Antidepressant Drugs

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Chapter: Essential pharmacology : Drugs Used In Mental Illness: Antidepressant And Antianxiety Drugs

These are drugs which can elevate mood in depressive illness. Practically all antidepressants affect monoaminergic transmission in the brain in one way or the other and many of them have other associated properties.






I. Reversible Inhibitors of MAOA (RIMAs)


Moclobemide, Clorgyline


II. Tricyclic Antidepressants (TCAs)



a.              NA + 5HT reuptake inhibitors Imipramine, Amitriptyline, Trimipramine, Doxepin, Dothiepin, Clomipramine


b.             Predominantly NA reuptake inhibitors Desipramine, Nortriptyline, Amoxapine, Reboxetine



III. Selective Serotonin Reuptake Inhibitors (SSRIs)


Fluoxetine, Fluvoxamine, Paroxetine, Sertraline, Citalopram, Escitalopram


IV. Atypical Antidepressants


Trazodone, Mianserin, Mirtazapine, Venlafaxine, Duloxetine, Tianeptine, Amineptine, Bupropion



Many other drugs like Protriptyline, Maprotiline, Nafazodone are marketed in other countries.




MAO is a mitochondrial enzyme involved in the oxidative deamination of biogenic amines (Adr, NA, DA, 5HT). Two isoenzyme forms of MAO have been identified.


MAO-A: Preferentially deaminates 5HT and NA, and is inhibited by clorgyline, moclobemide.


MAO-B: Preferentially deaminates phenylethylamine and is inhibited by selegiline.


Dopamine is degraded equally by both isoenzymes. Their distribution also differs. Peripheral adrenergic nerve endings, intestinal mucosa and human placenta contain predominantly MAOA, while MAOB predominates in certain areas (mainly serotonergic) of brain and in platelets. Liver contains both isoenzymes. Two hydrazine drugs—isoniazid and iproniazid were used for tuberculosis in 1951; the latter was especially found to cause disproportionate elevation of mood. Its capacity to inhibit degradation of biogenic amines was soon discovered and was believed to be responsible for the mood elevating action. Its less hepatotoxic congeners like phenelzine and isocarboxazid and some nonhydrazine MAO inhibitors (related to amphetamine) like tranylcypromine were used as antidepressants in the 1960s. They inhibited MAO irreversibly and were nonselective for the two isoforms. Because of high toxicity and interactions with foods and other drugs, they have become obsolete.


The selective MAO-A inhibitors possess antidepressant property. Selegiline selectively inhibits MAO-B at lower doses (5–10 mg/day), but these are not effective in depression. It is metabolized to amphetamine and at higher doses it becomes nonselective MAO inhibitor— exhibits antidepressant and excitant properties.


Nonselective  MAO  Inhibitors


The nonselective MAO inhibitors elevate the mood of depressed patients; in some cases it may progress to hypomania and mania. Excitement and hypomania may be produced even in nondepressed individuals.


The active metabolites of non-selective MAO inhibitors inactivate the enzyme irreversibly. The drugs themselves stay in the body for relatively short periods, but their effects last for 2–3 weeks after discontinuation: they are ‘hit and run’ drugs—return of MAO activity depends on synthesis of fresh enzyme; tissue monoamine levels remain elevated long after the drug has been largely eliminated.




These drugs inhibit a number of other enzymes as well, and interact with many food constituents and drugs.


1. Cheese reaction


Certain varieties of cheese, beer, wines, pickled meat and fish, yeast extract contain large quantities of tyramine, dopa, etc. In MAO inhibited patients these indirectly acting sympathomimetic amines escape degradation in the intestinal wall and liver reaching into systemic circulation they displace large amounts of NA from transmitter loaded adrenergic nerve endings hypertensive crisis, cerebrovascular accidents. When such a reaction occurs, it can be treated by i.v. injection of a rapidly acting α blocker, e.g. phentolamine. Prazosin or chlorpromazine are alternatives.


2. Cold and cough remedies


They contain ephedrine or other sympathomimetics—hypertensive reaction can occur.


3. Reserpine,  guanethidine,  tricyclic  antidepressants


Excitement, rise in BP and body temperature can occur when these drugs are given to a patient on MAO inhibitors. This is due to their initial NA releasing or uptake blocking action.


4. Levodopa


Excitement and hypertension occur due to increase in biological t½ of DA and NA that are produced from levodopa.


5. Antiparkinsonian anticholinergics


Hallucinations and symptoms similar to those of atropine poisoning occur.


6. Barbiturates, alcohol, opioids, antihistamines


Action of these drugs is intensified and prolonged. Respiration may fail.


7. Pethidine


High fever, sweating, excitation, delirium, convulsions and severe respiratory depression have occurred. The most accepted explanation is—MAO inhibitors retard hydrolysis of pethidine but not its demethylation. Thus, excess of norpethidine (normally a minor metabolite—see p. 459) is produced which has excitatory actions.


Reversible Inhibitors of MAO-A (RIMAs)




It is a reversible and selective MAOA inhibitor with short duration of action; full MAO activity is restored within 1–2 days of stopping the drug. Because of competitive enzyme inhibition, tyramine is able to displace it—potentiation of pressor response to ingested amines is weak, dietary restrictions are not required. Clinical trials have shown moclobemide to be an efficacious antidepressant, comparable to TCAs, except in severe cases. It lacks the anticholinergic, sedative, cognitive, psychomotor and cardiovascular adverse effects of typical TCAs and is safer in overdose. This makes it a particularly good option in elderly patients and in those with heart disease.


Dose:  150 mg BDS–TDS (max 600 mg/day)


RIMAREX 150, 300 mg tabs.


Adverse effects are nausea, dizziness, headache, insomnia, rarely excitement and liver damage. Chances of interaction with other drugs and alcohol are little, but caution is advised while coprescribing pethidine, SSRIs and TCAs.


Moclobemide has emerged as a well tolerated alternative to TCAs in mild to moderate depression and in social phobia.




Imipramine, an analogue of CPZ was found during clinical trials (1958) to selectively benefit depressed but not agitated psychotics. In contrast to CPZ, it inhibited NA and 5HT reuptake into neurones. A large number of congeners were soon added and are collectively called tricyclic antidepressants (TCAs).


Pharmacological Actions


The most prominent action of TCAs is their ability to inhibit norepinephrine transporter (NET) and serotonin transporter (SERT) located at neuronal/platelet membrane at low and therapeutically attained concentrations.


The TCAs inhibit monoamine reuptake and interact with a variety of receptors viz. muscarinic, α adrenergic, histamine H1, 5HT1, 5 HT2 and occasionally dopamine D2. However, relative potencies at these sites differ among different compounds. The newer selective serotonin reuptake inhibitors (SSRIs) and atypical antidepressants interact with fewer receptors and have more limited spectrum of action (produce fewer side effects). The actions of imipramine are described as prototype.


1. CNS


Effects differ in normal individuals and the depressed.


In normal individuals It induces a peculiar clumsy feeling, tiredness, light-headedness, sleepiness, difficulty in concentrating and thinking, unsteady gait. These effects tend to provoke anxiety. There is no mood elevation or euphoria; effects are rather unpleasant and may become more so on repeated administration.


In depressed patients Little acute effects are produced, except sedation (in the case of drugs which have sedative property). After 2–3 weeks of continuous treatment, the mood is gradually elevated, patients become more communicative and start taking interest in self and surroundings. Thus, TCAs are not euphorients but only antidepressants. In depressed patients who have preponderance of REM sleep, this phase is suppressed and awakenings during night are reduced. The EEG effects of low doses are similar to hypnotics but high doses cause desynchronization. Sedative property varies among different compounds: (see Table 33.1). The more sedative ones are suitable for depressed patients showing anxiety and agitation. The less sedative or stimulant ones are better for withdrawn and retarded patients.


The TCAs lower seizure threshold and produce convulsions in overdose. Clomipramine, maprotiline and bupropion have the highest seizure precipitating potential. Amitriptyline and imipramine depress respiration in overdose only.


Mechanism Of Action


The TCAs and related drugs inhibit active reuptake of biogenic amines NA and 5HT into their respective neurones and thus potentiate them. They, however, differ markedly in their selectivity and potency for different amines (see classification above).


Most of the compounds do not inhibit DA uptake, except bupropion. Moreover, amphetamine and cocaine (which are not antidepressants but CNS stimulants) are strong inhibitors of DA uptake. However, it has been proposed that TCAs indirectly facilitate dopaminergic transmission in forebrain that may add to the mood elevating action.


Reuptake inhibition results in increased concentration of the amines in the synaptic cleft in the CNS and periphery. Tentative conclusions drawn are:


     Inhibition of DA uptake correlates with stimulant action; but is not primarily involved in antidepressant action.

     Inhibition of NA and 5HT uptake is associated with antidepressant action.


Several findings indicate that uptake blockade is not directly responsible for antidepressant action, e.g. uptake blockade occurs quickly but antidepressant action develops after weeks; mianserin is antidepressant but has no uptake blocking action. Initially the presynaptic α2 and 5HT1 autoreceptors are activated by the increased amount of NA/5HT in the synaptic cleft resulting in decreased firing of locus coeruleus (noradrenergic) and raphe (serotonergic) neurones. However, on long-term administration, antidepressants desensitise presynaptic α2, 5HT1A, 5HT1D autoreceptors and induce other adaptive changes in the number and sensitivity of pre and post synaptic NA and/or 5HT receptors as well as in amine turnover of brain, the net effect of which is enhanced noradrenergic and serotonergic transmission. Thus, uptake blockade appears to initiate a series of time-dependent changes that culminate in antidepressant effect.


Trimipramine is a weak NA/5HT reuptake blocker, but an equally effective antidepressant. None of these compounds, except amoxapine and to some extent maprotiline, block DA receptors or possess antipsychotic activity.


2. ANS


Most TCAs are potent anticholinergics—cause dry mouth, blurring of vision, constipation and urinary hesitancy as side effect. The anticholinergic potency is graded in Table 33.1


They potentiate exogenous and endogenous NA by blocking uptake, but also have weak α1 adrenergic blocking action. Some, e.g. amitriptyline, doxepin, trimipramine have slight H1 antihistaminic action as well.


3. CVS Effects on cardiovascular function are prominent, occur at therapeutic concentrations and may be dangerous in overdose.


Tachycardia: due to anticholinergic and NA potentiating actions.

Postural Hypotension: due to inhibition of cardiovascular reflexes and α1 blockade.


ECG Changes And Cardiac Arrhythmias: T wave suppression or inversion is the most consistent change. Arrhythmias occur in overdose due to interference with intraventricular conduction, combination of NA potentiating + ACh blocking actions and direct myocardial depression. Older patients are more susceptible. The SSRIs and atypical antidepressants are safer in this regard.


Tolerance And Dependence


Tolerance to the anticholinergic and hypotensive effects of imipramine like drugs develops gradually, though antidepressant action is sustained.


Psychological dependence on these drugs is rare, because their acute effects are not pleasant.


There is some evidence of physical dependence occurring when high doses are used for long periods—malaise, chills, muscle pain may occur on discontinuation and have been considered withdrawal phenomena. Gradual withdrawal is recommended, but antidepressants do not carry abuse potential.




The oral absorption of TCAs is good, though often slow. They are highly bound to plasma and tissue proteins—have large volumes of distribution (~20 L/kg). They are extensively metabolized in liver; the major route for imipramine and amitriptyline is demethylation whereby active metabolites—desipramine and nortriptyline respectively are formed. Few others also produce active metabolites. Inactivation occurs by oxidation and glucuronide conjugation. Various CYP isoenzymes like CYP2D6, CYP 3A4, CYP 1A2 and others metabolise tricylic and related anti-depressants. Metabolites are excreted in urine over 1–2 weeks. The plasma t½ of amitriptyline, imipramine and doxepin range between 16–24 hours. The t½ is longer for some of their active metabolites. Because of relatively long t½s, once daily dosing (at bed time) is practicable in the maintenance phase.


An unusual therapeutic window phenomenon has been observed, i.e. optimal antidepressant effect is exerted at a narrow band of plasma concentrations (between 50–200 ng/ml of imipramine, amitriptyline, nortriptyline). Both below and above this range, beneficial effects are suboptimal.


Wide variation in the plasma concentration attained by different individuals given the same dose has been noted. Thus, doses need to be individualized and titrated, but plasma concentrations are not a reliable guide for adjusting the dose of TCAs.


Adverse Effects


Side effects are common with tricyclic antidepressants.


        Anticholinergic: dry mouth, bad taste, constipation, epigastric distress, urinary retention (especially in males with enlarged prostate), blurred vision, palpitation.


    Sedation, mental confusion and weakness, especially with amitriptyline and more sedative congeners.


       Increased appetite and weight gain is noted with most TCAs and trazodone, but not with SSRIs and bupropion.


   Some patients receiving any antidepressant may abruptly switch over to a dysphoricagitated state or to mania. Most likely, these are cases of bipolar depression, the other pole being unmasked by the antidepressant. Patients receiving higher doses and TCAs are at greater risk than those receiving lower doses and SSRIs or bupropion.


            Sweating and fine tremors are relatively common.


   Seizure threshold is lowered—fits may be precipitated, especially in children. Bupropion, maprotiline, clomipramine, amoxapine have greater propensity, while desipramine and SSRIs are safer in this regard.


     Postural hypotension, especially in older patients; less severe with desipramine-like drugs and insignificant with SSRIs.


   Cardiac arrhythmias, especially in patients with ischaemic heart disease—may be responsible for sudden death in these patients. Amitriptyline and dosulpin are particularly dangerous in overdose; higher incidence of arrhythmias is reported.


       Rashes and jaundice due to hypersensitivity are rare. Mianserin is more hepatotoxic.


Acute Poisoning


It is frequent; usually self-attempted by the depressed patients, and may endanger life. Manifestations are:


Excitement, delirium and other anticholinergic symptoms as seen in atropine poisoning, followed by muscle spasms, convulsions and coma. Respiration is depressed, body temperature may fall, BP is low, tachycardia is prominent. ECG changes and ventricular arrhythmias are common.


Treatment is primarily supportive with gastric lavage, respiratory support, fluid infusion, maintenance of BP and body temperature. Acidosis must be corrected by bicarbonate infusion.


Diazepam may be injected i.v. to control convulsions and delirium. Most important is the treatment of cardiac arrhythmias, for which propranolol/lidocaine may be used; class IA and IC antiarrhythmics and digoxin prolong cardiac conduction—are contraindicated.


Physostigmine (0.5–2 mg i.v.) reverses many central and peripheral anticholinergic and sometimes cardiac effects. However, it is seldom used since arrhythmias are occasionally worsened and hypotension accentuated by this treatment.




·      TCAs potentiate directly acting sympathomimetic amines (in cold/asthma remedies). Adrenaline containing local anaesthetic should be avoided. However TCAs attenuate the actions of indirect sympathomimetics (ephedrine, tyramine).


·      TCAs abolish the antihypertensive action of guanethidine and clonidine by preventing their transport into adrenergic neurones.


·         TCAs potentiate CNS depressants, including alcohol and antihistaminics.

·     Phenytoin, phenylbutazone, aspirin and CPZ can displace TCAs from protein binding sites and cause toxicity.


·      Phenobarbitone induces as well as competitively inhibits imipramine metabolism.


·       Carbamazepine and other enzyme inducers enhance metabolism of TCAs.


·   SSRIs inhibit metabolism of several drugs (see later) including TCAs—dangerous toxicity can occur if the two are given concurrently.


·      By their anticholinergic property, TCAs delay gastric emptying and retard their own as well as other drug’s absorption. However, digoxin and tetracyclines may be more completely absorbed. When used together, the anticholinergic action of neuroleptics and TCAs may add up.


·      MAO inhibitors—dangerous hypertensive crisis with excitement and hallucinations has occurred when given with TCAs.




This tetracyclic compound is unusual in that it blocks dopamine D2 receptors in addition to inhibiting NA reuptake. It is chemically related to the antipsychotic drug loxapine and has mixed antidepressant + neuroleptic properties—offers advantage for patients with psychotic depression. Risk of extrapyramidal side effects is also there. Seizures (including status epilepticus) occur in its overdose.




This is a newer selective NA reuptake blocker with weak effect on 5HT reuptake. Antimuscarinic and sedative actions are minimal. It appears to produce fewer side effects and may be safer in overdose than the older TCAs. Usual side effects are insomnia, dry mouth, constipation, sexual distress and urinary symptoms.


Dose: 4 mg BD or 8 mg OD.


NAREBOX 4, 8 mg tab.




The major limitations of conventional TCAs are:


·    Frequent anticholinergic, cardiovascular and neurological side effects.

·    Relatively low safety margin, hazardous in overdose; fatalities common.

·    Lag time of 2–4 weeks before antidepressant action manifests.

·    Significant  number  of  patients  respond incompletely and some do not respond.


To overcome these shortcomings, a large number of newer antidepressants have been developed since 1980s. The most significant of these are the SSRIs which selectively inhibit membrane associated SERT. Though, none of the newer drugs has surpassed older TCAs in overall efficacy, some patients not responding to one type of drug may respond to the other. More importantly the newer drugs have improved tolerability, both in therapeutic use as well as in overdose. It has been claimed that certain drugs (bupropion, venlafaxine, mirtazapine) have faster onset of antidepressant action, this has not been unequivocally established.


The relative safety and better acceptability of SSRIs has made them 1st line drugs in depression and allowed their extensive use in anxiety, phobias, OCD and related disorders. The SSRIs produce little or no sedation, do not interfere with cognitive and psychomotor function or produce anticholinergic side effects. They are devoid of α adrenergic blocking action—postural hypotension does not occur—suitable for elderly patients. They have practically no seizure precipitating propensity and do not inhibit cardiac conduction—overdose arrhythmias are not a problem. Prominent side effects are gastrointestinal; all SSRIs frequently produce nausea (due to 5HT3 receptor stimulation), but tolerance develops over time. Weight gain is not a problem with SSRIs, but they more commonly interfere with ejaculation or orgasm. A new constellation of mild side effects, viz. nervousness, restlessness, insomnia, anorexia, dyskinesia, headache and diarrhoea is associated with them, but patient acceptability is good. Increased incidence of epistaxis and ecchymosis has been reported, probably due to impairment of platelet function. Gastric blood loss due to NSAIDs may be increased by SSRIs.


The SSRIs inhibit drug metabolizing isoenzymes CYP2D6 and CYP3A4: elevate plasma levels of TCAs, haloperidol, clozapine, terfenadine, astemizole, warfarin, β blockers, some BZDs and carbamazepine. ‘Serotonin syndrome’ manifesting as agitation, restlessness, sweating, twitchings followed by convulsions can be precipitated when any serotonergic drug is taken by a patient receiving SSRIs. Some degree of tolerance to antidepressant action of SSRIs has been noted in few patients after months of use. Discontinuation reaction consisting of paresthesias, bodyache, bowel upset, agitation and sleep disturbances occurs in some patients. However, risk of switching over to hypomania during treatment is less with SSRIs than with TCAs.


The overall antidepressant efficacy of SSRIs is similar to that of TCAs, though some patients not responding to one may respond to the other. Because of freedom from psychomotor and cognitive impairment, SSRIs are preferred for prophylaxis of recurrent depression.


In severe depression, however, TCAs appear to be more efficacious. Metaanalysis of comparative trials has shown no significant difference in efficacy among individual SSRIs, but there are pharmacokinetic differences and incidence of particular side effects differs somewhat.




A bicyclic compound, prototype of the SSRIs and the longest acting; plasma t½ is 2 days and that of its active demethylated metabolite is 7–10 days. It has been approved for use in children 7 years or older for depression and OCD on the basis of similar efficacy and side effect profile as in adults, but should be given to children only when psychotherapy fails. It has caused more agitation and dermatological reactions than other SSRIs. Because of slower onset of antidepressant effect, it is considered less suitable for patients needing rapid effect, but is more appropriate for poorly compliant patients. Its stimulant effect could worsen patients showing agitation.




It is a shorter-acting SSRI with a t½ of 18 hours and no active metabolite.

Relatively more nausea, agitation and discontinuation reactions have been reported with fluvoxamine. However, it has been more commonly used in hospitalized patients and in some anxiety disorders or OCD.




Another short acting SSRI (t½ 20 hours) which does not produce active metabolite. A higher incidence of g.i. side effects and discontinuation reaction than with other SSRIs has bee noted.




This SSRI has gained popularity, since in clinical trials fewer patients stopped sertraline due to side effects. Efficacy in juvenile depression has been demonstrated. Drug interactions due to inhibition of CYP isoenzymes are less likely to occur with it. Its plasma t½ is 26 hours and it produces a longerlasting active metabolite.




This SSRI shares with sertraline a lower propensity to cause drug interactions. Its t½ is 33 hours and no active metabolite is known. However, few deaths due to overdose of citalopram are on record, because of which it is to be avoided in patients likely to attempt suicide.




It is the active S(+) enantiomer of citalopram, effective at half the dose, with similar properties. Side effects are milder and safety is improved.


Other Uses of SSRIs


The SSRIs are now 1st choice drugs for OCD, panic disorder, social phobia, eating disorders, premenstrual dysphoric disorder and post traumatic stress disorder. They are also being increasingly used for many anxiety disorders, body dysmorphic disorder, compulsive buying and kleptomania. Elevation of mood and increased work capacity has been reported in post-myocardial infarction and other chronic somatic illness patients. Thus, SSRIs are being used to improve outlook on life and to feel good, even in apparently nondepressed patients. Wisdom of such use though is questionable.







It is the first atypical antidepressant; selectively but less efficiently blocks 5HT uptake and has prominent α blocking as well as weak 5HT2 antagonistic action. The latter may contribute to its antidepressant effect. It is sedative but not anticholinergic, causes bradycardia rather than tachycardia, does not interfere with intracardiac conduction—less prone to cause arrhythmia—better suited for the elderly. Nausea is felt, especially in the beginning. Mild anxiolytic effect has been noted and it has benefited cases of OCD. Inappropriate, prolonged and painful penile erection (priapism) occurs in few recipients resulting in impotence in a fraction of these. The α1 adrenergic blocking property has been held responsible for this effect as well as for postural hypotension. In general, trazodone is well tolerated and relatively safe in overdose: seizures donot occur. Its t½ is short (~6 hr).




It is unique in not inhibiting either NA or 5HT uptake; but blocks presynaptic α2 receptors—increases release and turnover of NA in brain which may be responsible for antidepressant effect. Antagonistic action at 5HT2, 5HT1c as well as H1 receptors has also been shown. It is a sedative—relieves associated anxiety and suppresses panic attacks. While anticholinergic and cardiac side effects are less prominent, it has caused seizures in overdose—but fatality is low. Blood dyscrasias and liver dysfunction have been reported—have restricted its use.




This antidepressant is reported to increase rather than inhibit 5HT uptake, and is neither sedative nor stimulant. It has shown efficacy in anxio-depressive states, particularly with psychosomatic symptoms, as well as in endogenous depression. Side effects are dry mouth, epigastric pain, flatulence, drowsiness/ insomnia, tremor and bodyache.


Dose:  12.5 mg BD–TDS; STABLON 12.5 mg tab.




Like tianeptine it enhances 5HT uptake, but has antidepressant property. It produces anticholinergic side effects including tachycardia, confusion and delirium. Postural hypotension, conduction disturbances and arrhythmias can occur, especially in patients with heart disease.


Dose: 100 mg BD at breakfast and lunCh. No.


SURVECTOR 100 mg  tab.




A novel antidepressant referred to as ‘serotonin and noradrenaline reuptake inhibitor’ (SNRI), because it inhibits uptake of both these amines but, in contrast to older TCAs, does not interact with cholinergic, adrenergic or histaminergic receptors or have sedative property. Trials have shown it to be as effective antidepressant as TCAs and may work in some resistant cases. A faster onset of action has also been indicated. Venlafaxine does not produce the usual side effects of TCAs; tends to raise rather than depress BP and is safer in overdose. Prominent side effects are nausea, sweating, anxiety, dizziness and impotence.




A newer SNRI similar to venlafaxine. It is neither sedative, nor anticholinergic, nor antihistaminic, nor α blocker. Side effects, including g.i. and sexual problems are milder, but some agitation, insomnia and rise in BP can occur. Antidepressant efficacy is comparable to TCAs and duloxetine is also indicated in panic attacks, diabetic neuropathic pain and stress urinary incontinence in women (because it increases urethral tone).




This antidepressant acts by a novel mechanism, viz. blocks α2 auto (on NA neurones) and hetero (on 5HT neurones) receptors enhancing both NA and 5HT release. The augmented NA further increases firing of serotonergic raphe neurones via α1 receptors. Selective enhancement of antidepressive 5HT1 receptor action is achieved by concurrent blockade of 5HT2 and 5HT3 receptors which are held responsible for some of the adverse effects of high serotonergic tone. Accordingly, it has been labelled as “noradrenergic and specific serotonergic antidepressant” (NaSSA). It is a H1 blocker and quite sedative, but not anticholinergic or antidopaminergic. Efficacy in mild as well as severe depression is reported to be comparable to TCAs and benefit may start earlier.




This inhibitor of DA and NA uptake has excitant rather than sedative property. It is metabolized into an amphetamine like compound. It has been marketed in a sustained release formulation as an aid to smoking cessation. In clinical trials it has been found to yield higher smoking abstinence and quitting rates than placebo. Bupropion may be acting by augmenting the dopaminergic reward function. Better results have been obtained when it is combined with nicotine patch. The nicotine withdrawal symptoms were less severe in bupropion recipients. However, long-term efficacy is not known, and it can cause insomnia, agitation, dry mouth and nausea, but not sexual side effects. Seizures occur in over dose; the dose of 150 mg BD should not be exceeded.





Endogenous (Major) Depression:


The aim is to relieve symptoms of depression and restore normal social behaviour. The tricyclic and related antidepressants are of proven value. Response takes at least 2–3 weeks to appear, full benefits take still longer. Choice of a particular drug for an individual patient depends on the secondary properties (sedative, anticholinergic, hypotensive, cardiotoxic, seizure precipitating, etc.) as described above. The SSRIs are currently used as first choice for their tolerability and safety. The newer atypical agents also offer some advantages. The only antidepressants clearly shown to be effective in juvenile depression are fluoxetine and sertraline. The TCAs are mostly used as alternatives in nonresponsive cases, and are still the most effective in severely depressed adults. Moclobemide is a better tolerated option for mild to moderate depression, especially suited for elderly and cardiac patients. However, antidepressants are not the answer to every grief, loss, set back and other sad events that are part of life, but the less toxic and more patient friendly SSRIs/ newer atypical antidepressants are now more readily prescribed for depressive illness. After a depressive episode has been controlled, continued treatment at maintenance doses (about 100 mg imipramine/day or equivalent) for months is recommended to prevent relapse. Therapy is generally not continued beyond one year. ECT may be given in the severely depressed, especially initially while the effect of antidepressants is developing, because no antidepressant has been clearly demonstrated to act fast enough. The TCAs or SSRIs must be combined with lithium / valproate/ lamotrigine for bipolar depression, and not used alone due to risk of switching over to mania.


Combination of a SSRI with an atypical antipsychotic (such as olanzapine for its antimanic property) is also accepted as a treatment option of bipolar depression.


Obsessive-Compulsive And Phobic States:


The SSRIs are the drugs of choice due to better patient acceptability. TCAs, especially clomipramine, are highly effective in OCD and panic disorders: more than 25% improvement occurs in OCD rating scale and panic attacks are reduced in >75% patients. SSRIs and TCAs also reduce compulsive eating in bulimia, and help patients with body dysmorphic disorder, compulsive buying and kleptomania, though these habits may not completely die.


Anxiety Disorders:


Antidepressants, especially SSRIs, exert a delayed but sustained beneficial effect in many patients of generalized anxiety disorder; may be used along with a short course of BZDs to cover exacerbations. SSRIs have also proven helpful in posttraumatic stress disorder.


Neuropathic Pain:


Imipramine affords considerable relief in diabetic and some other types of chronic pain. Amitriptyline reduces intensity of postherpetic neuralgia in ~50% patients.


Attention Deficit-hyperactivity Disorder In Children:


TCAs with less depressant properties like imipramine, nortriptyline and amoxapine are now first line drugs in this disorder, comparable in efficacy to amphetaminelike drugs, with the advantage of less fluctuating action and fewer behavioral side effects.




In children above 5 years, imipramine 25 mg at bedtime is effective, but bed wetting may again start when the drug is stopped. Eldery subjects with bed wetting have also benefited.




Amitriptyline has some prophylactic value, especially in patients with mixed headaches.




Some tricyclics have antipruritic action. Topical doxepin has been used to relieve itching in atopic dermatitis, lichen simplex, etc.


NOCTADERM  5%  cream.


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