Monoamine Reuptake Inhibitors

Antidepressant and Antimanic Medications: Monoamine Reuptake Inhibitors
Inhibition of monoamine reuptake at presynaptic nerve terminals defines this group of drugs, which includes the original TCAs, the selective serotonin reuptake inhibitors (SSRIs), and the new mixed-uptake inhibitors with minimal receptor-blocking properties (e.g., venlafaxine). The majority of these drugs were derived from the TCA imipramine. The older drugs in this group tend to be pharmacologically nonselective and often have active metabolites. The newer drugs (e.g., SSRIs, venlafaxine) tend to be more selective for reuptake blockade and so have fewer side effects.

These drugs are metabolized through hepatic microsomal systems, and major differences in absorption, in volume of distribution, and in excretion exist between individual drugs, causing clinically meaningful differences in plasma levels following routine dosing. All of the drugs in this group (and about 90% of all drugs in clinical practice) are metabolized by the hepatic cytochrome P450 (CYP) 2D6 and 2A(3 and 4) enzymes. The CYP2D6 enzyme has two subtypes (isoenzymes) because of a genetic polymorphism. One subtype causes slower metabolism (10% of the population), and the other leads to relatively faster metabolism. Persons with the slower metabolism subtype (so-called slow metabolizers) develop much higher plasma concentrations of drugs metabolized by the CYP2D6 enzyme. Genetic polymorphisms for the CYP2A enzymes are not known to exist. Knowing which CYP enzyme is responsible for metabolism of a drug can be important in assessing the potential influence of drugs that inhibit subsets of these enzymes. This is especially true for the SSRIs, some of which are potent inhibitors of CYP2D6.

Norepinephrine Reuptake Inhibitors
With the exception of reboxetine, NE reuptake inhibitors are TCAs with secondary-amine side chains. The TCAs include desipramine, nortriptyline, protriptyline, and maprotiline. Maprotiline is, in essence, a TCA with an ethylene bridge spanning the rings, which is why it is referred to as a tetracyclic. The drugs in this class vary in side-effect profile primarily because of differences in receptor-blocking properties. These drugs are metabolized through hepatic hydroxylation and glucuronidation and excretion by the kidneys.

Reboxetine is the first truly selective NE reuptake inhibitor to become clinically available. Reboxetine was approved for use as an antidepressant in much of Western Europe, South America, and Mexico in 1998. As of this writing, data in support of its new drug application for the treatment of depression was under FDA review. Reboxetine potently inhibits the reuptake of NE without having significant effects on the reuptake of serotonin or DA. It does not inhibit MAO, nor does it bind to serotonin type 1a (5-HT1A) or type 2a (5-HT2A), dopamine type 1 (DA1) or type 2 (DA2), α- or β-adrenergic, muscarinic cholinergic, gamma-aminobutyric acid (GABA), benzodiazepine, or histamine1 receptors. Reboxetine is rapidly absorbed and demonstrates linear pharmacokinetics. It is metabolized in the liver, but the specific CYP isoenzymes have not been identified. It has a large number of metabolites, but it is not yet clear if any of these are active. Reboxetine demonstrates a half-life of 12-14 hours. Early studies suggest that it does not alter CYP isoenzymes to a clinically significant extent. It is extensively bound to α1-glycoproteins. Plasma levels are elevated in the elderly, requiring lower dosing strategies in these patients.

All of these drugs have been shown to be effective in the acute treatment of MDE in 45%-63% of outpatients and 48%-63% of inpatients. The TCAs appear to be less effective in the treatment of OCD (Lelliott and Montiero 1986) than are SSRIs or MAOIs and less effective in the treatment of panic disorder than are SSRIs, MAOIs, or other TCAs. Therapeutic doses of these drugs vary. The usual therapeutic dosage for desipramine is 150-300 mg/day; for nortriptyline and maprotiline, 75-150 mg/day (maximum 225 mg/day for maprotiline); and for protriptyline, 20-60 mg/day. For reboxetine, the therapeutic dosage is usually 8-12 mg/day.

Nortriptyline has gained a well-deserved reputation for being better tolerated in elderly patients. Although nortriptyline is slightly more anticholinergic than desipramine, clinical doses of nortriptyline are usually one-half of the usual doses of desipramine. Thus, at the doses used in clinical practice, nortriptyline is less anticholinergic than most TCAs. Nortriptyline appears to be less likely to cause orthostatic hypotension compared with any other TCA, another feature leading to its greater level of tolerability in elderly patients.

Selective Serotonin Reuptake Inhibitors
SSRIs are relatively new and were developed because they are potent and selective inhibitors of serotonin reuptake. The five drugs in this class are fluoxetine, sertraline, paroxetine, fluvoxamine, and citalopram. They have similar side effects and have a similar therapeutic spectrum of action, being effective in the treatment of MDE, OCD, and panic disorder.

Early clinical experience suggests that although these drugs are more similar than different, there are differences in side-effect profiles among the five that are unexplained by current knowledge. These differences include 1) sedation or asthenia versus activation and 2) a propensity to cause nausea. In general, fluvoxamine and paroxetine are more frequently associated with a sedation-like “blah” feeling referred to as asthenia and with nausea, whereas fluoxetine and sertraline are more “activating.” Citalopram is intermediate in most side effects compared with other SSRIs, which probably accounts for its popularity in Europe and the United States. Another interesting difference is the potency of sertraline in blocking DA reuptake and in binding to sigma receptors. These properties suggest that the use of sertraline may be problematic in psychotic depression. Paroxetine is an inhibitor of the enzyme nitric oxide synthase, which could possibly lead to a slightly higher rate of sexual dysfunction compared with other SSRIs.

All of the SSRIs are metabolized in the liver and eliminated through the urine, with more than 90% of the parent compound inactivated. Fluoxetine and sertraline have active metabolites—norfluoxetine and N-desmethylsertraline—and both are also SSRIs. One of the most significant known differences between SSRIs is in their elimination half-lives. The range is quite broad, with fluvoxamine having the shortest half-life (15 hours) and fluoxetine the longest (48 hours). Norfluoxetine has a half-life of 146 hours. The pharmacokinetics of the SSRIs are summarized in

Table 39-6.

Fluoxetine, fluvoxamine, and paroxetine have potent inhibitory effects on the hepatic microsomal enzyme system and cause clinically significant increases in drugs metabolized by this system. This can be problematic in elderly patients taking other medications and can be a cause of unexplained delirium. All of the SSRIs are potentially lethal when combined with MAOIs, and this combination should be considered an absolute contraindication. Because of its long half-life and significant accumulation, fluoxetine should be discontinued at least 6 weeks before initiation of an MAOI, and other SSRIs should be discontinued at least 2 weeks before initiation of an MAOI. Although the syndrome that occurs with the combination of an SSRI and an MAOI has been referred to as the serotonin syndrome, it closely resembles the neuroleptic malignant syndrome and malignant hyperthermia.

Mixed Norepinephrine/Serotonin Reuptake Inhibitors
The mixed NE/serotonin reuptake inhibitors include the tertiary-amine TCAs (imipramine, amitriptyline, doxepin, and trimipramine) and the non-TCA venlafaxine. The TCA members of this family are demethylated in the liver and converted to secondary-amine active metabolites. The secondary-amine metabolites of these medications (e.g., desipramine, nortriptyline) are potent NE reuptake inhibitors, and clinically significant plasma levels of these metabolites usually develop during routine clinical use.

The TCAs in this group have established efficacy in the treatment of MDEs and serve as comparison medications for most newer antidepressants. All of these TCAs have been shown to be effective in both inpatient and outpatient populations. Clinical doses are roughly similar for all the TCAs in this group, and the therapeutic dosage range is between 150 and 300 mg/day. Imipramine has also been shown to be effective in the treatment of panic disorder, and amitriptyline and doxepin have been shown to be effective in the treatment of chronic pain syndromes.

All of these older TCA compounds have prominent side effects related to their anticholinergic and antihistamine properties. They are usually sedating and cause dry mouth, constipation, and some orthostatic hypotension. Blurred vision, urinary retention, and excessive perspiration (cause unknown) are frequently observed. The most difficult of these agents to tolerate are amitriptyline and doxepin.

Venlafaxine is the newest drug in this group and stands out from the others in having minimal effects on blockade of neurotransmitter receptors (Muth et al. 1986). At dosages less than 150 mg/day, it is as potent a blocker of serotonin reuptake as imipramine but is a weaker blocker of NE reuptake, making it slightly more selective for serotonin than for NE. Potent NE reuptake inhibition is thought to occur with dosages above 150 mg/day. Venlafaxine does not inhibit MAO and does not significantly bind to serotonin, NE, DA, muscarinic cholinergic, α1-adrenergic, or histamine1 receptors. It is rapidly absorbed after oral administration, with peak plasma levels being achieved in less than 2 hours. The half-life is extremely short and ranges from 3 to 5 hours, although an active metabolite, O-desmethylvenlafaxine, has a half-life ranging from 9 to 11 hours. Clinically therapeutic dosages of venlafaxine range from 150 to 300 mg/day in divided doses (tid). The extended-release form of venlafaxine can be dosed once daily and is associated with a more favorable side-effect profile.

Approved by the FDA for the treatment of MDEs in 1994, venlafaxine fared well in placebo-controlled studies and has been shown to be effective in inpatients and outpatients with MDE and in patients with MDE with melancholia (Feighner 1993). It has been suggested that venlafaxine may be more effective than fluoxetine in inpatients with MDE (Montgomery 1993). One case report described improvement of OCD symptoms with venlafaxine in a patient with OCD refractory to several SSRIs (Zajecka et al. 1990).

Because it does not possess receptor antagonist properties, venlafaxine appears to have fewer side effects than do the TCAs. The most common side effects are nausea, somnolence, dizziness, dry mouth, headaches, and increased perspiration. Sexual dysfunction has been reported, with up to 12% of patients describing abnormal ejaculation; 6%, impotence; and 2%, anorgasmia. However, because these estimates are based on spontaneous reporting, the true rate of sexual dysfunction is likely to be much higher. Sexual dysfunction may occur less at higher doses than at lower doses because of the relative selectivity of low-dose venlafaxine for blocking serotonin reuptake. Venlafaxine has been reported to cause dose-related diastolic hypertension in some patients, making blood pressure monitoring important during treatment. Venlafaxine appears to be as safe as SSRIs in overdose: in 12 patients who attempted suicide using doses up to 2.75 g, side effects included drowsiness and lethargy.

Dopamine/Norepinephrine Reuptake Inhibitors
Only one drug, bupropion, has been included in this group, but sertraline has been shown to possess significant potency as a DA reuptake inhibitor (Bolden-Watson and Richelson 1993). Bupropion is structurally related to phenylethylamines and unrelated to TCAs, SSRIs, or MAOIs. It is also unique in that it has no significant potency at binding to any known neurotransmitter receptors. It has no significant effects at blocking reuptake of serotonin or NE, although its primary metabolite, 306U73 (hydroxybupropion), has significant NE reuptake-blocking properties. Hydroxybupropion is produced rapidly in humans, with peak plasma levels up to three times those of bupropion and a half-life of 24 hours.

Bupropion is a very weak DA reuptake blockade inhibitor; its behavioral profile in laboratory animals and humans is that of a central nervous system (CNS) stimulant and indirect DA agonist. Bupropion increases locomotor activity and causes stereotyped behaviors in laboratory animals. In humans it can cause restlessness, insomnia, anorexia, and psychosis.

Clinical studies have demonstrated that bupropion is effective in the treatment of MDEs. Although early studies suggested that bupropion might be less likely to cause hypomania or mania in bipolar patients, subsequent studies suggested that it can cause mania and psychosis in bipolar patients, especially those with high pretreatment levels of the DA metabolite homovanillic acid (HVA).

The first series of phase III clinical trials with the immediate-release formulation of bupropion was discontinued by the FDA in the early 1980s because of a high incidence of seizures. Total daily dosages used in those trials were up to 900 mg. When subsequent trials with the immediate-release formulation were conducted with a maximum total daily dosage of 450 mg, efficacy was demonstrated for MDE, with an incidence of seizures approximating 0.4%. This incidence is similar to the 0.1% seen with TCAs. The incidence of seizures with immediate-release bupropion increases 10-fold for dosages between 450 and 600 mg/day, and the risk is increased substantially by predisposing factors such as prior history of seizures, head trauma, brain tumor, bulimia nervosa, or anorexia nervosa. Bupropion should also be used with caution in patients concurrently taking medications that lower seizure threshold such as theophylline, in patients taking antipsychotic drugs, or in patients who are alcoholic or are abusing benzodiazepines. Precautions to avoid seizures with the sustained-release formulation include using divided doses, with the maximum single dose not exceeding 150 mg.

The sustained-release formulation of bupropion may be associated with a lower risk of seizures. The data from clinical trials reveal a risk of seizures of 0.1% in patients treated with dosages between 100 and 300 mg/day and a rate of 0.4% at the maximum recommended daily dosage of 400 mg. However, although the half-life of the sustained-release formulation is 21 hours, the immediate- and sustained-release formulations are bioequivalent with regard to rate and extent of absorption during steady state, the most important parameters in estimating seizure incidence. Because of this, similar precautions aimed at reducing the risk of seizures should be used when prescribing either formulation of bupropion. Both formulations are contraindicated in patients with a history of seizures or bulimia.

Sustained-release bupropion is available in 100-mg and 150-mg tablets. Because of the longer half-life, it can be dosed twice daily, with the maximum dose being 200 mg bid.

Monoamine Oxidase Inhibitors » »

Check also:
Antidepressant and Antimanic Medications
Depression-Focused Psychotherapies
Psychodynamic Psychotherapies
Combined Medication and Psychotherapy
Electroconvulsive Therapy
Light Therapy
Treatment-Resistant Mood Disorders
Treatment of Mood Disorders in the Medically Ill Patient
Strategies and Tactics in the Treatment of Depression


Provided by ArmMed Media
Revision date: July 8, 2011
Last revised: by Jorge P. Ribeiro, MD