A nurse is caring for a client who has atypical depression and is taking phenelzine

Drug withdrawal

In a study of the use of phenelzine in continuation therapy after recovery from an acute episode of depression, relapse rates were higher in patients subjected to tapered withdrawal than in those who continued taking the therapeutic dose [10].

In a study of the effects of sudden drug withdrawal in 34 patients taking phenelzine and 17 taking tricyclic antidepressants who had been treated for a mean duration of over 9 months, depressed patients taking phenelzine had significantly more symptoms than depressed patients taking tricyclic antidepressants, and a third of them relapsed, compared with a quarter taking the tricyclic [11]. At 3 months follow-up 47% of the patients taking phenelzine had resumed treatment compared with 23% taking the tricyclic. An attempt to distinguish between withdrawal symptoms and relapse on the basis of the rapidity and severity of symptoms was unsuccessful, but about a third of the patients in both groups developed new symptoms of adrenergic hyperactivity, including anxiety and perceptual disturbances.

Acute psychotic symptoms have been reported in two young women shortly after withdrawal of long-term phenelzine 90 mg/day [12].

Drug–drug interactions

See also Cyclobenzaprine; Lithium

Treatment Modalities

Persons with mild to moderate major depression may benefit equally from psychotherapy or medication. Severely depressed patients benefit more from antidepressant medication, alone or in combination with psychotherapy, than from psychotherapy alone. Three types of psychotherapeutic options have proven to be effective for the treatment of depression: CBT, interpersonal therapy (IPT), and problem-solving therapy (PST). The aim of CBT is to modify distorted thoughts and problematic reinforcing behaviors to yield more positive emotions. It may help to prevent relapse in patients with a history of recurrent depression. IPT requires the capacity for insight and targets conflicts and role transitions that may be contributing to depression. In PST, patients learn to cope better with specific everyday problems.

Clinicians face a wide array of antidepressant drug options (Table 10.6). The most commonly prescribed drugs are the second-generation antidepressants: SSRIs, serotonin and norepinephrine reuptake inhibitors (SNRIs), and bupropion. First-generation antidepressants (tricyclic antidepressants [TCAs] and monoamine oxidase inhibitors [MAOIs]) offer similar effectiveness but with more toxicity. Generally, TCAs are avoided because of considerable degrees of dry mouth, constipation, and dizziness; they are relatively contraindicated in patients with coronary artery disease, congestive heart failure, and arrhythmias. TCAs are also potentially fatal in overdose. MAOIs are also used infrequently, even by psychiatrists, because of the many associated dietary restrictions and the potential for hypertensive crisis. The selegiline patch (20-mg formulation) is a MAOI approved by the US Food and Drug Administration (FDA) that does not require dietary tyramine restrictions. Antidepressant selection is based on tolerability, safety, evidence of effectiveness in the patient or a first-degree relative, and cost. The goal of treatment is complete remission of symptoms and return to normal functioning. About 50% of patients achieve full remission with antidepressant therapy, whereas the other half achieve partial remission or are nonresponders. For the first episode, antidepressant treatment may take 1 to several months until remission is achieved, and medication should be continued for another 4–9 months. Some clinicians advocate treatment for at least 1 year to maintain remission for a full annual cycle of holidays and anniversaries. For patients older than 70 years who respond to an SSRI, treatment for 2 years may be considered in order to prevent recurrence. Increasing the dose of the current medication or changing medications is often necessary. For a partial response, the dose of the initial agent should be maximized as tolerated before switching to another medication or adding a second drug. When a partial response continues, the clinician can refer for psychotherapy, change antidepressants, or augment treatment with bupropion, mirtazapine, or a nontraditional agent. Compared with withdrawing one drug and initiating another, combination therapy offers faster effects and avoids withdrawal symptoms when stopping the first agent. Combinations of MAOIs and either SSRIs or TCAs are not recommended because of an increased risk for serotonin syndrome (with confusion, nausea, autonomic instability, and hyperreflexia). Although more research is needed, adding adjunctive atypical antipsychotics, psychostimulants, and thyroid hormone are other potential therapeutic options. Antipsychotics added to SSRIs for treatment-resistant depression show some benefit but also carry significant risks, so they should be used with caution and prescribed in collaboration with a psychiatrist (Shelton and Papakostas, 2008). A Cochrane review of monotherapy treatment with psychostimulants (dexamphetamine, methylphenidate, methyl amphetamine, and pemoline) for moderate to severe depression found short-term improvement in depression symptoms and fatigue (Candy et al., 2008). A second review of 19 controlled trials in adults older than 65 years supported this recommendation for methylphenidate (Hardy, 2009).

Overview

Phenelzine is indicated for the treatment of depression, but because of potential serious side effects, it is not a drug of first-choice. Furthermore, phenelzine is useful in the treatment of therapy-resistant depression, ie, patients who have failed to respond to treatment with selective serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants (TCAs). Phenelzine is also used (unlabeled) to treat drug-resistant chronic migraine, posttraumatic stress disorder, panic disorder, agoraphobia, bulimia nervosa, and social anxiety (Drug Facts and Comparisons, 2015; DrugPoints® System, 2015; Krishnan, 2009).

Psychopharmacology

First, a thorough medical workup should be performed in any new case of mood disorder. The National Institutes of Health (NIH)-sponsored STAR∗D study (Sequenced Treatment Alternatives to Relieve Depression) recommends the initial choice of a selective serotonin reuptake inhibitor (SSRI) (citalopram [Celexa]). In the study, nonresponders were then switched to sertraline (Zoloft) and/or venlafaxine XR (Effexor XR). In clinical practice, other factors have to be weighed when choosing the first antidepressant.Prior response history (italics added) to a specific antidepressant or to an overall treatment modality should take precedence in the first choice of treatment. If such a history is unavailable, any family history of response to a specific treatment should be considered. Response to treatment seems to be similar among blood relatives.Table 5 includes a list of the more common medications used in clinical practice for the treatment of unipolar and bipolar disorder. Given the possibility of manic switch with antidepressants, it is recommended that in bipolar depression, mood stabilizers be started concomitantly with antidepressants.

Although myriad side effects are known to exist for each medication, all SSRIs and serotonin norepinephrine reuptake inhibitors (SNRIs) are generally well tolerated. Any trial of medications should be continued for 4 to 6 weeks before failure is declared. However, clinical judgment in assessing each circumstance, especially regarding suicide risk, is crucial. Often in the initial phase of response, the physical symptom of low energy remits first while cognitive symptoms of depression (persistent thoughts of death) persist. The coexistence of higher energy and thoughts of death may constitute a temporary suicide risk in the initial phase of antidepressant treatment. Currently, biological markers for the prediction of treatment response and side effects are being considered. Psychiatric EEG Evaluation Registry (PEER), by using quantitative EEG technology, compares variations of normal awake EEG readings with a large database of medication responders. Results are available for antidepressants, mood stabilizers, stimulants, second-generation antipsychotics, and so forth. The validity of PEER has been supported by a wealth of published literature; however, more recently the usefulness of PEER has been disputed. The AmpliChip CYP450 Test is a method that predicts side effects by measuring the activity of genes that control the P450 hepatic enzyme system and, implicitly, the ability to metabolize a specific drug. Both methods are promising, but high cost and questions about large individual variability of response, have had so far prevented general use.

Given the risk of suicide, close monitoring during the treatment of major depression is required. The choice of medication and adjustment has to be tailored according to the most dominant initial presentation. For patients with severe insomnia, an SSRI is indicated. If the initial choice (e.g., citalopram [Celexa], escitalopram [Lexapro], or sertraline [Zoloft]) shows little impact in improving sleep, the temporary addition of a sleep aid is a reasonable choice. Alternatively, some clinicians prefer to avoid hypnotics, which may allow close monitoring of the natural improvement in sleep during the first 2 weeks of SSRI treatment. This in turn may predict a good response. In geriatric patients, long-term SSRI treatment has been found to delay progression from mild cognitive impairment to dementia. For many years, in patients with hypersomnia and hyperphagia—a variant known as “atypical depression”—the first choice was a monoamine oxidase inhibitor (MAOI). Currently, for atypical depression, clinicians prefer as a first choice a norepinephrine/serotonin reuptake inhibitor (venlafaxine [Effexor], desvenlafaxine [Pristiq]), or a norepinephrine/dopamine active medication (bupropion [Wellbutrin]). Response to medications is often difficult to predict. Again, early in treatment, a thorough medical workup, which should always include a thyroid panel, should be the norm. Sometimes, switches to other classes of antidepressants (dopamine enhancers, tricyclics) are necessary before a result is obtained. Pharmacologic augmentation with mood stabilizers, neuroleptics, and thyroid hormone has been used in cases of treatment-resistant depression. In cases where severe anxiety, insomnia, and poor appetite dominate the picture, the early addition of a second-generation neuroleptic (olanzapine [Zyprexa]1, quetiapine [Seroquel XR], risperidone [Risperdal]1, aripiprazole [Abilify], and, more recently, cariprazine [Vraylar]1) is recommended (seeTable 5). Medication resistance (after several failed trials) dictates the reassessment of diagnosis to further rule out psychiatric and medical comorbidity. For medication-resistant mood disorders,Table 6 presents a list of further biological treatments. Some of these treatments are promising but have yet to be included as routine choices in some of the most difficult-to-treat patients.

Monoamine oxidase inhibitors (MAOIs)

Phenelzine and tranylcypromine irreversibly and nonselectively inhibit both type A and type B monoamine oxidase. Isoniazid is another irreversible and nonselective MAOI that is used to treat tuberculosis. Nonselective MAOIs reduce the degradation of DA, 5-HT, and NE. Selegiline is a type B-selective MAOI, marketed in the USA as an antiparkinsonian agent, that will be discussed below in the section with other antiparkinsonian drugs. A transdermal form of selegiline for treating depression is available. Type B-selective MAOIs reduce degradation of DA but not 5-HT and NE in usual therapeutic doses.

Phenelzine and tranylcypromine profoundly suppress REM sleep in depressed patients (Landolt et al., 2001; Wilson and Argyropoulos, 2005) with REM rebound reported during withdrawal from the medications (Mayers and Baldwin, 2005). All of the MAOIs have been associated with insomnia, and tranylcypromine, which bears some resemblance to amphetamine structurally, is considered more stimulating than phenelzine. Tranylcypromine also decreased S4 sleep in depressed patients (Nolen et al., 1993).

6.06.7.4.2 Compounds available

Phenelzine is the most widely used and widely studied compound. Isocarboxazid is reported to have fewer side effects than phenelzine and can be useful for patients who respond to the latter drug but suffer from its side effects of hypotension or sleep disorder. Tranylcypromine differs from the other compounds in combining the ability to inhibit MAO with an amphetaminelike stimulating effect. There are more reports of adverse drug and food reactions with tranylcypromine than other MAOIs, so it should be prescribed with particular caution.

Moclobemide is the most recently developed MAOI to be marketed. It differs from the other compounds in selectively binding to MAO-A, which it inhibits in a reversible way. This results in a lack of significant interactions with foodstuffs and a quick offset of action (see below).

Phenelzine

Phenelzine is a non-selective and irreversible monoamine oxidase inhibitor (MAOI) which is used for refractory CM that is not responsive to other pharmacological preventive medications. By inhibiting amine metabolism, phenelzine significantly increases extracellular levels of serotonin, norepinephrine, dopamine, and melatonin. Consequently, tyramine-containing foods can cause a severe hypertensive crisis, and dietary restriction of tyrosine-containing foods is essential when this medication is used. A partial list of restricted foods includes smoked, aged, or pickled meats; fermented products, including alcohol; chocolate; and certain fruits and nuts.

Phenelzine has antidepressant and anti-anxiety effects, and is particularly useful in atypical depression.75 Its use is limited by significant dietary restrictions, adverse events, and the fact that it cannot be used with triptans. Common adverse reactions include hypotension and weight gain, dry mouth, constipation, and insomnia. Liver function abnormalities can also occur. It can be used with close supervision in combination with amitriptyline or beta-blockers, but therapy should be initiated under inpatient observation. A 2007 review demonstrated elevated levels of neurotransmitters in the hypothalamus and amygdala of migraine patients.76 Dosing is generally initiated at 15 mg per day and slowly increased to doses as high as 75 mg. The average dose in CM is typically 45 mg qd.

Drug administration

Monoamine Oxidase Inhibitors

The MAO antidepressants include phenelzine (Nardil) and tranylcypromine (Parnate). These drugs are infrequently used because of the potential for severe reactions with many classes of drugs, both psychiatric and nonpsychiatric. MAO inhibitors can interact with sympathomimetic agents such as epinephrine, amphetamines, decongestants, and even excessive amounts of caffeine and can result in hypertensive crisis. MAO inhibitors should be stopped at least 2 weeks before elective surgical procedures to allow complete elimination. If emergency surgery is necessary, the anesthesiologist should be notified so that sympathomimetic agents can be avoided and careful monitoring can be performed. A poorly understood and potentially fatal interaction can occur between MAO inhibitors and meperidine (Demerol). Patients become agitated, disoriented, cyanotic, hyperthermic, hypertensive, and tachycardic. The MAO inhibitors may also interact with the SSRIs, leading to autonomic instability, hyperthermia, rigidity, myoclonus, confusion, and coma. There should be at least a 2-week interval between using MAO inhibitors and agents of these classes. Because long-term use of fluoxetine (Prozac) can saturate the tissues, the interval between long-term fluoxetine and MAO inhibitors should be 5 weeks.