Section 3.2.1.1

Serotonin-Specific Reuptake Inhibitors

(SSRIs)

General Description

The serotonin-specific reuptake inhibitors (SSRIs) are a structurally diverse class of antidepressants with distinct pharmacokinetic profiles. These drugs potently inhibit the reuptake of serotonin without significant effects on the reuptake of norepinephrine and dopamine. They have no major interactions with adrenergic, histaminergic, muscarinic and serotonergic receptors.

Consequently, SSRIs cause fewer troublesome side effects, such as anticholinergic side effects, weight gain and sedation, than the tricyclic or tetracyclic antidepressants. SSRIs are also much safer when taken in overdose compared to tricyclic antidepressants.

SSRIs that have been approved for the treatment of depression are: fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), and citalopram (Celexa). In addition, fluvoxamine (Luvox) has been approved for treatment of obsessive-compulsive disorder, as have fluoxetine, sertraline, and paroxetine. Fluoxetine is also approved for the treatment of bulimia nervosa, sertraline and paroxetine for the treatment of panic disorder, and paroxetine is further approved for the treatment of social anxiety disorder.

Indications for Medication

SSRIs have been shown to be effective in a number of disorders including depressions, obsessive-compulsive disorder, impulse control disorders, post-traumatic stress disorder, borderline personality disorder and eating disorders.

Fluoxetine is as effective as the classic antidepressant drugs in the short-term treatment of major depressive disorder. Fluoxetine is also effective in the treatment of mild depressive disorders and dysthymic disorder. Literature studies report its efficacy as an adjunct to antipsychotics for the treatment of schizophrenia related depression.

Fluoxetine is approved for the treatment of obsessive-compulsive disorder and it has been reported to be useful in the treatment of panic disorder. Fluoxetine has also been reported to be useful in the treatment of obesity. In the literature, it has also been reported to be useful in the treatment of post-traumatic stress disorder and premenstrual dysphoric disorder.

Sertraline is comparable to tricyclics in antidepressants efficacy. It is effective for a variety of moderate or severe depressions, those with or without melancholia, those with or without anxiety, those with psychomotor agitation or without psychomotor retardation and those with or without insomnia.

Sertraline may also be useful in some other disorders, such as post-traumatic stress disorder. However, its efficacy in these other conditions has not been fully evaluated and reported in the psychiatric literature.

Paroxetine is the most potent SSRI available. It is as effective as the classic antidepressant drugs in the treatment of major depressive disorder. Paroxetine is also effective in the treatment of mild depressive disorders and possibly dysthymic disorder. Studies also report its efficacy as an adjunct to antipsychotics for the treatment of schizophrenia related depression.

Fluvoxamine, although not markedly different from the other SSRIs, is approved only for the treatment of obsessive-compulsive disorder. Based on preliminary reports, it may be as effective an antidepressant as the other SSRIs. Research articles report its benefit with severe and moderate depressions - both primary depressions and secondary depressions associated with schizophrenia.

Citalopram (Celexa) was introduced in Europe in 1989, and approved by the US FDA in July 1998 for the treatment of depression. It is not the most potent SSRI, but it is highly selective (hence, its trade name). It may also have applications in the treatment of OCD, panic disorder, and an expanding range of behavioral disorders.

Clinical Guidelines

In general, SSRIs are given once a day, usually in the morning. The starting dose is often the same as a full therapeutic dose for most patients. Abrupt discontinuation of the SSRIs may result in a withdrawal syndrome. However, when discontinuing the SSRI, dose titration is not commonly required.

Fluoxetine is usually prescribed at 20mg a day, at breakfast (with food). Fluoxetine may be increased to 40mg a day after a three-week trial at the 20mg daily dose. Patients with obesity or bulimia nervosa may need a dose of 60mg a day; and patients with obsessive-compulsive disorder may require a dose of 80mg a day.

Sertraline should be initiated with a dose of 50mg a day. Patients not responding to 50mg a day may be titrated to range of 100-200mg day. Sertraline can be administered once daily, either in the morning or evening; food significantly increases the absorption of zoloft. The therapeutic effects usually occur in 2-4 weeks. Care should be used in patients with renal or hepatic impairment.

Paroxetine is available in 20mg and 30mg tablets. Most patients respond to the 20mg daily dose, usually prescribed as a single dose in the morning. Patients with GI upset may benefit by taking the drug with food. Many patients experience some relief of their depression with 2-4 weeks. However, an adequate trial of the SSRIs usually requires 6 weeks of administration.

Fluvoxamine should be administered within a range of 50-300mg a day. A starting dose of 50mg is usually recommended for the first week. Fluvoxamine may be administered as a single evening dose to minimize its side effects, but a total daily dose of more than 100mg should be given in two divided doses. It should be taken with water and food without chewing the tablet.

Citalopram is available in 20- and 40-mg scored tablets, and treatment can be initiated at 20 mg daily, in the morning or evening, with or without food. Elderly patients or those with hepatic disease may need to begin at a lower dose, and take no more than 20 mg per day. According to the manufacturer, dosages above 40 mg daily are not usually recommended, but in trials and in European experience, patients have taken as much as 80 mg daily.

Adverse Effects

Common side effects from SSRIs include anxiety, insomnia, gastrointestinal symptoms (such as nausea and diarrhea), headache, decreased appetite and sexual dysfunction (such as delayed orgasm and decreased libido). Other general adverse effects may include lethargy, fatigue, sweating, tremor and other extrapyramidal side effects.

Fluoxetine side effects usually include the central nervous system and the GI system. The statistics show that 25% of fluoxetine patients experience nausea and vomiting, 21% experience nervousness, restlessness and anxiety, and 19% experience insomnia.

Fluoxetine also causes anorgasmia, delayed orgasm and impotence in a significant percentage of patients. Various types of rashes occur in 4% of patients. There have been rare reports of extrapyramidal side effects. Seizures occur in 0.2%, approximately the incidence with other types of antidepressants.

Sertraline side effects usually include the GI system. The statistics show that 21% of sertraline patients experience nausea and vomiting. Sertraline should be taken with food. Sertraline also produces minimal anticholinergic, antihistaminic and antiadrenergic side effects. Male sexual dysfunction (usually delayed ejaculation) can occur with sertraline.

Paroxetine side effects usually include the central nervous system and the GI system. Paroxetine can be taken with food if GI upset occurs. The statistics show that 29% of paroxetine patients experience nausea and vomiting, 24% experience sedation, 20% experience headache and 20% experience dry mouth. Sexual dysfunction including delayed ejaculation, anorgasmia and decreased libido are also reported.

Fluvoxamine side effects are more frequent than the other SSRIs and also involve the central nervous system and the GI system. The statistics show that 37% of fluvoxamine patients experience nausea and vomiting, 26% experience sedation, 26% experience dry mouth and 22% experience headache. Abnormal ejaculation is also a problem with fluvoxamine.

Citalopram is non-activating but is minimally sedating in a dose-dependent fashion. Some reported adverse events may include nausea (21% vs 14% in placebo), dry mouth (20% vs 14%), ejaculation disorder (6% vs 1%), somnolence (18% vs 10%), or insomnia (15% vs 14%).

SSRIs are remarkably safe in overdoses. Lethal overdoses by taking one of the SSRIs are extremely rare. SSRIs are therefore safe to prescribe for suicidal patients compared with tricyclic and tetracyclic antidepressants that can be highly lethal in overdose.

SSRIs have not been fully studied in pregnancy. SSRIs should be used during pregnancy only if the potential benefits justify the potential risks. With breast feeding, SSRIs should be avoided in women. Fluoxetine, sertraline, paroxetine and fluvoxamine are all excreted in breast milk.

Drug-Drug Interactions

Fluoxetine interacts with multiple medications. The co-administration of fluoxetine with tricyclic antidepressants or benzodiazepines increases plasma levels of the antidepressants and benzodiazepines. Fluoxetine may also change levels of carbamazepine, lithium and antipsychotics. The clinician should consult the PDR for any drugs co-administered with fluoxetine.

Sertraline also interacts with multiple medications potentially causing changes in plasma concentrations. Sertraline does not significantly alter steady state lithium levels. Sertraline may increase prothrombin time when co-administered with warfarin. The clinician should also consult the PDR for any drugs co-administered with sertraline.

Paroxetine also interacts with multiple medications potentially causing changes in plasma concentrations. Paroxetine's own level may be decreased with phenytoin. Paroxetine should be used with caution in patients taking barbiturates. When paroxetine is used with warfarin, bleeding time is increased. The clinician should consult the PDR for any drugs co-administered with paroxetine.

Fluvoxamine also interacts with multiple medications potentially causing changes in plasma concentrations. Prolongation of the elimination of drugs (like warfarin, phenytoin, and theophylline) which are metabolized by the liver has been noted. Fluvoxamine and diazepam should not be co-administered because of the substantial accumulation of both drugs. The clinician should consult the PDR for any drugs co-administered with fluvoxamine.

Citalopram is considered a weak inhibitor of the cytochrome P450 isoenzymes 1A2, 2D6, and 2C19, and should be unlikely to materially alter the pharmacokinetics of other drugs that use the P450 system. But co-administration with citalopram doubled concentrations of metoprolol (Lopressor), and when imipramine was co-administered, desipramine concentrations increased 50%. Citalopram is metabolized by P4503A4 and 2C19, so potent inhibitors, such as azole antifungals or macrolide antibiotics (e.g., erythromycin), might elevate its levels. Omeprazole (Prilosec, a 2C19 inhibitor), could raise citalopram levels, as might cimetidine (Tagamet). Carbamazepine (Tegretol) might be expected to lower levels through enzyme induction.

SSRIs should not be co-administered with monoamine oxidase inhibitors (MAOIs). At least two weeks should elapse between starting any SSRI and the discontinuation of the MAOI.

The consent form for these medications is "Antidepressant (Anti-Obsessive-Compulsive Medication / SSRIs & dopaminergic acting medications)".

SSRI Interactions