Antidepressant therapies are used in the treatment of depression and numerous anxiety disorders, such as obsessive–compulsive disorder (OCD), posttraumatic stress syndrome (PTSD), and other panic disorders. Antidepressant therapies are also used in the management of neuropathic pain syndromes (Kirkwood et al., 2011).
All antidepressant agents work by increasing the binding of one or more of the central neurotransmitters (norepinephrine, serotonin, and dopamine) to their target receptors, which can occur in several different ways. Antidepressants may enhance the action of these neurotransmitters by decreasing the metabolism of the neurotransmitter and increasing neurotransmitter levels; by decreasing the cellular reuptake of the neurotransmitter, thus leaving higher amounts to exert action at the receptor site in the synapse; or by acting as a substitute neurotransmitter and actively binding to these receptors, thus enhancing activity. They differ in selectivity and the extent to which they affect each of these neurotransmitters, which affects both their therapeutic actions and their side effects (Bloom, 2001; Carl & Johnson, 2006).
Generally, when choosing an antidepressant, the prescribing physician considers the patient’s concurrent drug therapy and disease states in an effort to minimize adverse drug reactions (side effects) and drug interactions. An antidepressant that has worked for the patient or the patient’s family member in the past often will have good antidepressant effects. Concurrent disease states that should be considered include neuropathic pain, enuresis, migraine headache, OCD, PTSD, generalized anxiety disorder, anorexia, bulimia, insomnia, seizure disorders, and cardiovascular disease (Baldessarini, 2001; Jackson, 2002; Kando et al., 2002; Kirkwood et al., 2011; Meyer, 2011; O’Donnell & Shelton, 2011).
The onset of antidepressant action is delayed, and a minimum of 4 wk is needed to assess antidepressant response. The physician should explain this to the patient so that failure to see immediate results does not result in discouragement and discontinuation of therapy during the initial titration phase. Antidepressant therapy should be initiated at low doses and titrated every 1 to 3 days until a usually effective dose is achieved; this dose should be maintained for at least 4 wk in order to assess the therapeutic effect of the medication. This minimizes the time that the patient experiences dose-related side effects, which occur during the titration period (Baldessarini, 2001; Jackson, 2002; Kando et al., 2002; Meyer, 2011; O’Donnell & Shelton, 2011).
Most antidepressants have long half-lives—typically 12 to 36 h. Therefore, they are often administered only once daily. A few antidepressants have a short half-life and are dosed more often than once daily. These include trazodone (Desyrel), nefazodone (Serzone), and venlafaxine (Effexor); these products are also available in slow-release formulations. Several agents have active metabolites that can double or even triple the length of the effects. These include amitriptyline (Elavil), clomipramine (Anafranil), doxepin (Sinequan), imipramine (Tofranil), trimipramine (Surmontil), amoxapine (Asendin), fluoxetine (Prozac), sertraline (Zoloft), and venlafaxine (Effexor). Fluoxetine (Prozac) has a half-life of 50 h and an active metabolite that extends action to 240 h. It comes in a delayed-release formulation that allows once-weekly dosing (Baldessarini, 2001; Chapman et al., 2003; Jackson, 2002; Kando et al., 2002; Meyer, 2011; O’Donnell & Shelton, 2011; Teter et al., 2011).
Patients taking antidepressants for at least 6 wk should not abruptly discontinue the medication but rather should taper the dose before discontinuance. At least 20% of patients who abruptly discontinue antidepressant therapy develop discontinuation syndrome. Symptoms of discontinuation syndrome include flu-like symptoms, insomnia, nausea, imbalance, sensory disturbances, hyperarousal, agitation, crying spells, and irritability. More serious cases can involve development of psychosis, catatonia, or severe cognitive impairment. Discontinuation syndrome is most often associated with long-term use or with use of shorter-acting antidepressants such as bupropion (Wellbutrin; half-life of 12-30 h), duloxetine (Cymbalta; half-life of 8-17 h), and venlafaxine (Effexor; half-life of 3-13 h). Symptoms associated with discontinuation syndrome usually resolve in 7 to 10 days (Guthrie, 2007).
Antidepressants are classified into four categories based on mechanism of action: tricyclic antidepressants (TCA), monoamine oxidase inhibitors (MAOI), selective serotonin reuptake inhibitors (SSRI), and selective serotonin and norepinephrine reuptake inhibitors (SSNRI). SSRI and SSNRI have become preferred over the older TCA and MAOI because their side effect and drug interaction profiles are improved (Baldessarini, 2001; Jackson, 2002; Kando et al., 2002; Meyer, 2011; O’Donnell & Shelton, 2011).
- TCAs. Tricyclic agents (TCAs), which have been available since the 1960s, include amitriptyline (Elavil), clomipramine (Anafranil), doxepin (Sinequan), imipramine (Tofranil), trimipramine (Surmontil), amoxapine (Asendin), desipramine (Norpramin), maprotiline (Ludiomil), nortriptyline (Pamelor), and protriptyline (Vivactil). TCAs block serotonin and norepinephrine reuptake, thus enhancing the availability of these neurotransmitters at the synapse. TCAs are structurally related to the phenothiazine antipsychotic agents. In fact, the significant dopamine-blocking action of amoxapine (Asendin) causes neuroleptic effects and side effects in addition to antidepressant effects. Although TCAs are effective, most have a delayed onset of 2 to 3 wk and require slow upward titration due to their side effects, which include anticholinergic side effects, sedation, and orthostatic hypotension. Once they have been titrated over several weeks to the maximum effects, most TCA can be administered as a single bedtime dose. Some TCAs with strong sedative properties are used at bedtime to assist with depression-associated insomnia. Once the agents of choice, TCAs use as antidepressants has declined because their associated side effects of seizures and cardiac arrhythmias are difficult to treat and can be deadly in the case of an overdose. In addition, because many TCAs have strong anticholinergic effects that can increase sedation, altered cognition, and the risk of falls, their use is discouraged in the elderly. TCAs can cause weight gain, and the side effects of unpleasant taste, altered taste, and xerostomia can affect medication adherence (Baldessarini, 2001; Jackson, 2002; Kando et al., 2002; Meyer, 2011; O’Donnell & Shelton, 2011; Tom-Revson & Lee, 2006).
- MAOIs. Monoamines is another name for the catecholamines, which include the neurotransmitters norepinephrine, epinephrine, and dopamine. The enzyme monoamine oxidase (MAO) metabolizes catecholamines to inactive products. MAO inhibitors (MAOIs) block this metabolism, leaving more active neurotransmitters available to act at the receptors, thus enhancing neurotransmitter effects. MAOIs are antidepressants which first became available in the 1960s and include phenelzine (Nardil), tranylcypromine (Parnate), and isocarboxazid (Marplan). Use of MAOIs in the treatment of depression is limited by serious toxicity associated with interactions with certain medications and foods. MAOIs are generally not considered first-line agents for treating depression due to these interactions and the necessary medication and dietary restrictions. A transdermal form of selegiline (Emsam) was recently introduced for the treatment of major depression. In low doses, selegiline is selective for monoamine oxidase-B and does not pose the risk of many of the food and drug interactions that occur with the monoamine oxidase-A inhibitors. However, because this selectivity is lost in high doses, many of the food and drug interactions exist when the transdermal form (Emsam) is used (Baldessarini, 2001; Jackson, 2002; Jacobson et al., 2007; Kando et al., 2002; Meyer, 2011; O’Donnell & Shelton, 2011).
- SSRIs. Selective serotonin reuptake inhibitors (SSRIs) selectively block the reuptake of serotonin by the cell, thus providing more serotonin at the site of the receptor in the synapse and enhanced effects of serotonin. Their blocking effects on norepinephrine and dopamine neuronal uptake are weak. SSRIs are the agents most often used in the treatment of depression. They are also useful in treating OCD, generalized anxiety disorder, anorexia, bulimia, panic disorder, and PTSD. Compared with TCAs, SSRIs have fewer cardiac side effects and pose less chance of precipitating seizures. However, they do have significant drug interactions that can precipitate a serious condition called serotonin syndrome. Although akathisia is normally associated with antipsychotics, SSRIs can also produce akathisia (Jacobson et al., 2007; Kirkwood, 2011; Tom-Revson & Lee, 2006).
- SSNRIs. Selective serotonin and norepinephrine reuptake inhibitors (SSNRIs) block reuptake of serotonin and norepinephrine and weakly block reuptake of dopamine, resulting in increased levels and effects of these neurotransmitters. SSNRIs include bupropion (Wellbutrin, Zyban), duloxetine (Cymbalta), mirtazapine (Remeron), nefazodone (Serzone), and trazodone (Desyrel). The brand name nefazodone is no longer available due to concerns regarding its hepatotoxicity, but the generic product is still made. Zyban is used to help with smoking cessation, Cymbalta is used to treat neuropathic pain, and Remeron is frequently used to improve appetite and insomnia associated with depression (Baldessarini, 2001; Jackson, 2002; Kando et al., 2002; Meyer, 2011; O’Donnell & Shelton, 2011).
Table 4.1 lists the antidepressants and provides information on dosing and important side effects that can affect rehabilitation. The risk and type of drug interactions vary widely depending on the class of antidepressant used.