glycyrrhiza uralensis Mulethi Root Liquiritin (Flavones)

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

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

https://doi.org/10.15406/jabb.2017.03.00082

Antidepressants: mechanism of action, toxicity and possible amelioration 445
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

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

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

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

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

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

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

Antinociceptive Properties, Effect on
Pain And Depression

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

Effect on Anxiolytic And
Antidepressant Activities, Anxiety
And Depression.

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

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

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

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

Siphocampylus
verticillatus Siphocampylus Aerial Parts

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

Interaction With Adrenergic,
Dopaminergic, Glutamatergic And
Serotonergic System

Sphaeranthu sindicus
East Indian Globe
Thistle Whole Part Hydroalcoholic Extract

Effect On Anxiety, Depression And
Convulsions

Tabebuia avellaneda
Lapacho, Taheboo
Tree Bark Ethanolic Extract

Effect Of The Association Of The
Extract With The Antidepressants

[86]

Table Continued..

https://doi.org/10.15406/jabb.2017.03.00082

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

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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Title

Abstract
Keywords
Abbreviations
Introduction
Pathophysiology of depression
Antidepressants
Antidepressants and their classification
Interaction of antidepressants with the cellular receptors
Selective serotonin reuptake inhibitors (SSRIs)
The antidepressant acting as serotonin/norepinephrine/dopamine reuptake inhibitor (SNRI)
Depressants as norepinephrine and dopamine reuptake inhibitor (Bupropion)
Antidepressants showing α-2 antagonism plus serotonin-2 and serotonin-3 antagonism
The antidepressants acting as a noradrenalin specific reuptake inhibitor (NRI) (Reboxetine)
Antidepressants as a serotonin reuptake enhancer (Tianeptine)
Phytochemicals as antidepressants
Conclusion
Acknowledgements
Conflict of interest
References
Table1
Table 2
Table 3
Table 4
Table 5
Table 6
Table 7

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