Antidepressants

History
Prior to 1954, ECT was the only available option for treating depression. In 1954, it was observed that some TB patients developed mood elevation following use of the antitubercular drug IPRONIAZID. Its mode of action was through inhibition of the enzyme monoamine oxidase (MAO) which breaks down catecholamines. However it had significant toxicity, hence later other MAO inhibitors (MAOIs) were introduced. Independently, IMIPRAMINE, whose chemical structure is similar to phenothiazines, was being investigated for treatment of agitation in psychotic patients. It was found to be ineffective, but, it was found to improve symptoms of depression. Kuhn then reported in 1958 that imipramine was an effective antidepressant.

Theories of antidepressant action

their appearance)

(in order of

1)Chemical imbalance theory/Serotonin hypothesis: By increasing serotonin (5-HT) levels in the brain 2)Catecholamine theory of depression: By inhibiting the reuptake of 5-HT and NE (norepinephrine) at the synapses

3)Receptor sensitivity theory: by causing a slow decrease in the sensitivity of presynaptic serotonergic autoreceptors, leading to increase in serotonergic function after days to weeks. This explains the delay in the onset of antidepressant action. An additional receptor sensitivity change thought to be important in the mechanism of action of antidepressants involved changes in the sensitivity of receptors for glucocorticoids where it was found that antidepressants produce an overall improvement of inhibitory feedback on the hypothalamicpituitaryadrenal axis. 4)By increasing neurotrophic factors in the brain(through action on intracellular pathways): neurotrophins reverse the effects of stress in some brain areas, they lead to birth of new neurons in hippocampus 5)By increasing serotonin uptake at nerve endings: tianeptine 6)Through blockade of central substance P receptors

Classification
1)Tricyclic antidepressants: inhibitors of serotonin and norepinephrine reuptake eg: amitriptyline, clomipramine, dosulepin(dothiepin), doxepin, imipramine, amoxapine, desipramine, maprotiline, nortriptyline, tianeptine(serotonin reuptake enhancer)

2)Selective serotonin reuptake inhibitors (SSRIs): eg: fluoxetine, fluvoxamine, citalopram, escitalopram, paroxetine, sertraline 3)Monoamine oxidase inhibitors (MAOIs): eg: isocarboxazid, phenelzine, tranylcypromine, selegiline (irreversible MAOIs); moclobemide and brofaromine (reversible MAOIs) 4)Norepinephrine dopamine reuptake inhibitor (NDRI): Bupropion, MOA- by releasing NE and DA 5)Serotonin norepinephrine reuptake inhibitors (SNRIs): eg: venlafaxine, desvenlafaxine, duloxetine, milnacipran 6)Norepinephrine and specific serotonergic agent (NaSSA) and alpha-2 blocker: Mirtazapine 7)Serotonin 2 antagonist/reuptake inhibitors (SARIs): Trazodone, nefazodone, MOA- block 5-HT 2A receptor and inhibit serotonin transporter 8)Norepinephrine reuptake inhibitor (NRI): Reboxetine, atomoxetine 9)Melatonin agonist: Agomelatine 5-HT2C blocker, increases firing of DA neurons in cortex and raphe nucleus leading to increased serotonin release restores sleep-wake cycle low SE profile, no sexual SEs effective in GAD

Triple reuptake inhibitors (NE, 5-HT and DA blockers): under development

Side-effects
1)TCAssedation (H1 blockade) dry mouth, blurring of vision, urinary retention, constipation, dizziness, tachycardia (muscarinic blockade) orthostatic hypotension (alpha blockade) weight gain 2)MAOIscardiac conduction delays and heart block dizziness, headache, insomnia, dry mouth, blurred vision, nausea, constipation, forgetfulness, difficulty with urination, and weakness sexual dysfunction, including anorgasmia, impotence, delayed ejaculation, and decreased desire insomnia 3)SSRIsagitation, anxiety, headache, sleep disturbance, tremor sexual dysfunction anorgasmia, erectile dysfunction nausea, dry mouth, sweating, weight change 4)Trazodone- sedation, orthostatic hypotension, priapism 5)Bupropion- appetite suppression, agitation, insomnia, aggravates tics in ADHD and Tourette

syndrome, psychosis with delusions and hallucinations, seizure risk at doses above 450 mg/d 6)Mirtazapine- sedation, increased appetite, weight gain 7)Venlafaxine- hypertension Common to all antidepressants is the risk of manic switch

Toxic effects

(symptoms in overdose)

1)TCAs- restlessness, excitement, myoclonus, dystonia, seizures, hypertension, hypothermia, depressed reflexes, respiratory depression, coma anticholinergic effects: mydriasis, flushed skin, dry membranes, tachycardia, delirium 2)MAOIsCheese reaction with foods rich in tyramine eg: aged cheeses, wine, beer, yogurt, aged, canned and processed meats, chocolate, coffee onset: 20 min- 1h following food intake characterized by nausea, apprehension, occasional chills, sweating, restlessness and hypotension with occipital headache, palpitations, and possibly vomiting. Neck stiffness, piloerection, dilated pupils, fever, and motor agitation are seen on examination. In severe forms the reaction can lead to delirium, hyperpyrexia, cerebral hemorrhage, and death

3)Serotonin syndromeoccurs when an SSRI and MAOI are combined characterized by sweating, diarrhoea, abdominal pain, fever, tachycardia, elevated blood pressure, myoclonus, hyper-reflexia, and with irritability and agitation. In its severe form, there can be severe hyperpyrexia, motor irritability, cardiovascular shock, and death

Usage in reproductive age women, pregnancy and lactation

Can be used safely in reproductive age women During pregnancy, must be avoided or prescribed at the lowest possible dose in first trimester, can be used in second and third trimesters and again must be reduced to the lowest during labour Secreted in breast milk but no serious consequences

Indications
Depression- unipolar and bipolar moderate to severe, dysthymia Anxiety disorders panic disorder, GAD, OCD (clomipramine), social phobia, PTSD Eating disorders- bulimia nervosa Insomnia - trazodone

 Narcolepsy Sleep apnea Chronic pain syndromes Alcohol dependence fluoxetine is useful as an anti-craving agent Smoking cessation- bupropion Nocturnal enuresis imipramine ADHD- TCAs, atomoxetine Premenstrual disorders Neurological disorders Parkinsons disease bupropion Behavioral disturbances in Alzheimers selegiline

Drug interactions
Barbiturates and carbamazepine which induce hepatic enzymes (CYP3A4) can accelerate tricyclic metabolism and reduce steady state blood levels Valproate can reduce tricyclic drug clearance Neuroleptics, cimetidine, methylphenidate can inhibit metabolism of TCAs SSRIs inhibit TCA metabolism (CYP1A2, 2D6 and 3A4) SSRIs increase warfarin levels

TCAs reduce effects of guanethidine and clonidine TCAs increase levels of phenytoin, warfarin MAOIs have many interactions- with anesthetics, cough syrup, decongestants, stimulants, dopamine and sympathomimetic agents Trazodone can potentiate barbiturates and alcohol to produce increased sedation, can produce serotonin syndrome in combination with SSRIs, and can increase digoxin, warfarin and phenytoin levels