Shedding Light: Understanding Antidepressant Therapies

Depression is a mental health disorder.
Characterized by symptoms like sad mood, loss of interest and pleasure, low energy, worthlessness, guilt, psychomotor retardation or agitation, change in appetite and/ or sleep, melancholia, suicidal thoughts, etc.
It may be unipolar (only depression) or bipolar (cycle of mood swings from mania to depression).
It is the leading psychiatric disorder.
The mood change may have a psychotic basis with delusional thinking or occur in isolation.
Antidepresants are the drugs which can elevate mood in depressive illness.

1. Antidepressants DRUGS Komal Chandra Assistant Professor (Pharmacology) Department of Pharmaceutical Sciences, Bhimtal Kumaun University Nainital

2. INTRODUCTION Depression is a mental health disorder. C haracterized by s ymptoms like sad mood, loss of interest and pleasure, low energy, worthlessness, guilt, psychomotor retardation or agitation, change in appetite and/ or sleep, melancholia, suicidal thoughts, etc. It may be unipolar (only depression) or bipolar (cycle of mood swings from mania to depression). It is the leading psychiatric disorder. The mood change may have a psychotic basis with delusional thinking or occur in isolation.

3. ANTIDEPRESSANT DRUGS These are the drugs which can elevate mood in depressive illness. Classification: I. Reversible inhibitors of MAO-A (RIMAs) : Moclobemide , Clorgyline II. Tricyclic antidepressants (TCAs) A. NA + 5-HT reuptake inhibitors : Imipramine, Amitriptyline, Trimipramine , Doxepin, Dothiepin , Clomipramine B. Predominatly NA reuptake inhibitorsns : Desipramine , Nortriptyline , Amoxapine , Reboxetine III. Selective serotonin reputake inhibitors (SSRIs): Fluoxetine, Fluvoxamine, Paroxetine, Setraline , Citalopram, Escitalopram , Dapoxetine IV. Serotonin and noradrenaline reputake inhibitors (SNRIs): Venlafaxine, Duloxetine V. Atypical antidepressants: Trazodone , Mianserin , Mirtazapine, Bupropion, Tianeptine , Amineptine , Atomoxetine

4. Mechanism of action of MAO inhibitors A monoaminergic is a chemical which functions to directly modulate the serotonin, dopamine, nonepinephrine , epinehrine and or histamine neurotransmitter systems in the brain. Monoaminergics include catecholamine (adrenergic and dopaminergics ), serotonergics , and histaminergics . Monoamine oxidase (MAO) is a enzyme present in mitochondria of a cell. They breakdown monoamine and are involved in the oxidative deamination of biogenic amines ( Adr , NA, DA, 5-HT) and leads to inactivation of monoamine neurotransmitters.

5. MAO is of two forms: MAO-A : Preferentially deaminates 5-HT and NA, and is inhibited by clorgyline MAO-B: Preferentially deaminates phenylethylamine and is inhibited by selegiline . Dopamine is degraded equally by both isoenzymes . In depression monoamine oxidase enzyme is overexpressed than in normal condition and leads to deficiency of monoamines such as norepinephrine, serotonin, dopamine etc . as it breakdowns them. Due to which inactivation of monoamine neurotransmission also occur. MAO inhibitors inhibit monoamine oxidase enzyme due to which monoamine deficiency can be restored and depression can be cured. MAO inhibitors are also known as first generation antidepressants.

6. Reversible inhibitors of MAO-A(RIMAs) Moclobemide : It is reversible and selective MAO-A inhibitor with short duration of action; full MAO activity is restored within 1-2 days of stopping the drug. Inhibition due to moclobemide leads to a decrease in the metabolism and destruction of monoamines in the neurotransmitters. This results in an increase in the monoamines, relieving depressive symptoms.

7. It lacks various adverse effects which occur due to tricyclic antidepressants (TCAs) therefore clinically it is an efficacious antidepressant comparable to TCAs. Good option for elderly and heart disease patients. Dose : 150 mg BD-TDS (max 600mg/day). Adverse effects: Nausea, dizziness, headache, insomnia, rare excitement and liver damage.

8. Tricyclic antidepressants (ACAs) : These are the older compounds congeners of Imipramine an analogue of chlorpromazine which inhibit NA and 5-HT reuptake into neurones . Imipramine was found to be selectively benefit in depression during clinical trials in 1958. Mechanism of action: TCAs and related drug inhibit NET (Norepinephrine transporter) and SERT(Serotonin transporter) which mediate active reuptake of biogenic amines NA and 5-HT and thus potentiate them. Due to which there is increased concentration of the amines in the synaptic cleft in both CNS and periphery.

9. Adverse effects: Anticholinergic (dry mouth, bad taste, constipation etc.), sedation, mental confusion, weakness, increased appetite, weight gain, sweating, sexual distress, cardiac arrhythmias, rashes, jaundice etc. Acute poisoning: poisoning with TCAs is frequent, usually self-attempted by the depressed patient and may endanger life. Manifestations are excitement, delirium and other anticholinergic symptoms as seen in atropine poisoning, followed by muscle spasm, convulsion and coma. Respiration is depressed , body temperature may fall, BP is low etc. Treatment: gastric lavage, respiration assistance, fluid infusion, maintenance of BP and body temperature. Acidosis must be corrected by bicarbonate infusion.

10. TCAs: Amoxapine : It has antidepressants + neuroleptic properties as it also block D2 receptor and offers advantage for patients with psychotic depression. Seizures occur in overdose. Reboxetine : It blocks NA reuptake and has weak effect on 5-HT reuptake . Usal side effects are insomnia, sexual distress and urinary symptoms. Dose: 4mg BD or 8mg OD.

11. These are also second generation antidepressants that have a selective action on amine uptake and inhibit noradrenaline reuptake and therefore are known as selective noradrenaline reuptake inhibitors ( SNRIs). Venlafaxine: It inhibits both NA and 5-HT. It has faster onset of action. Do not produce side effects as TCAs but prominent side effects are nausea, sweating, anxiety, dizziness etc. Used in mood changes, anxiety, eating disorders etc. Duloxetine: A newer SNRIs similar to venlafaxine neither sedative, nor anticholinergic nor antihistaminics nor α blockers. Side effects include g.i . and sexual problems, imsomnia , rise in BP etc . Serotonin and noradrenaline reuptake inhibitors (SNRIs)

12. SELECTIVE SEOTONIN REUPTAKE INHIBITORS First generation antidepressants (TCAs) major limitations are: Frequent anticholinergic, cardiovascular and neurological side effects. Low safety margin. Antidepressants actions manifests after 2-4 weeks. Significant n.o of patient respond incompletely and some do not respond. They are second generation antidepressants that have a selective action on amine uptake and inhibit serotonin reuptake and therefore are known as selective serotonin reuptake inhibitors (SSRIs). Due to their relative safety and better acceptability they are first line drug in depression.

13. SSRIs Fluxetine : First SSRIs and longest acting (t1/2 2 days). Its action is slowest therefore it is not suitable for patient needed rapid effect. It is approved for children of age 7 or above but it should be used only when psychotherapy fails. Fluvoxamine : It is shorter acting SSRI (t1/2 18 hrs) and do not produce active metabolite due to which it is used in anxiety and obsessive compulsive disorder(OSD) rather than for depression. Relative more nausea, nervousness, discontinuation reactions etc has been reported with its use. Paroxetine: Another short acting (t1/2 20 hrs) which does not produce active metabolite. A higher incidence of g.i . side effects, sexual distress, agitation etc. has been noted. .

14. SSRIs Sertraline : It produces longer-lasting active metabolite and its t1/2 is 26 hrs. R ecommended for anxiety and post-traumatic stress disorder and causes less drug interactions. Citalopram: Cause less interactions and its t ½ is 33 hours. It produce no active metabolite. Deaths has been recorder due to its overdose hence it is to be avoided in patients likely to attempt suicide. It is preferred in mood disorders in premenstrual syndrome. Dapoxeine : Used to promote delaying premature ejaculation. It acts rapidly and when combined with behavioural therapy help many sufferers. Side effects are nausea, vomiting, loose motions, headache etc. Dose: 60 mg taken 1 hour before sexual intercourse; older patients 30 mg. Other uses: 1 st choice of drugs for OCD, panic disorder, social phobia, eating disorders etc.

15. ATYPICAL ANTIDEPRESSANTS Trazodone : Less efficiently blocks 5-HT uptake and has prominent α adrenergic and weak 5-HT2 antagonistic actions (which is responsible for its antidepressant effect). It is beneficial in OCD but in depression its use is infrequent. Mianserin : It blocks presynaptic α 2 receptors and thereby increase release and turnover of NA in brain which may be responsible for its antidepressant effects. It is a sedative- relieves associated anxiety and suppress panic attacks. Mirtazapine: It blocks α 2 auto (present on NA neurones ) and hetero (on 5-HT neurones ) receptors enhancing both NA and 5-HT release. Efficacy is similar to TCAs in depression.

16. Bupropion: It is metabolized into an amphetamine like compound which can cause presynaptic release of DA and NA. Sustained release formulations is marketed with aid of smoking cessation. It has infrequent use in depression. Tianeptine : Efficacious in anxiodepressive states. Side effects are dry mouth, epigastric pain, tremor, bodyache etc. Dose 12.5mg BD-TDS. Uses: Obsessive compulsive and phobic states: Characterized by unreasonable thoughts and fears that leads to compulsive behaviours . Preferred drug fluxamine and clomipramine. Endogenous (major) depression: It is mood disorder characterized by persistent and intense feeling of sadness for extended period of time. SSRIs are first choice of drug with TCAs as alternatives. Anxiety disorders: SSRIs are used with BZDs.

17. Enuresis (involuntary urination especially by children at night) : Imipramine 25 mg at bedtime is effective but bed wetting may again starts when the drug is stopped. Attention deficit-hyperactivity disorder in children: Prefered drug TCAs. Others uses of antidepressants drugs are in premature ejaculation, migraine, neuropathic pain etc.

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