Chapter 19. Antidepressant Agents

Major depression is one of the most common forms of mental illness in the United States with as many as 6% of the population depressed at any given moment (point prevalence), and an estimated 10% of people becoming depressed during their lifetime (lifetime prevalence). The symptoms of depression can be both psychologic and physiologic, and are often subtle and unrecognized by patients and health-care professionals. Symptoms may include intense feelings of sadness and despair, sleep disturbances (too much or too little), anorexia, fatigue, somatic complaints, and suicidal thoughts.

Depression is a heterogeneous disorder that has been classified as (1) “reactive” or “secondary” depression (most common), occurring in response to stimuli such as grief or illness; (2) “endogenous” depression or major depressive disorder, a genetically determined biochemical disorder of depressed mood without any obvious medical or situational causes, manifested by an inability to experience ordinary pleasure or to cope with ordinary life events; and (3) depression associated with bipolar affective (manic-depressive) disorder.

Physical therapists may encounter patients taking antidepressant medications under a number of circumstances. Many patients who have experienced life-changing disabilities become depressed and may require medication for a limited time to control their depression. Other patients may have a history of chronic depression not related to their therapy diagnosis and require long-term treatment. Drugs used in treating depressive disorders are highly effective in some patients but only modestly, or not at all, effective in others. No patients are cured. The major subclasses of antidepressant drugs are outlined in Figure 19–1.

The amine hypothesis of mood postulates that brain amines, particularly norepinephrine (NE) and (serotonin, 5-HT), are neurotransmitters in pathways that function in the expression of mood. According to the hypothesis, a functional decrease in the activity of such amines is thought to result in depression; a functional increase in activity results in mood elevation. The amine hypothesis is largely based on studies showing that drugs (such as reserpine) that deplete central amines cause depression, and that most drugs capable of alleviating the symptoms of a major depressive disorder enhance the actions of the neurotransmitters 5-HT and NE in central synapses. Difficulties with this hypothesis include the facts that (1) postmortem studies do not reveal any decreases in the brain levels of NE or 5-HT in untreated patients suffering from endogenous depression; (2) although antidepressant drugs may cause biochemical changes in brain amine activity within hours, weeks may be required for them to achieve clinical effects; (3) with chronic use, most antidepressants ultimately cause a down-regulation of amine receptors; and (4) at least one effective antidepressant, bupropion, has minimal effects on brain NE or 5-HT.

While the amine hypothesis is undoubtedly too simplistic, it has provided the major experimental models for the discovery of new antidepressant drugs. As a result, all the currently available antidepressant drugs—except bupropion—have significant actions on the metabolism or reuptake of these amines, or are antagonists at presynaptic serotonin or norepinephrinereceptors or both.

Drugs that have been found to have antidepressant activity are grouped into categories based on their chemical structures or purported mechanisms of action. The categories include the tricyclic antidepressants (TCAs), heterocyclics (second- and third-generation drugs that followed the TCAs), monoamine oxidase inhibitors (MAOIs), and selective serotonin reuptake inhibitors (SSRIs). Table 19–1 is a selective list of common antidepressant drugs.

Tricyclic Antidepressants

Tricyclic antidepressants (e.g., imipramine, amitriptyline) were the first successful antidepressants. They are structurally related to the phenothiazine antipsychotics and share certain of their pharmacologic effects. The TCAs are well absorbed orally but may undergo first-pass metabolism. They have high volumes of distribution and are not readily dialyzable. Extensive hepatic metabolism is required for their elimination; plasma half-lives of 8 to 36 hours usually permit once-daily dosing. Both amitriptyline and imipramine form active metabolites, nortriptyline and desipramine, respectively.

Heterocyclic Antidepressants

These drugs have varied structures and include second-generation antidepressants (e.g., amoxapine, bupropion, maprotiline, trazodone) and newer, third-generation drugs (duloxetine, mirtazapine,nefazodone,venlafaxine). The pharmacokinetics of most of these agents are similar to those of the TCAs. Nefazodone and trazodone are exceptions; their half-lives are quite short and usually require administration two or three times daily.

Monoamine Oxidase Inhibitors

The MAOIs (e.g., phenelzine, tranylcypromine) are structurally related to amphetamines and are orally active. They inhibit both MAO-A, which metabolizes NE, 5-HT, and tyramine, and MAO-B, which metabolizes dopamine. Tranylcypromine is the fastest in onset of effect but has a shorter duration of action (about 1 week) than other MAOIs (2 to 3 weeks). In spite of these prolonged actions, the MAOIs are given daily. It is prudent to assume that the drug effect will persist from 7 days (tranylcypromine) to 2 or 3 weeks (phenelzine) after discontinuance of the drug. These drugs are inhibitors of hepatic drug-metabolizing enzymes and cause many drug interactions.

Selective Serotonin Reuptake Inhibitors

Fluoxetine is the prototype of a group of drugs that are SSRIs. All of them require hepatic metabolism and have half-lives of 18 to 24 hours. However, fluoxetine forms an active metabolite with a half-life of several days (the basis for a once-weekly formulation). Other members of this group (e.g., sertraline, citalopram, escitalopram, fluvoxamine, paroxetine) do not form long-acting metabolites.

Potential sites of action of antidepressants at CNS synapses are shown in Figure 19–2. Most antidepressant drugs appear to cause potentiation of the neurotransmitter actions of norepinephrine, serotonin, or both. The only exception is bupropion, which has an unknown mechanism of action. Long-term use of tricyclics and MAOIs, but not SSRIs, leads to down-regulation of β-adrenergic receptors.

Tricyclic Antidepressants

The acute effect of tricyclic drugs is to inhibit the reuptake mechanisms (NET [NE transporter] and SERT [serotonin transporter]) responsible for the termination of the synaptic actions of NE and 5-HT in the brain. This presumably results in potentiation of their neurotransmitter actions at postsynaptic receptors.

Heterocyclic Antidepressants

Some second-generation drugs inhibit the reuptake of NE (e.g., maprotiline); others have more effect on 5-HT reuptake (e.g., trazodone). The third-generation drugvenlafaxine, although not a tricyclic, is a potent inhibitor of the 5-HT transporter and, at higher doses, of the NE transporter as well. Mirtazapine has a unique action; it increases amine release from nerve endings by antagonism of presynaptic α2 adrenoceptors involved in feedback inhibition. However, antagonism of presynaptic 5-HT2A and 5-HT2C receptors has also been implicated in the antidepressant actions of mirtazapine, nefazodone, and trazodone.

Monoamine Oxidase Inhibitors

The MAOIs increase brain amine levels by interfering with their metabolism in the nerve endings, resulting in an increase in the vesicular stores of NE and 5-HT. When neuronal activity discharges the vesicles, increased amounts of the amines are released, presumably enhancing their actions.

Selective Serotonin Reuptake Inhibitors

The acute effect of the SSRIs is a highly selective action on 5-HT transporters. They block the reuptake of 5-HT without affecting reuptake of other amine neurotransmitters. Because of their selectivity, they produce fewer and less troublesome adverse effects than nonselective antidepressant drugs.

The major indication for these drugs is to treat depression, but a number of other uses have been established by clinical experience and controlled trials.

Depression

Patients with major depression typically vary in their responsiveness to individual agents. Because of more tolerable adverse effects and greater safety in overdose (see discussion below), the newer drugs (SSRIs, certain heterocyclics) are now the most widely prescribed antidepressants. However, none of the newer antidepressants has been shown to be more effective overall than tricyclic drugs. As alternative agents, tricyclic drugs continue to be most useful in patients with psychomotor retardation, sleep disturbances, poor appetite, and weight loss. MAOIs may be most useful in patients with significant anxiety, phobic features, and hypochondriasis. SSRIs may decrease appetite and overweight patients often lose weight on these drugs, at least during the first 6 to 12 months of treatment.

Panic Disorder

Imipramine, a TCA, was first shown in 1962 to have a beneficial effect in the acute episodes of anxiety that have come to be known as panic attacks. Recent studies have shown imipramine to be as effective as MAOIs and benzodiazepines. It has also been demonstrated that SSRIs are effective in panic disorder. In some instances, benzodiazepines are preferred, as they are well tolerated and their clinical effects become evident promptly. Alternatively, if one wishes to avoid the physiologic dependence associated with chronic benzodiazepine use, SSRIs are acceptable for many patients, although they require several weeks to produce full therapeutic effects.

Obsessive-Compulsive Disorder

The SSRIs have been shown to be uniquely effective for treating this disorder. Recent studies have focused on fluoxetine and other SSRIs although clomipramine, a mixed serotonin and norepinephrine uptake inhibitor, may be more potent. Fluvoxamine is marketed exclusively for obsessive-compulsive disorder in the United States.

Chronic Pain

Clinicians in pain clinics have found tricyclics to be useful for treating a variety of chronically painful states that often cannot be definitively diagnosed. Whether such painful states represent depressive equivalents or whether such patients become secondarily depressed after some initial pain-producing insult is not clear. It is even possible that the tricyclics work directly on pain pathways.

Controlled studies of higher doses of venlafaxine and duloxetine, which inhibit both norepinephrine and serotonin uptake, also show efficacy in pain states. SSRIs, however, are not effective for chronic pain.

Other Clinical Uses

TCAs are also used in the treatment of bipolar affective disorders, enuresis, and attention deficit hyperkinetic disorder. In addition to their common use in depressive disorders, the SSRIs are also effective in patients who suffer from generalized anxiety disorders, social phobias, bulimia, and premenstrual dysphoric disorder and may also be useful in the treatment of alcohol dependence. Trazodone is frequently prescribed for insomnia. Bupropion is used for management of patients attempting to withdraw from nicotine dependence.

Most common unwanted effects of antidepressant drugs are minor, but they may seriously affect patient compliance. The more seriously depressed the patient is, the more likely it is that unwanted effects will be tolerated. Adverse effects of various antidepressants are summarized in Table 19–2.

Tricyclic Antidepressants

Some of the adverse effects of TCAs are predictable from their pharmacodynamic actions. These include (1) excessive sedation, lassitude, fatigue, and, occasionally, confusion; (2) sympathomimetic effects, including tachycardia, agitation, sweating, and insomnia; (3) antimuscarinic effects (especially amitriptyline); (4) orthostatic hypotension, electrocardiographic abnormalities, and cardiomyopathies; (5) tremor and paresthesias; and (6) weight gain. Overdosage with tricyclics is extremely hazardous, and the ingestion of as little as a 2-week supply has been lethal. Manifestations of overdose include (1) agitation, delirium, neuromuscular irritability, convulsions, and coma; (2) respiratory depression and circulatory collapse; (3) hyperpyrexia; and (4) cardiac conduction defects and severe arrhythmias. The “3 Cs”—coma, convulsions, and cardiotoxicity—are characteristic.

Heterocyclic Antidepressants

These second- and third-generation drugs have varied adverse effects. Mirtazapine causes weight gain and is markedly sedating, as is trazodone. Amoxapine, maprotiline, mirtazapine, and trazodone cause some autonomic effects. Amoxapine is also a dopaminereceptor blocker and may cause akathisia, pseudo-parkinsonism, and the amenorrhea-galactorrhea syndrome. Adverse effects of bupropion include dizziness, dry mouth, aggravation of psychosis, and, at high doses, seizures. Seizures and cardiotoxicity are prominent features of overdosage with amoxapine and maprotiline. Venlafaxine causes asthenia and somnolence and overdosage is cardiotoxic. Nefazodone is hepatotoxic, and patients and caregivers are advised to be alert for signs and symptoms of liver dysfunction such as anorexia, gastrointestinal complaints, and jaundice.

Selective Serotonin Reuptake Inhibitors

Fluoxetine and the other SSRIs may cause nausea, headache, anxiety, agitation, insomnia, and sexual dysfunction. Jitteriness can be alleviated by starting with low doses or by adjunctive use of benzodiazepines or low-dose trazodone. Extrapyramidal effects early in treatment may include akathisia, dyskinesias, and dystonic reactions. Seizures are a consequence of gross overdosage. A withdrawal syndrome has been described for SSRIs that includes nausea, dizziness, anxiety, tremor, and palpitations.

Monoamine Oxidase Inhibitors

Adverse effects of the MAOIs include hypertensive reactions in response to sympathomimetics, hyperthermia, and CNS stimulation leading to agitation and convulsions. Hypertensive crisis may occur in patients taking MAOIs who consume food or medications that contain high concentrations of sympathomimetics such as tyramine (Table 19–3).

In the absence of sympathomimetics, MAOIs typically lower blood pressure; overdosage with these drugs may result in shock, hyperthermia, and seizures.

Studies suggesting an increased risk of suicide in children and adolescents taking antidepressants have received heavy media attention. While it is not clear that the drugs (rather than the disease) are responsible, the incidence of suicide is increased in untreated as well as treated depressed individuals. For this reason, parents, other family, and caregivers of children and adolescents being treated with antidepressants should be aware of potential warning signs such as agitation, irritability, and unusual changes in behavior, and any other indicators of suicidal tendencies. Monitoring should be done on a daily basis and any changes should be reported to the prescribing practitioner immediately.

Patients may have both pharmacodynamic and pharmacokinetic interactions when taking antidepressants with other drugs. Tricyclic drug interactions include additive depression of the CNS with other central depressants, including ethanol, barbiturates, benzodiazepines, and opioids. Tricyclics may also cause reversal of the antihypertensive action of guanethidine by blocking its transport into sympathetic nerve endings. Less commonly, tricyclics may interfere with the antihypertensive actions of methylnorepinephrine (the active metabolite of methyldopa) and clonidine.

Of the heterocyclic drugs, both nefazodone and venlafaxine are inhibitors of cytochrome P450 isozymes. Through this action, nefazodone inhibits the metabolism of alprazolam and triazolam, and venlafaxine inhibits the metabolism of haloperidol.

The SSRIs are also inhibitors of hepatic cytochrome P450 isozymes, an action that has led to increased activity of other drugs, including TCAs and warfarin. Citalopram and escitalopram cause fewer drug interactions than other SSRIs. A serotonin syndrome was first described for an interaction between fluoxetine and an MAOI. This life-threatening syndrome includes severe muscle rigidity, myoclonus, hyperthermia, cardiovascular instability, and marked CNS stimulatory effects, including seizures. Drugs implicated include MAOIs, TCAs, meperidine, and possibly illicit recreational drugs such as methylenedioxymethamphetamine (MDMA; “ecstasy”). Antiseizure drugs, muscle relaxants, and blockers of 5-HT receptors have been used in the management of the syndrome. Table 19–4 outlines drug interactions observed with antidepressant medications.

Antidepressant drugs are frequently prescribed to patients suffering from stroke, multiple sclerosis, spinal cord injury, amputation, and severe trauma. Therapists treating patients who have sustained a catastrophic injury or illness are therefore likely to encounter the use of antidepressant agents to improve the patient’s mood and feeling of well-being. There is some evidence to suggest that use of these agents early in the rehabilitation process may improve functional gains and outcomes. Effective treatment of depression is however a difficult clinical task. Even with appropriate pharmacologic and psychologic treatment, some patients do not respond. Treatment of 1 month or more may be required before the benefits of drug treatment are realized. Also, the adverse effects of drug treatment vary from individual to individual. Adverse effects must be monitored closely and changes in the drug regimen made until the optimal drug for each individual is identified.

Adverse Drug Reactions

Tricyclics/Heterocyclics

• Sedation
• Orthostatic hypotension
• Sympathomimetic effects (tremor)
• Antimuscarinic effects (constipation, urinary hesitancy, blurred vision)

SSRIs

• Insomnia, agitation (the “jitters”)
• Nausea and diarrhea

MAOIs

• CNS excitation and possible hypertensive crisis
• Postural hypotension

Effects Interfering with Rehabilitation

• Sedation
• Cardiovascular considerations
  • Orthostatic hypotension
  • Hypertensive crisis

Possible Therapy Solutions

• Orthostatic hypotension: compressive garments, tilt table, allow patient’s BP time to adjust to postural changes; monitor response to exercise.

Potentiation of Functional Outcomes Secondary to Drug Therapy

• In many cases, antidepressant medications can help with overall functional outcomes at both the activity and participation levels owing to their psychologic effects.

Brief History: The patient is a 44-year-old male with a primary diagnosis of amputation of the right lower leg secondary to trauma sustained in a motor vehicle accident. The patient was initially treated at a hospital with level 1 trauma status. The patient underwent surgery to remove his leg and foot. The patient was left with an 8-inch stump distal to the knee. While in the hospital, he received standard physical therapy, occupational therapy, and social services. He was discharged to outpatient therapy for further intervention and permanent prosthesis training.

Current Status and Drug Therapy: Upon initial examination at the body functions and structures level, the patient demonstrated moderate weakness in his right lower extremity. The patient had tenderness and increased sensitivity in the residual limb. At the activity level, the patient had limited function with sit-to-stand transfers, gait, and stairs, complaining of significant pain in his right residual limb with all weight-bearing activities. At the participation level, the patient stated he was unable to work and was very concerned since he was self-employed with a lawn and landscaping service. He stated this made him very anxious and unable to sleep at night. He was occasionally taking diazepam at night to help him sleep and tramadol as needed for pain.

Rehabilitation Setting: The patient began rehabilitation intervention consisting of therapeutic exercise, gait training, and activities of daily living training. On several occasions, the therapist noted that the patient complained of not being able to take a deep breath and a burning and “squeezing” feeling in his chest. Upon questioning, he stated that this happened almost every night in the early evening and occasionally during the day. He also stated that he was having a hard time sleeping at night but did not like taking the diazepam as it made him feel “sleepy” in the morning.

Problem/Clinical Options: With the patient’s approval, the physical therapist contacted the patient’s physician to inform him of the patient’s major complaints. The patient subsequently had a complete cardiac work-up that proved negative. The patient’s physician, hypothesizing that he was suffering from secondary depression, prescribed paroxetine twice a day and esomeprazole daily.

Outcome: The patient tolerated this drug regimen with no major adverse reactions. He continued with rehabilitation therapy, and over the next several weeks, he reported an improvement in his sleep pattern as well as a cessation of the burning and squeezing feeling in his chest. The therapist noted an improvement in the patient’s attitude toward rehabilitation and compliance with his home exercise program and prosthetic training. The patient continued with his therapy program and was eventually discharged as independent with all functional activities. He was eventually able to return to work.

Tricyclics

Amitriptyline (generic, Elavil, others)

Oral: 10-, 25-, 50-, 75-, 100-, 150-mg tablets

Parenteral: 10 mg/mL for IM injection

Clomipramine (generic, Anafranil; labeled only for obsessive-compulsive disorder)

Oral: 25-, 50-, 75-mg capsules

Desipramine (generic, Norpramin, Pertofrane)

Oral: 10-, 25-, 50-, 75-, 100-, 150-mg tablets

Doxepin (generic, Sinequan, others)

Oral: 10-, 25-, 50-, 75-, 100-, 150-mg capsules; 10 mg/mL concentrate

Imipramine (generic, Tofranil, others)

Oral: 10-, 25-, 50-mg tablets (as hydrochloride); 75-, 100-, 125-, 150-mg capsules (as pamoate)

Parenteral: 25 mg/2 mL for IM injection

Nortriptyline (generic, Aventyl, Pamelor)

Oral: 10-, 25-, 50-, 75-mg capsules; 10 mg/5 mL solution

Protriptyline (generic, Vivactil)

Oral: 5-, 10-mg tablets

Trimipramine (Surmontil)

Oral: 25-, 50-, 100-mg capsules

Second-Generation and Subsequent Drugs

Amoxapine (generic, Asendin)

Oral: 25-, 50-, 100-, 150-mg tablets

Bupropion (generic, Wellbutrin)

Oral: 75-, 100-mg tablets; 100-, 150-mg sustained-release tablets

Duloxetine (Cymbalta)

Oral: 20-, 30-, 60-mg capsule

Maprotiline (generic, Ludiomil)

Oral: 25-, 50-, 75-mg tablets

Mirtazapine (Remeron)

Oral: 15-, 30-, 45-mg tablets

Nefazodone (Serzone)

Oral: 50-, 100-, 150-, 200-, 250-mg tablets

Trazodone (generic, Desyrel)

Oral: 50-, 100-, 150-, 300-mg tablets

Venlafaxine (Effexor)

Oral: 25-, 37.5-, 50-, 75-, 100-mg tablets; 37.5-, 75-, 150-mg extended-release tablets

Selective Serotonin Reuptake Inhibitors

Citalopram (Celexa)

Oral: 20-, 40-mg tablets

Escitalopram (Lexapro)

Oral: 5-, 10-, 20-mg tablets

Fluoxetine (generic, Prozac)

Oral: 10-, 20-mg pulvules; 10-mg tablets; 20 mg/5 mL liquid

Oral delayed release (Prozac Weekly): 90-mg capsules

Fluvoxamine (Luvox, labeled only for obsessive-compulsive disorder)

Oral: 25-, 50-, 100-mg tablets

Paroxetine (Paxil)

Oral: 10-, 20-, 30-, 40-mg tablets; 10 mg/5 mL suspension; 12.5-, 25-, 37.5-mg controlled-release tablets

Sertraline (Zoloft)

Oral: 25-, 50-, 100-mg tablets

Monoamine Oxidase Inhibitors

Phenelzine (Nardil)

Oral: 15-mg tablets

Tranylcypromine (Parnate)

Oral: 10-mg tablets

Other

Atomoxetine (Strattera)

Oral: 10-, 18-, 25-, 40-, 60-mg capsule