Atypical Antidepressants

Atypical Antidepressants

Bupropion is a unicyclic antidepressant which acts by selec-tively inhibiting neuronal reuptake of dopamine, noradrenaline, and serotonin. It also has moderate anticholinergic activity. The chemical structure of this propiophenone is similar to amphetamine and diethylpropion, although its pharmacologic effects and adverse effects are distinctive. Apart from its use as an antidepressant, bupropion is also said to be effective in the treatment of attention deficit disorder, reduction of cocaine use, and even in diminishing the craving for chocolates. It has also been used as an aid in smoking cessation. Owing to the risk of seizure induction, bupropion must never be combined with other drugs which can lower the seizure threshold.

Bupropion is well-absorbed orally, with peak plasma levels within 2 hours. It is protein bound to the extent of 85%, has a volume of distribution of 19.8 to 47 L/kg, and a half-life ranging from 3.8 to 23 hours. 99% of the dose is metabolised to M-chlorohippuric acid, hydroxybupropion, erythrohydrobu-propion, and threohydrobupropion. 87% of the dose is excreted in the urine, mostly as metabolites.

Overdose results in vertigo, vomiting, miosis, tachycardia, hypokalaemia, and convulsions. In most cases, seizures are of short duration and may not require ongoing treatment. Sometimes, the onset of convulsions may be delayed; one patient developed seizures 19 hours after ingestion of sustained release bupropion. Massive overdose has resulted in cardiac arrest, severe hypoxia, and mixed respiratory and meta-bolic acidosis. Auditory and visual hallucinations have been described frequently following bupropion overdose. Psychosis may result. Cardiovascular overdose effects include primarily tachycardia and rarely hypotension.

Serotonin syndrome following bupropion therapy or over-doses has not been reported to date. Bupropion has dopamine agonist properties, but does not affect serotonin and does not inhibit monoamine oxidase.

Chronic use can cause rash, nocturia, ataxia, convulsions, dystonia, hallucinations, and hypomania. Tremor is a common effect in higher therapeutic doses (400 to 600 mg/day). Use of bupropion during pregnancy has been associated with an increased incidence of spontaneous abortion. Bupropion and its metabolites are excreted into human breast milk.

Treatment of overdose involves control of convulsions with IV diazepam, phenytoin, or barbiturates, and if necessary neuro-muscular blockade (with a non-depolarising agent). Obtain serum electrolytes. Cardiac monitoring may be necessary. Monitor for seizures and mental status changes. Urine myoglobin, serum creatinine and creatine kinase levels, etc., should be monitored for detecting rhabdomyolysis. Hypokalaemia must be corrected. If the patient has been seen within a short time of the overdose, activated charcoal can be administered. Emesis and gastric lavage are known to aggravate convulsive tendency.

Life- threatening toxicity is unusual. Survival has ben recorded even after overdoses of 9 gm in adults. Deaths that have been reported are preceded by multiple uncontrolled seizures, bradycardia, cardiac failure and cardiac arrest.

Mirtazepine is a tetracyclic antidepressant belonging tothe piperazinoazepine group of compounds. It is a 5-HT₂ and receptor antagonist, a histamine-1 receptor antagonist, a moderate peripheral alpha-1 adrenergic antagonist, and a moderate muscarinic receptor antagonist. It is a noradrenergic and specific serotonergic antidepressant (NaSSA). Mirtazepine acts by increasing neuronal serotonin and noradrenaline through alpha₂-adrenergic antagonism. It is a very recent entrant and is said to hold great promise as an antidepressant. Mirtazapine is recommended for the short-term treatment (less than 6 weeks) of major depressive disorders.

Adverse effects are fewer as compared to other drugs, and even in overdose mirtazepine is said to be more benign. Reported adverse effects include tachycardia, hypertension/ hypotension, CNS depression, including somnolence and confusion, arthralgia, myalgia, dry mouth, constipation, and rarely, liver dysfunction.^5-HT

Overdose experience is limited. The main features include CNS depression and tachycardia. Miosis has been reported following overdose with mirtazapine. Seizures have only been reported in one patient out of 2,796 in premarketing clinical trials, and in none of the 8 overdose cases reported so far. Overdoses of 10 to 30 times the maximum recommended dose produced no serious adverse effects in one series of patients. Overdoses of 30 and 50 times the normal daily dose produced no complications in some patients.

Treatment is mainly supportive. Monitor CBC, urinalysis, and liver and kidney function tests in patients with significant exposures. It is also advisable to monitor vital signs and insti-tute continuous cardiac monitoring. Support respiratory and cardiovascular function. Since mirtazapine is 85% bound to plasma protein, it is unlikely that haemodialysis or peritoneal dialysis would be effective in enhancing elimination.

Nefazodone is also a recent entrant and is approved for usein the treatment of major depression. It is a phenylpiperazine with some similarity to trazodone (vide infra). Nefazodone has pharmacologic actions in both the serotonergic and noradren-ergic systems, and is indicated for the treatment of depression.

Following oral administration, nefazodone is almost completely absorbed. It is subject to extensive first-pass metabolism, resulting in approximately 20% variable bioavail-ability. Food delays absorption and decreases bioavailability by about 20%, which is believed to be clinically insignificant. Nefazodone appears to be highly and loosely protein -bound (> 99%). The volume of distribution ranges from 0.22 to 0.87 litres. Nefazodone is metabolised in the liver to three active metabolites: hydroxy-nefazodone (OH-nefazodone), desethyl hydroxynefazodone (triazole dione), and m-chlorophenylpip-erazine (mCPP).

Adverse effects are less common. Common adverse effects at therapeutic doses include headache, dizziness, light-headed-ness, somnolence, dry mouth, diaphoresis, nausea, confusion and blurred vision. Liver failure has been reported following chronic therapy.

Serotonin syndrome has resulted following therapeutic doses of nefazodone and mirtazapine (both partial serotonin antagonists) in some patients. Nefazodone should not be used with a MAOI, or within 14 days of discontinuing use of a MAOI because of the risk of precipitating serotonin syndrome. A period of at least 1 week should be awaited after discontinuing nefazodone before starting a MAOI. Nefazodone may cause increased serum levels of drugs which are metabolised by cytochrome P450IIIA4 or P450 3A4 isoenzyme. Nefazodone is a weak inhibitor of cytochrome P450 2D6. Some of the drugs affected by nefazodone include terfenadine, astemizole, alprazolam, and triazolam. Concomitant intake of ethanol and nefazodone is not advisable.

Overdose results in nausea, vomiting, hypotension, bradycardia, prolonged QT interval, seizures, sedation, and somnolence. Hepatitis has been reported following overdoses with nefazodone.

Treatment is symptomatic and supportive. Following nefazodone overdose, monitor heart rate, ECG, blood pres-sure, liver function tests, neurologic and respiratory status.

Nefazodone overdose alone has not prolonged QRS duration and there is no evidence that therapies used in tricyclic anti-depressant overdose (hyperventilation, sodium bicarbonate) are useful. There is only a small risk for seizures in overdose, thus prophylactic treatment with anticonvulsants is not recom-mended. Hypotension usually responds to intravenous fluids. Atropine is indicated if significant bradycardia or heart block occur. Give 1 mg IV and repeat in three to five minutes if asystolic cardiac arrest persists.

Nefazodone is highly protein bound and largely excreted as metabolites. Although one metabolite is active, it is unknown if forced diuresis will be beneficial, and it is generally not recommended.

Trazodone is a triazalopyridine derivative and acts by5-HT₂ antagonism as well as serotonin reuptake blocking activity. It is chemically and structurally unrelated to tricyclic and tetracyclic antidepressants, but related to nefazodone; it is an “atypical” tetracyclic antidepressant since it has antidepres-sant and also anxiolytic and hypnotic activities.

Trazodone is rapidly and completely absorbed, with peak levels occurring in 1/2 to 2 hours. In vitro, trazodone is report-edly 89 to 95% protein bound. It is extensively metabolised in the liver by N-oxidation and hydroxylation. Seventy -five percent is excreted renally, mostly as metabolites. Less than 1% is excreted unchanged in the urine.

Trazodone is particularly suited for the treatment of major depression in elderly patients, because it lacks anticholinergic and cardiac adverse effects. However it causes orthostatic hypo-tension. Myoclonus and convulsions can also occur. Cholestasis has been reported in a few cases. Peripheral oedema has been reported in 10% of patients receiving therapeutic doses.

Since therapeutic use is associated with priapism, there may be a role for trazodone in the treatment of male impotence. Surgery was required in 26 of 84 cases of priapism reported to the manufacturer, and subsequent impotence may be permanent. Prolonged or inappropriate erections should be referred to a physician after immediately discontinuing the drug.

A trazodone withdrawal syndrome has been reported following the gradual discontinuation of therapeutic doses of trazodone. It has been suggested that development of this syndrome may be due to serotonergic effects and short half-lives of trazodone and its metabolite, m- chlorophenylpiper-azine, which may result in noradrenergic rebound following discontinuation. Withdrawal signs/symptoms have consisted of insomnia, vivid dreams, lassitude, nausea, diarrhoea, abdominal pain, anxiety, palpitations, hypomania, headache, myalgia, rest-less legs and formication. Rapid withdrawal has been reported to result in predominantly gastrointestinal symptoms which respond to administration of atropine. It has been suggested that a cholinergic rebound may occur following rapid withdrawal.

Overdose is associated with CNS depression and hypoten-sion. Lethargy, drowsiness, and ataxia are frequent symptoms. Coma is rare, but can be prolonged. Nausea and vomiting are also frequent. Mydriasis and tinnitus have occurred in some cases. Although seizures and mild cardiovascular abnormalities have been described, these are relatively rare. Hypotension, bradycardia and transient first degree heart block have been the most frequently reported cardiovascular effects. Hyponatraemia and marked hypokalaemia have been reported following overdose.

Treatment consists of symptomatic and supportive meas-ures. There is no specific treatment for trazodone overdose other than supportive care. Trazodone overdose alone has not produced prolonged QRS duration and there is no evidence that therapies used in tricyclic depressant overdose (bicarbonate, phenytoin) are useful. Phenytoin should actually be avoided due to the potential effect of trazodone on the QTc interval. There are only a few cases of seizures in overdose, thus prophy-lactic treatment with anticonvulsants is not recommended. Hypotension has responded to intravenous fluids. Atropine is indicated if significant bradycardia or heart block occurs. Give 1 mg IV and repeat in three to five minutes if asystolic cardiac arrest persists. Control convulsions with a benzodiazepine (diazepam or lorazepam). If seizures persist or recur administer phenobarbitone.

Priapism is an emergency requiring immediate consult with a urologist. It has been suggested that administration of anticholinergics (e.g. benztropine) or beta-blockers may be effective in reversing trazodone-induced priapism, but clinical studies will be needed to verify efficacy.