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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/

    http://crossmark.crossref.org/dialog/?doi=10.15406/jabb.2017.03.00082&domain=pdf

    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

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

    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

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

    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

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

    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

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

    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..

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

    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:

    ©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

    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

    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..

    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

    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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    • 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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