Selective Serotonin Reuptake Inhibitors (SSRI) - Antidepressants

Selective Serotonin Reuptake Inhibitors (SSRI)

These drugs constitute the second generation of antidepressant drugs and are much safer and better tolerated than the first generation drugs (cyclics and monoamine-oxidase inhibitors). Important examples include citalopram, duloxetine, escit-alopram, fluoxetine, fluvoxamine, milnacipran, oxaflozane, paroxetine, pizotifen, sertraline, venlafaxine. A related group of drugs comprises the selective serotonin-noradrenaline reup-take inhibitors (SNRIs), mainly represented by venlafaxine,milnacipram, and duloxetine. For the sake of convenience, both groups are discussed together under one heading.

Uses

Treatment of

■■   Depression

■■  Panic disorder

■■ Obsessive-compulsive disorder

■■ Sleep disorders

■■ Migraine

■■  Substance abuse.

Toxicokinetics

·            All SSRIs (except paroxetine) are rapidly absorbed on oral administration. Because of slower absorption in the case of paroxetine, symptoms of toxicity can be delayed. Peak plasma concentrations are generally reached in about 2 to |8 hours depending on the drug. Sertraline is also slowly absorbed; peak plasma concentrations are reached approxi- mately 5 to 8 hours after oral dosing.

·            Protein binding ranges from 50% (for citalopam) to 99% (for sertraline). Fluoxetine binds to plasma proteins to the extent of 94%.

·            The primary route of elimination of most of these drugs appears to be renal. Elimination half-lives range from 15 to 26 hours.

Mode of Action

The SSRIs specifically inhibit the reuptake of serotonin, thereby potentiating the activity of neuronally released serotonin.

■■They also alter the sensitivity of serotonin subtype 5HT_1A or 5HT_1C receptors.

■■   Sertraline has a greater selectivity for inhibiting 5-HT uptake relative to noradrenaline than any other drug in this class of therapeutic agent.

Adverse Effects

·            Anorexia, dry mouth, nausea, vertigo, blurred vision, tremor, drowsiness, sexual dysfunction, seizures; suicidal ideation, mania, and paranoia; extrapyramidal effects; cardiac arrhythmias; hyponatraemia and SIADH; and serum sickness or flu-like symptoms.

·            Serotonin syndrome: The serotonin syndrome is a disorder that can be caused by use of drugs or combinations of drugs which increase serotonin availability. It most often occurs when two or more drugs which increase serotonin avail- ability by different mechanisms are used simultaneously. Similarly, the more severe cases tend to result from drug interactions, especially when a monoamine oxidase inhibitor is involved. It may develop after therapeutic use or overdose. The SSRIs may cause the development of this syndrome when used alone, or (more commonly) when administered along with other serotonergic agents especially monoamine oxidase inhibitors (MAOIs).

o     Main features include agitation, restlessness, confusion, disorientation, hallucinations, drowsiness or insomnia, tachypnoea, flushing, abdominal pain, ataxia, tremor, hypomania, myoclonus, muscle rigidity, opisthotonus, trismus, hyperactivity, convulsions, sweating, saliva-tion, tachycardia, mydriasis, nystagmus, teeth chat-tering, hyper- or hypotension, hyperpyrexia, coma and diarrhoea.

o     Sternbach’s diagnostic criteria for serotonin syndrome include at least three of the following features: mental status changes (confusion, hypomania), agitation, myoclonus, hyperreflexia, sweating, shivering, tremor, diarrhoea, incoordination and fever.

o     Hunter serotonin toxicity criteria: Hunter serotonin toxicity criteria was developed by using the Hunter Area Toxicology Service (HATS) dataset of overdoses with any serotonergic drug. Following the use/overdose of a serotonergic agent, a diagnosis of serotonin toxicity can be made if the patient meets any of the following 5 criteria:

––  If the patient has spontaneous clonus.

–– If the patient has inducible clonus, and agitation or diaphoresis.

–– If the patient has ocular clonus, and agitation or diaphoresis.

––  If the patient has tremor and hyperreflexia.

–– If the patient is hypertonic, and has a temperature greater than 38°C and ocular clonus or inducible clonus.

·              Any ‘yes’ decision on any of the decision rules suggests definite or significant serotonin toxicity of sufficient clinical significance to require consideration of treat-ment with specific 5 -HT_2A antagonists. It was found that the presence of a temperature equal or greater than 38.5°C and/or marked hypertonia or rigidity (particu-larly truncal) indicated severe serotonin toxicity with a high risk of progression to respiratory compromise. These new criteria are simpler, more sensitive (84% vs 75%) and more specific (97% vs 96%) than Sternbach’s criteria.

·              The syndrome usually occurs in the first 2 hours of the first dose of the drug and usually resolves within 6 to 24 hours of stoppage of the medication. Some cases resolve even without discontinuation of the drug. Sometimes however, complications ensue including metabolic acidosis, lactic acidosis, rhabdomyolysis, myoglobi - nuria, renal and hepatic dysfunction, DIC, or ARDS.

·              Hyperthermia is characteristic of serotonin syndrome. In severe cases core temperature may exceed 42°C. Apart from the SSRIs, there are several other drugs which can cause the serotonin syndrome (Table 19.6). Serum electrolytes, glucose, renal function tests, CK and an ECG are recommended in all patients with suspected serotonin syndrome. Obtain liver function tests, PT/PTT or INR, platelets, and arterial blood gases in patients with severe hyperthermia, hypotension or other severe effects.

·              It is important to note that the serotonin syndrome has many similarities with neuroleptic malignant syndrome (NMS). However, NMS tends to have a slower onset and more prolonged duration of symptoms. Also, it is more frequently associated with fever and muscle rigidity than serotonin syndrome. On the other hand, serotonin syndrome is more likely to have myoclonus and hyperreflexia.

Treatment of serotonin syndrome:

–– Benzodiazepines for agitation. –– Rapid external cooling.

–– Benzodiazepines or barbiturates for convulsions. Neuromuscular blockade (with non-depolarising paralytics) in severe cases.

–– Nitroprusside for severe hypertension; noradrena-line, adrenaline, or phentolamine (NOT dopamine) for severe hypotension.

–– Benefit may be obtained in some cases with cypro-heptadine (4 mg/hr), methysergide (2 mg twice daily), or propranolol. Chlorpromazine has also been used to treat cases of serotonin syndrome.

Drug Interactions

■■  Diazepam—Concurrent administration of diazepam, withfluoxetine, may result in increased serum diazepam levels due to inhibition of diazepam metabolism by fluoxetine.

■■  MAO inhibitors—The combined use of fluoxetine (andother SSRIs) with MAO inhibitors may induce serotonin syndrome.

■■  Tricyclics—Plasma levels of tricyclics may be greatlyincreased when coadministered with fluoxetine and other SSRIs. Sertraline is a weak inhibitor of several hepatic enzymes. Inhibition appears to be dose-dependant, with higher doses, such as in overdoses, resulting in possible clinical relevance of drug interactions, particularly with tricyclic antidepressants (resulting in increased serum levels of TCA and toxicity).

Clinical (Toxic) Features

·      Acute SSRI overdose results in abdominal pain, nausea, vomiting, diarrhoea, vertigo, lethargy, insomnia, diplopia, CNS depression, tremors, and rarely convulsions.

·      There is also likelihood of ECG abnormalities (junctional rhythm, bigeminy and ventricular tachycardia, and QTc prolongation associated with ventricular tachycardia). Left bundle branch block has been reported with citalopram. Hypotension has also been reported.

·            Abrupt withdrawal of an SSRI after prolonged therapeutic use may cause vertigo, nausea, vomiting, fatigue, and myalgia. A discontinuation syndrome of dizziness, light-headedness, insomnia, fatigue, anxiety, agitation, nausea, headache, and sensory disturbances has been described after abrupt discontinuation of therapy with fluoxetine. A constel-lation of symptoms have been reported following discontinu-ation of sertraline therapy. Symptoms have included: fatigue, nausea, abdominal cramps, diarrhoea, shortness of breath, memory impairment, dizziness, insomnia, chills, headache, eye discomfort, tinnitus, ataxia, abnormal sensations (“elec-tric shocks”, skin tingling sensations, and involuntary move-ments). Symptoms typically resolve spontaneously, generally within 3 weeks, or with reinstatement of sertraline therapy.

·      Paroxetine exposure in utero, with maternal doses ranging from 20 to 120 mg/day, has resulted in a neonatal syndrome with effects including jitteriness, vomiting, irritability, hypoglycaemia, and necrotising enterocolitis. Withdrawal is also common in adults; the FDA (USA) has published a new product warning concerning severe paroxetine withdrawal effects, which could lead to drug dependency.

Treatment

·      Treatment involves supportive measures. Syrup of ipecac is contraindicated, while stomach wash is usually not neces-sary.

·      Serum levels are not clinically useful in managing overdose.

·      Monitor for evidence of serotonin syndrome.

·      Admit those with significant clinical effects including seizures or persistent lethargy or arrhythmias.

·      Sodium bicarbonate may be useful in treating QRS prolon-gation or arrhythmias. A reasonable starting dose is 1 to 2 mEq/kg intravenous bolus, repeated as necessary. Monitor arterial blood gases to maintain a pH of 7.45 to 7.55.

·      Because of the large volume of distribution and high degree of protein binding of SSRIs, haemodialysis, forced diuresis, haemoperfusion and exchange transfusion would not be expected to be useful in overdose.