Other Antidepressants

Monoamine oxidase inhibitors such as tranylcypromine (Parnate) for a time went into disfavor because of their extreme toxicity to the central 

Several so-called atypical antidepressants are currently on the market in the United States. This brief review is not intended to be comprehensive in regard to their adverse effects. 

Venlafaxine (Effexor), approved by the FDA in December 1993, was described in more detail early in this chapter. It is one of the newer antidepressants implicated in causing suicidality. It is a NSRI that also strongly inhibits the reuptake of epinephrine. Its profile is very similar to the SSRIs in producing stimulation, including anxiety, nervousness, insomnia, anorexia, and weight loss. It causes the various emotional and behavioral abnormalities that go along with stimulation, such as agitation and mania, and has been associated with hostility, paranoid reaction, psychotic depression, and psychosis. It can cause hypertension. 

In my experience, any of the antidepressants can produce a variety of unexpected and sometimes severe emotional reactions, including apathy, lethargy, and depression, or euphoria, paranoia, and mania. Frequently, these adverse effects are mentioned as possibilities on the FDA-approved label. 

Keep in mind that as a group, antidepressants affect diverse neurotransmitter systems in a complex, little understood manner. Even the supposedly selective SSRIs end up producing generalized dysfunction in the brain and hence the mind. 

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MAO Is The MAOIs are less frequently prescribed than other antidepressants, probably because of the risk of hypertensive crisis when food containing tyramine is ingested during M AOI therapy. Fhtients receiving MAOIs... 

Anxiety disorders are common in the population of opioid-addicted individuals however, treatment studies are lacking. It is uncertain whether the frequency of anxiety disorders contributes to high rates of illicit use of benzodiazepines, which is common in methadone maintenance programs (Ross and Darke 2000). Increased toxicity has been observed when benzodiazepines are co-administered with some opioids (Borron et al. 2002 Caplehorn and Drummer 2002). Although there is an interesting report of clonazepam maintenance treatment for methadone maintenance patients who abuse benzodiazepines, further studies are needed (Bleich et al. 2002). Unfortunately, buspirone, which has low abuse liability, was not effective in an anxiety treatment study in opioid-dependent subjects (McRae et al. 2004). Current clinical practice is to prescribe SSRIs or other antidepressants that have antianxiety actions for these patients. Carefully controlled benzodiazepine prescribing is advocated by some practitioners. 

There is, however, a unique risk in the bipolar form that antidepressant treatment may trigger a switch into mania. This may occur either as the natural outcome of recovery from depression or as a pharmacological effect of the drug. Particular antidepressants (the selective serotonin reuptake inhibitors) seem less liable to induce the switch into mania than other antidepressants or electroconvulsive therapy. Treatment for mania consists initially of antipsychotic medication, for instance the widely used haloperidol, often combined with other less specific sedative medication such as the benzodiazepines (lorazepam intramuscularly or diazepam orally). The manic state will usually begin to subside within hours and this improvement develops further over the next 2 weeks. If the patient remains disturbed with manic symptoms, additional treatment with a mood stabilizer may help. 

Trazodone routinely causes sedation, which is why it is used far more often as an adjunct with other antidepressants for sleep than as a primary agent for the treatment of depression. Priapism is a rare but serious adverse effect in males who take trazodone. In addition, orthostatic hypotension and dizziness are more common with trazodone than with nefazodone because the latter agent has a weaker effect at a-adrenergic receptors and also has a balancing of adrenergic effects owing... 

Although many patients believe that dietary supplements will not interact with medications, recent literature suggests otherwise. Recently, many St. John s wort-drug interactions have been reported in the literature. Cases of patients developing symptoms of serotonin syndrome have been reported with St. John s wort alone and in concomitant therapy with other antidepressants such as monoamine oxidase inhibitors, serotonin reuptake inhibitors, and venlafaxine. St. John s wort may exacerbate the sedative effects of benzodiazepines, alcohol, narcotics, and other sedatives. St. John s wort may decrease the levels of protease inhibitors, cyclosporine, digoxin, and theophylline. 

MAOIs are reserved for the most difficult or refractory panic disorder patients. Side effects and dietary and drug restrictions affect patient acceptance (see Chap. 70 for food and drug restrictions). Fluoxetine must be stopped 5 weeks before phenelzine (or another MAOI) is started. Other antidepressants should be stopped 2 weeks before phenelzine is started. 

Tricyclics and other antidepressants known to be metabolized by CYP2D6. 

Hesse LM, Venkatakrishnan K, Court MH, et al. CYP2B6 mediates the in vitro hydroxyla-tion of bupropion potential drug interactions with other antidepressants. Drug Metab Dispos... 

Studies in mice have shown a hypericum extract to increase exploration in an unfamiliar environment, prolong sedative sleep time, and antagonize the effects of reserpine. Other antidepressant-like effects are found on the water-wheel test, and chronic administration decreased aggression in socially isolated male mice (Okpanyi and Weischer 1987). 

Hypomania and use with other antidepressants One case has been reported of concurrent use of hypericum with an SSRI. Gordon (1998) reported a case of a 50-year-old woman taking 600 mg/day of hypericum for chronic depression. She had discontinued taking Paxil 10 days prior to hypericum and experienced no ill effects at that time. However, she added 20 mg of paroxetine to her regimen of hypericum to improve her sleep. She presented with lethargy, nausea, and weakness, but vital signs and mental status were normal. Following discontinuation of medications, she returned to normal status the next day. 

Harmala alkaloids are potent inhibitors of monoamine oxidase (Callaway and Grob 1998). Thus, if combined with other antidepressants, such as selective serotonin reuptake inhibitors, there is potential for serious side effects. Harmaline or its metabolites also cross the placental barrier (Okonmah et al. 1988). 

Bupropion is an atypical antidepressant drug that is the only nonnicotine-based prescription medicine approved for smoking cessation by the FDA. Its mechanism of action is presumed to be mediated by its capacity to block neuronal reuptake of dopamine and/or norepinephrine (Fiore et al. 2000). Relative to other antidepressants, bupropion has a relatively high affinity for the dopamine transporter (Baldessarini 2001). There is also evidence that bupropion acts as a functional nicotine antagonist, suggesting another potential mechanism by which bupropion could reduce smoking rates (Slemmer et al. 2000). 

Atypical Antidepressants. The atypical antidepressants are not a true class in the same sense as SSRIs or TCAs. There is no unifying property to these antidepressants. Each of these antidepressants is actually a class unto itself that is structurally and functionally different from all other antidepressants. The atypical antidepressants include trazodone (Desyrel), bupropion (Wellbutrin), venlafaxine (Effexor), duloxetine (Cymbalta), nefazodone (Serzone), and mirtazapine (Remeron). 

When switching between a MAOl and other antidepressants that affects serotonin activity, the first medication must be allowed to wash out of the patient s system before the new antidepressant is started. The duration of this washout period is determined by the half-life of the antidepressant that is being discontinued. If a washout is neglected, then a potentially dangerous serotonin syndrome may result. 

Other Antidepressants. Antidepressant refinements for the next 30 years primarily consisted of the development of new TCAs. However, in 1988, a novel antidepressant class, the selective serotonin reuptake inhibitors (SSRIs), was introduced in the United States. The chief innovation of the SSRIs was that they afforded the comparable effectiveness of the TCAs with fewer side effects and minimal toxicity. The debut of the SSRIs coincided with the reworking of the nosology of the anxiety disorders in DSM-III and DSM-IV. As a result, the SSRIs have been studied extensively in each of the respective anxiety disorders and in many cases have obtained FDA approval for the treatment of one or more of these anxiety syndromes. The SSRIs currently available in the United States include citalopram (Celexa), escitalo-pram (Lexapro), fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), and sertraline (Zoloft). 

In the past decade, other antidepressants have been introduced. Many of these act, at least in part, via serotonin-mediated mechanisms and, as such, have been tested in the treatment of one or more anxiety disorders. These additional antidepressants include two dual serotonin-norepinephrine reuptake inhibitors (SNRIs),... 

Methylphenidate (Ritalin). Methylphenidate was developed in the late 1950s and its first use was the treatment of what we now call ADHD. Since that time, it has also been approved for the treatment of narcolepsy. Its only other use is the treatment of severe refractory depression either in medically ill patients who need rapid clinical improvement or as an augmentation agent when added to other antidepressants. In the treatment of ADHD, methylphenidate not only improves attention but also reduces hyperactivity and impulsivity. Verbal and physical aggression typically decreases as well. 

Bupropion is an a-aminoketone that is structurally related to amphetamines, and it exhibits unique activity comparable to that of other antidepressants. It is believed that bupropion restores the total amount of norepinephrine in the body. This compound is a poor reuptake inhibitor of dopamine, and does not exhibit anticholinergic activity or inhibit MAO. Its efficacy as an antidepressant is comparable to that of tricyclic antidepressants, and as a serotonin uptake inhibitor it is comparable to fluoxetine. It is preferable to use amoxapine. Synonyms of bupropion are amphebutamon and wellbutrin. 

The efficacy of fluoxetine in treating patients with moderate depression is comparable to the efficacy of tricyclic antidepressants. It is capable of elevating mood and removing feelings of fear and stress. It does not have a sedative effect. Fluoxetine is used in depression as well as in bulemic neuroses. Use of fluoxetine is preferred in cases when sedative, hypotensive, and anticholinergic side effects caused by other antidepressants are con-traindicative to patients. Prozac is a synonym for fluoxetine. 

Suicidality in children and adolescents Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of trazodone or any other antidepressant in a child or adolescent must balance this risk with the clinical need. Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Trazodone not approved for use in pediatric patients (see Clinical worsening and suicide risk and Children sections in Warnings). 

Increasing the dosage above 300 mg/day-As with other antidepressants, the full antidepressant effect of the SR formula may not be evident until 4 weeks of treatment or longer. Consider an increase in dosage to the maximum of 400 mg/day given as 200 mg twice/day for patients in whom no clinical improvement is noted after several weeks of 300 mg/day treatment. 

Seizures Bupropion is associated with a dose-related risk of seizures. Discontinue bupropion and do not restart in patients who experience a seizure while on treatment. Use extreme caution when bupropion is administered to patients with a history of seizure, cranial trauma, or other predisposition(s) toward seizure, or prescribed with other agents (eg, antipsychotics, other antidepressants, theophylline, systemic steroids) that lower seizure threshold. 

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