Antidepressant and Antimanic Medications: Drugs With Mixed Pharmacological Properties
The drugs in this category (trazodone, nefazodone, amoxapine, clomipramine, and mirtazapine) have multiple pharmacologically relevant effects. These include combinations of monoamine reuptake blockade and direct receptor antagonist and agonist properties.

Trazodone
Trazodone, a 5-HT₂ receptor antagonist with weak serotonin reuptake inhibitor properties, is structurally distinct from TCAs or other classes of antidepressant drugs. It is metabolized into the compound m-chlorophenylpiperazine (mCPP), which is a 5-HT_1A, 5-HT_1B, and 5-HT_1C agonist as well as a 5-HT₂ and 5-HT₃ antagonist. Pharmacologically significant plasma levels of mCPP are found in patients taking therapeutic doses of trazodone, which raises questions about the role of mCPP in this agent’s therapeutic effects and side effects.

Trazodone has been shown to be more effective than placebo in the treatment of inpatients and outpatients with MDE. Some authors have suggested that lower doses are more effective than the maximum total dosages of 400 mg/day for outpatients and 600 mg/day for inpatients.

Side effects associated with trazodone include sedation, orthostatic hypotension, dissociative feelings, increased myocardial irritability, and priapism. Sedation is variable but is often a limiting factor in dosing. Because of its prominent sedating properties, trazodone is frequently used as a hypnotic in combination with the less sedating SSRIs. Priapism is one of the most serious side effects of trazodone and is considered a urological emergency, often requiring surgical intervention and sometimes leading to permanent impotence.

Nefazodone
Nefazodone is chemically related to trazodone and has similar pharmacological properties. It is a 5-HT₂ receptor antagonist with weak serotonin reuptake inhibitor properties. The major difference between the two agents is that nefazodone lacks significant α₁-adrenergic antagonist properties. This difference has been suggested to account for the lack of orthostatic hypotension, sedation, and priapism with nefazodone compared with trazodone. Nefazodone is also metabolized into mCPP, and plasma levels of mCPP are similar to those obtained with trazodone.

Nefazodone has been shown to be effective in placebo-controlled trials and has comparable efficacy to that of imipramine but fewer side effects. Unlike all other known antidepressants, nefazodone either increases or has no effect on rapid eye movement (REM) sleep in humans. Nefazodone has been reported to improve memory function and does not potentiate the depressant effects of alcohol. Clinical doses range from a starting dose of 100 mg bid to a maximum total dosage of 600 mg/day. The lower dosage range of 200-400 mg/day is recommended in elderly patients.

Nefazodone-associated side effects include headache, asthenia, dry mouth, nausea, and constipation. Nefazodone does not alter cardiac conduction or electrocardiographic indices. It is reported to be less sedating than imipramine and SSRIs and may not cause as much sexual dysfunction as do the SSRIs. It appears to have no effect on seizure threshold.

Amoxapine
Amoxapine is a TCA and NE reuptake inhibitor with potent D₂ and 5-HT₂ receptor-blocking properties. Some studies have examined the use of amoxapine for MDE with psychotic features, finding it more effective than placebo and frequently as effective as the combination of other TCAs with an antipsychotic drug. Amoxapine has been reported to cause extrapyramidal reactions and tardive dyskinesia, consistent with its D₂ antagonist properties. It has a high frequency of seizures and lethality in overdose.

Clomipramine
Clomipramine is included in this group because it has several pharmacological properties that raise questions about its mechanism of action. Clomipramine is a tertiary-amine TCA and a potent serotonin reuptake inhibitor with significant D₂ antagonist properties. It is metabolized into a potent secondary-amine NE reuptake inhibitor, norclomipramine. Clomipramine is unique among the TCAs in that it has been shown to be an effective treatment for OCD. It has also been used successfully in depression refractory to other TCAs.

Clomipramine has prominent side effects that often limit dosing and have led to its being described as a “strong medicine.” It often causes sedation and anticholinergic-type side effects, making gradual dose escalation important. Therapeutic dosages are between 150 and 250 mg/day. Like the SSRIs, it frequently causes anorgasmia, and, like the tertiary-amine TCAs, it can cause difficulty in maintaining an erection.

Mirtazapine
Mirtazapine is unique among antidepressants by virtue of the fact that it does not inhibit the reuptake of serotonin, NE, or DA. Its primary mechanism of action is related to its potent antagonism of α₂-adrenergic receptors and 5-HT₂ receptors. It is also a potent antagonist of 5-HT₃ and histamine₁ receptors, effects that influence its side-effect profile. Mirtazapine has no effects on DA, cholinergic, or α₁-adrenergic receptors.

By blocking α₂- but not the α₁-adrenergic receptors, mirtazapine leads to an increase in firing rate and release of both NE and serotonin (De Boer 1996). This is because α₂-adrenergic receptors are localized on both NE and serotonin neurons. On NE neurons, presynaptic α₂ receptors function as autoreceptors, inhibiting the release of NE. Blocking these receptors leads to an increased firing rate and release of NE in most brain regions. NE released near the cell bodies of serotonin neurons activates α₁-adrenergic receptors located on serotonin cell bodies, and because these receptors act in an excitatory fashion, the firing rate of serotonin neurons is increased. Serotonin neurons also have α₂-adrenergic receptors, but in this case the receptors are localized on serotonin terminals and function to inhibit the release of serotonin. Blocking these α₂-adrenergic receptors enhances the amount of serotonin released each time the neurons fire.

Mirtazapine is rapidly absorbed after oral dosing, and this is not affected by the presence of food. It demonstrates a linear pharmacokinetic profile, and the half-life ranges between 20 and 40 hours. Steady state is achieved within 3-5 days with daily dosing. Mirtazapine is 85% protein-bound. Although minor gender and age differences have been noted in plasma concentrations, these are believed to be clinically insignificant, and no alterations in dose are recommended for age or gender.

Mirtazapine is extensively metabolized in the liver by the CYP2D6, 1A2, and 3A4 isoenzymes. The only active metabolite, demethyl-mirtazapine, is 10-fold less active than the parent compound. Neither mirtazapine nor its metabolites significantly inhibit CYP isoenzymes, leading to few drug-drug interactions through these mechanisms. Moreover, because mirtazapine is metabolized by multiple CYP enzymes, there is less likelihood that its metabolism will be altered by other drugs.

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