Selective Serotonin Reuptake Inhibitors (SSRIS)

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

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.



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.


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