Evidence demonstrates that antidepressant medications are effective for the treatment of major depression and dysthymia. There are no compelling data, however, to support the use of antidepressant medication for patients with adjustment disorders or other minor depressive disorders. The initial treatment of choice for most patients with an adjustment disorder or other minor depressive episode is “watchful waiting,” which consists of physician support, office counseling, and close observation, with repeat assessment to document improvement, remission, lack of improvement, or possible transformation into major depression. Physicians can also support patient self-management goal setting and problem solving with Ultra-Brief Personal Action Planning (UB-PAP) (discussed earlier). Patients with minor depression who do not improve after 3–6 months of watchful waiting can be treated empirically with a trial of antidepressant medication or referred for psychotherapy.
Communicating With Patients About Medication
Patients initiating antidepressant medication for the first time sometimes are concerned about the stigma associated with their use. Some fear getting “hooked” on the medicine or that it will change their personality in some way. It is important to explain that antidepressants are nonaddictive medicines that can restore the natural balance of neurotransmitters and normalize neural pathways in the brain. It can be helpful to inform the patient about the possibility of experiencing some of the known side effects of the particular antidepressant and to refer to those side effects as an indicator of the drug’s potency to achieve the desired results. Finally, it is important to build a realistic expectation about the tempo of therapeutic effectiveness by letting the patient know that even though the symptoms of depression may persist for a week or two after starting the antidepressant, the healing process has already begun.
Adherence to treatment has been shown to be enhanced when the physician–patient alliance is optimized, when the patient’s attitudes toward and experience with treatment are thoroughly explored, and when the patient’s opinion in treatment decisions is explicitly valued.
The cyclic antidepressants include the TCAs, SSRIs, serotonin norepinephrine reuptake inhibitors (SNRIs), and a noradrenaline and specific serotonin antagonist (NaSSa). The cyclic antidepressants are generally equally effective; however, due to the adverse effect profile of the TCAs, they have been supplanted by the SSRIs, SNRIs, and NaSSa agents. Nevertheless, TCAs are still commonly employed as second-line antidepressants in patients who do not respond to first-line agents and for augmentation therapy.
Antidepressants illicit immediate first-dose pharmacological effects on the catecholamine reuptake system; however, these agents only begin to provide some symptom improvement after 1–2 weeks of treatment. An adequate trial of an antidepressant requires a minimum of 4–6 weeks at appropriate doses. Cyclic antidepressant response rates approximate 50–70%; hence, physicians should expect that up to half of the patients they treat with the first antidepressant may not respond. Patients with no response or minimal response should be switched to another agent. Patients with partial response can be managed with augmenting agents. If the first SSRI trial fails, patients may be switched to another SSRI (e.g., bupropion, venlafaxine, mirtazapine, or a TCA). Of note, 25–50% of patients who fail to respond to the first trial of an SSRI will respond to a different SSRI on a second trial. A list of antidepressant side effects, mechanisms of action, and dosages is listed in Table 25-8.
Table 25-8.Commonly used antidepressants. ||Download (.pdf) Table 25-8. Commonly used antidepressants.
|Drug ||Usual Daily Oral Dose (mg) ||Usual Daily Maximum Dose (mg) ||Sedative Effects* ||Anticholinergic Effects* ||Cost per Unit ||Cost for 30 Days Treatment Based on Maximum Dosage† |
|Citalopram (Celexa) ||20 ||40 ||<1 ||1 ||$2.53/40 mg ||$75.90 |
|Escitalopram (Lexapro) ||10 ||20 ||<1 ||1 ||$5.02/20 mg ||$150.60 |
|Fluoxetine (Prozac, Sarafem) ||5–40 ||80 ||<1 ||<1 ||$2.67/20 mg ||$320.40 |
|Fluvoxamine (Luvox) ||100–300 ||300 ||1 ||<1 ||$2.64/100 mg ||$237.60 |
|Nefazodone (Serzone) ||300–600 ||600 ||2 ||<1 ||$1.92/200 mg ||$172.80 |
|Paroxetine (Paxil) ||20–30 ||50 ||1 ||1 ||$2.65/20 mg ||$159.00 |
|Sertraline (Zoloft) ||50–150 ||200 ||<1 ||<1 ||$2.85/100 mg ||$171.00 |
|Vilazodone (Viibryd) ||40 ||40 ||<1 ||<1 ||$4.74/20 mg ||$147.20 |
|Tricyclic and Clinically Similar Compounds |
|Amitriptyline (Elavil) ||150–250 ||300 ||4 ||4 ||$1.16/150 mg ||$69.60 |
|Amoxapine (Asendin) ||150–200 ||400 ||2 ||2 ||$1.67/100 mg ||$200.40 |
|Clomipramine (Anafranil) ||100 ||250 ||3 ||3 ||$1.40/75 mg ||$149.70 |
|Desipramine (Norpramin) ||100–250 ||300 ||1 ||1 ||$1.50/100 mg ||$135.00 |
|Doxepin (Sinequan) ||150–200 ||300 ||4 ||3 ||$1.15/100 mg ||$103.50 |
|Imipramine (Tofranil) ||150–200 ||300 ||3 ||3 ||$1.22/50 mg ||$219.60 |
|Maprotiline (Ludiomil) ||100–200 ||300 ||4 ||2 ||$1.60/75 mg ||$192.00 |
|Nortriptyline (Aventyl, Pamelor) ||100–150 ||150 ||2 ||2 ||$1.46/50 mg ||$131.40 |
|Protriptyline (Vivactil) ||15–40 ||60 ||1 ||3 ||$3.07/10 mg ||$552.60 |
|Monoamine Oxidase Inhibitors |
|Phenelzine (Nardil) ||45–60 ||90 ||… ||… ||$0.84/15 mg ||$151.20 |
|Selegiline transdermal (Emsam) ||6 (skin patch) ||12 ||… ||… ||$23.77/6 mg patch ||$713.02 |
|Tranylcypromine (Parnate) ||20–30 ||50 ||… ||… ||$1.25/10 mg ||$187.50 |
|Other Compounds |
|Bupropion SR (Wellbutrin SR) ||300 ||400‡ || ||<1 ||$3.59/200 mg ||$215.40 |
|Bupropion XL (Wellbutrin XL) ||300§ ||450§ || ||<1 ||$4.77/300 mg ||$286.20 |
|Desvenlafaxine (Pristiq) ||50 ||100 ||1 ||<1 ||$5.41/100 mg ||$162.30 |
|Duloxetine (Cymbalta) ||40 ||60 ||2 ||3 ||$6.65/60 mg ||$199.50 |
|Mirtazapine (Remeron) ||15–45 ||45 ||4 ||2 ||$2.80/30 mg ||$85.53 |
|Trazodone (Desyrel) ||100–300 ||400 ||4 ||<1 ||$0.73/100 mg ||$87.60 |
|Trimipramine (Surmontil) ||75–200 ||200 ||4 ||4 ||$5.78/100 mg ||$346.80 |
|Venlafaxine XR (Effexor) ||150–225 ||225 ||1 ||<1 ||$4.67/75 mg ||$420.30 |
The TCAs have fallen out of favor predominantly because of their adverse effects and toxicity profile in the overdose setting. Common antimuscarinic effects include dry mouth, blurred vision, constipation, urinary retention, and sinus tachycardia; histamine receptor blockade effects include sedation, drowsiness, and weight gain; and alpha-1 receptor blockade effects include orthostatic hypotension and sedation. The TCAs also possess quinidine-like effects, such as QRS and QTc prolongation, which can predispose to ventricular dysrhythmias and torsades de pointes—especially in the overdose setting, or in patients with preexisting cardiac disease. A TCA overdose is a medical emergency, with significant risk of lethality. Tricyclic antidepressants lower the seizure threshold, with the potential for refractory seizures in overdose. To minimize the risk of lethal overdose in patients with suicidal ideation, principles of prudent care suggest that only limited amounts of TCAs should be prescribed at any one time (e.g., 7–10 days supply, especially in higher doses). Secondary amines, such as desipramine and nortriptyline, are favored over tertiary amines, such as amitriptyline and imipramine, because of a lower propensity to induce antimuscarinic adverse effects, less orthostatic hypotension, and less sedation. The adverse effects of the TCAs are dose related, and can be minimized by starting patients on low doses, and titrating upward slowly. Though the newer antidepressants seem to be generally as effective as the TCAs for the broad category of major depression, these older agents may be more effective for the more severe depressive disorders and, especially depression with melancholic features.
Selective Serotonin Reuptake Inhibitors
There are five SSRIs approved for major depression in the United States—fluoxetine, paroxetine, sertraline, citalopram, and escitalopram. The SSRIs have replaced the TCAs as first-line agents for major depression because they are generally better tolerated and are not life-threatening in overdose. Selective serotonin reuptake inhibitors are virtually free of antimuscarinic, antihistaminic, and antiadrenergic side effects. All SSRIs are equally effective; therefore, choice of any particular SSRI is generally based on side effect profiles, pharmacokinetics, drug interactions, dosage forms, cost, formulary availability, and so on. Table 25-9 demonstrates comparative SSRI adverse effects. As a class, many SSRIs have also been shown to be effective for PD, GAD, OCD, social anxiety disorder, PTSD, premenstrual dysphoric disorder, and bulimia nervosa. Fluoxetine is the only SSRI with an FDA indication for the treatment of childhood or adolescent depression and fluoxetine paroxetine, and sertraline have FDA indications for the treatment of childhood and adolescent OCD. Vilazodone, a new SSRI, is also a partial agonist at the 5HT1A receptors and appears to have less sexual dysfunction and potential for weight gain. With the exception of fluoxetine and paroxetine, SSRIs show very little inhibition of liver isoenzyme systems. Because of a common SSRI discontinuation syndrome, marked by GI and autonomic signs and symptoms, physicians taking patients off these medications should taper them slowly. Withdrawal from paroxetine seems to be more problematic than other SSRIs. Brief use of the long-acting SSRI fluoxetine (for several days) can be used to help “cover” SSRI withdrawal effects when discontinuing other SSRIs. In the overdose setting, SSRIs can cause dose-related toxicity, manifesting with nausea and vomiting, tremor, myoclonus, dysrhythmias, and seizures—plausibly all manifestations of the serotonin syndrome.
Table 25-9.Comparative adverse effects of SSRIs.*
Gastrointestinal Adverse Effects
The SSRIs inhibit serotonin reuptake, thereby activating 5-HT3 receptors, which can cause nausea and vomiting in 10–15% of patients. Due to desensitization of the 5-HT3 receptors, tolerance to nausea and vomiting usually occurs within 1–2 weeks. Short-term use of cyproheptadine (5-HT3 receptor antagonist) may decrease uncomfortable nausea and vomiting. To minimize GI irritation, nausea, and vomiting, it is useful to administer the SSRIs with food. Dose-related diarrhea is also a common adverse effect of the SSRIs, with the possible exception of paroxetine which possesses mild-to-moderate anticholinergic effects and can cause constipation.
Weight Gain & Weight Loss
Both weight gain and weight loss have been reported with the SSRIs. The incidence of SSRI-induced weight gain greater than 5–10% of body weight can approach 25%, especially in females and, especially in patients using paroxetine (possibly due to its anticholinergic effects). Addition of bupropion may decrease SSRI-induced weight gain. Anorexia and weight loss have also been reported during early treatment, especially in overweight individuals with carbohydrate cravings, underweight depressed patients, bulimics, or patients using fluoxetine.
Syndrome of Inappropriate Antidiuretic Hormone Secretion
A clinically relevant and underappreciated adverse effect of the cyclic antidepressants is the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Syndrome of inappropriate antidiuretic hormone secretion presents with serum hyponatremia and hypoosmolality, and urinary hypernatremia and hyperosmolality. This syndrome is caused by an excessive release of antidiuretic hormone, presenting with signs and symptoms such as nausea, vomiting, weakness, fatigue, confusion, and seizures. Syndrome of inappropriate antidiuretic hormone secretion has been reported with all antidepressants, and is reversible upon dose reduction or discontinuation. Management also includes fluid restriction and demeclocycline. Syndrome of inappropriate antidiuretic hormone secretion is more common in the context of tobacco use.
Many physicians, including psychiatrists are still unaware of recent reports (mostly retrospective case-controlled studies) associating SSRIs with a plethora of bleeding diatheses including GI bleeding, epistaxis, petechiae, purpura, and ecchymosis. Approximately 95% of serotonin is stored in the platelets, and serotonin is one of many chemotactic factors responsible for platelet aggregation. SSRIs possess an aspirin-like effect and inhibit platelet aggregation, but the potency and duration of this effect is not yet well elucidated. When SSRIs are administered with nonsteroidal antiinflammatory drugs (NSAIDs), the risk of NSAID-induced gastropathy can increase significantly. Physicians should be cautious when prescribing an SSRI in patients with a history of GI bleeding and in patients who are already taking other antiplatelet medications. In the context of concurrent NSAIDs, aspirin, or other antiplatelet therapy, physicians should consider adding a proton pump inhibitor for prophylaxis of gastropathy.
Decreased libido, orgasmic difficulties or anorgasmia, penile anesthesia, and erectile dysfunction (impotence) are very common adverse effects associated with the SSRIs in men and women. Sexual side effects occur in 25–75% of all patients, a higher prevalence than reported in package inserts because of underreporting and the short duration of clinical trials. The only available cyclic antidepressants that are less likely to cause sexual dysfunction are bupropion and mirtazapine. Sexual dysfunction in males, especially erectile dysfunction has been successfully managed with phosphodiesterase type-5 antagonists, such as sildenafil, tadalafil, and vardenafil. Other medications such as bupropion, yohimbine, amantadine, buspirone, bethanechol, neostigmine, and Ginkgo biloba have all been utilized with mixed results, with no clear evidence of efficacy from randomized, placebo-controlled clinical trials. Some clinicians will attempt a drug holiday, and skip the dose of the SSRI 24 hours prior to sexual activity (not effective with fluoxetine because of its long half-life). Because sexual dysfunction has such a significant impact on quality of life, this problem may be the most common limiting factor in use of SSRIs.
Poison control centers report over 27,000 toxic exposures to SSRIs annually, with 15% of these reporting a serotonin syndrome. The serotonin syndrome can occur in overdose or when two or more serotonergic agents are combined. Table 25-9 lists common serotonergic agents. The serotonin syndrome presents as a clinical triad of autonomic dysfunction (e.g., hyperthermia, labile blood pressure), neuromuscular dysfunction (e.g., clonus, hyperreflexia), and mental status changes (e.g., agitation, delirium). This spectrum of clinical findings can be mild and transient and include akathisia, tremor, and altered mental status; however, it can progress to life-threatening symptoms such as sustained clonus, muscular hypertonicity, and hyperthermia approaching 40°C. Severe serotonin syndrome is a medical emergency. Although it is important for physicians to be aware of the signs, symptoms, and risk factors for the serotonin syndrome, it is also important for physicians treating depression to understand that pharmacological combination and augmentation treatment strategies often include the cautious prescription of two or more medications with proserotonin effects. Bupropion does not have serotonin effects.
Venlafaxine is a bicyclic antidepressant, approved in 1994 as the first dual-acting antidepressant agent to inhibit the reuptake of both norepinephrine and serotonin. These agents are often referred to as SNRIs. At lower doses, venlafaxine exhibits relatively more serotoninergic activity; however, at doses above 150 mg daily the adrenergic and serotonergic effects become more balanced. Venlafaxine is also FDA approved for the management of generalized and social anxiety disorder and PD. The extended release form of the product (XR) has become preferred because it can be used once daily and has much lower propensity to cause nausea, vomiting, and increases in blood pressure (3% of patients on doses of 375 mg experience sustained elevation in blood pressure). Venlafaxine shows very low inhibition of liver isoenzyme systems and has much lower protein binding (about 30%) than most other antidepressants that are very highly protein bound. Discontinuation of venlafaxine is associated with an SSRI-like discontinuation syndrome, requiring gradual taper (or “covering” for withdrawal effects with fluoxetine). Desvenlafaxine is a newer preparation consisting of a metabolite of the desmethyl metabolite of venlafaxine. It offers simpler dosing at a starting dose of 50 mg that is the same as the full continuation dose. This is a modest advantage in that venlafaxine typically requires gradual increases in dosing to avoid GI side effects.
Approved by the FDA in 2004, duloxetine is a bicyclic SNRI antidepressant indicated for MDD, GAD, and diabetic peripheral neuropathic pain, fibromyalgia, and chronic musculoskeletal pain. Duloxetine, like venlafaxine can produce modest increases in blood pressure, nausea, sweating, insomnia, dizziness, and sexual dysfunction. Duloxetine is metabolized by CYP-1A2 and -2D6, and is a -2D6 inhibitor. Of clinical importance, physicians should be aware that when duloxetine is administered with 1A2 inhibitors, such as fluvoxamine or ciprofloxacin, or 2D6 inhibitors, such as paroxetine, duloxetine serum concentrations can increase considerably. Duloxetine should not be used in patients with a creatinine clearance less than 30 mL/min due to significant accumulation of the parent (two-fold) and numerous metabolites (nine-fold). Duloxetine has been associated with hepatotoxicity; in controlled trials, 1% of the patients experienced elevations in liver enzyme tests three times the upper limit of normal. Duloxetine is best avoided in patients with a history of alcohol abuse or hepatic disease, and in patients receiving concomitant hepatotoxic agents.
Mirtazapine, a tetracyclic noradrenaline and specific serotonin antidepressant (an NaSSa agent), is a potent serotonin-2 (5-HT2), serotonin-3 (5-HT3), and central alpha-2-adrenergic receptor antagonist. Advantages of mirtazapine include the following: it is less likely to cause sexual dysfunction, may reduce sleep latency and prolong sleep duration, may have anxiolytic effects, is relatively devoid of alpha-1 blocking effects such as orthostatic hypotension, and may cause less GI adverse effects than the SSRIs. Mirtazapine is a potent appetite stimulant, causing substantial weight gain in many patients. This can be advantageous in patients who are cachectic and nutritionally deficient, such as debilitated elderly, and cancer and HIV patients. However, in obese, diabetic, and patients with cardiovascular diseases, mirtazapine-induced weight gain is undesirable, and has been associated with deleterious effects on the lipoprotein profile (increased cholesterol and triglycerides). Patients should be warned about this side effect and often refuse to take it for this reason. Mirtazapine possesses significant antihistaminergic and minimal antimuscarinic effects, with the potential for considerable drowsiness, dry mouth, and constipation. Mirtazapine has a very low incidence of transient rise in liver enzymes (2%) and severe neutropenia or reversible agranulocytosis (0.1% incidence). It may be prudent for physicians to check white counts at initiation of the medication, semiannually, and with occurrence of infectious illnesses. Mirtazapine is unlikely to have clinically significant effects on the metabolism of other medications through liver enzyme systems.
The monocyclic antidepressant bupropion inhibits the reuptake of norepinephrine and dopamine into presynaptic neurons and is referred to as a norepinephrine dopamine reuptake inhibitor (NDRI). Bupropion does not inhibit serotonin reuptake and does not cause the serotonin syndrome. Bupropion is also indicated for smoking cessation under the trade name Zyban. Bupropion may enhance energy and motivation due to norepinephrine- and dopamine-induced activating effects. However, bupropion’s activating effect can also cause agitation, irritability, aggression, vivid dreams, nightmares, and insomnia. Despite this pronorepinephrine and prodopamine effect, only 2% of patients on this medication demonstrate elevations in blood pressure. Bupropion may be used for sexual dysfunction, it may promote weight loss, and it has a lower propensity to induce mania in patients with a bipolar diathesis.
Bupropion is contraindicated in patients with seizure disorders, bulimia, anorexia, and alcohol withdrawal. Bupropion-induced seizure disorders are dose related, and total daily doses above 450 mg, or single doses above 150 mg of immediate-release dosage or 200 mg of the sustained-release dosage forms increase the risk of seizures and should be avoided. Up to 450 mg of the XL form of the medication can be prescribed once a day, which is a major advantage for improving adherence. Bupropion has been shown to inhibit selective liver isoenzyme systems.
Black Box Warning on Antidepressant-Induced Suicide Ideation in Children & Adolescents
In 2004, the FDA issued a “black box” warning that the use of antidepressant medication in children and adolescents may be associated with an increase in suicide ideation and suicide attempts. In 2007, the “black box” warning was expanded to include young adults up to the age of 24 years. In brief, the warning results from a pooled analysis of 4400 subjects in 24 placebo-controlled drug trials with nine different antidepressant medications in children and adolescents for treating depression or OCD. The study found prevalence rates of treatment-emergent suicidal thoughts or suicide attempts in 4% of all patients in the active medication group, compared to 2% of patients taking placebo (a statistically significant difference). There were no completed suicides in any of the studies. Similar pooled analyses in adults found no difference between active drug and placebo in studies totaling more than 50,000 patients. The black box recommends that when prescribing antidepressant medication in children, adolescents, and young adults, physicians should warn patients and families to report immediately any increase in agitation or thoughts of suicide, and physicians should monitor patients through regular and frequent follow-up visits.
Physicians should also be aware of some important general epidemiologic findings. In the decade before this warning was issued, suicide attempts and completed suicides decreased significantly in children and adolescents, somewhat paralleling the increased use of antidepressant medications in the population. Since 2004, however, use of these medications in children and adolescents has decreased by 25%, and of interest and concern, rates of suicide attempts and completions in children and adolescents have increased for the first time in over a decade. Furthermore, large observational studies have documented that the risk of a suicide attempt actually decreases after patients begin taking medication and that communities with higher rates of antidepressant use have, on average, lower rates of suicide.
Whenever prescribing a new medication, practitioners must consider the possibility of drug–drug interactions. In addition, the use of the new drug in combination with another drug the patient is already taking may create a new condition of potential risk (e.g., additive sedative risks or potential serotonin syndrome). Because antidepressants are in such common use, questions of potential antidepressant drug interactions become issues of daily importance to most physicians, especially in the medically ill or the elderly.
Physicians should routinely use an electronic database to check potential drug interactions whenever they prescribe a new medication. They should understand the basic principles of enzyme substrates and enzyme inhibitors to be able to better interpret the results they receive from such an electronic database check on drug interactions.
All antidepressant medications are metabolized by cytochrome P450 liver enzyme subsystems. That is, they are substrates for one or more major P450 isoenzyme systems 1A2, 2C9, 2C19, 2D6, and 3A4. While all antidepressants are metabolized in the liver, only some of the SSRIs are moderate inhibitors of either 2C19 (fluoxetine and sertraline) or 2D6 (fluoxetine and paroxetine). Fluoxetine and paroxetine, for example, are moderate 2D6 inhibitors. As such, these drugs inhibit the metabolism of drugs metabolized by the 2D6 subsystem, for example, several beta-blockers, some antipsychotic medications, most TCAs, some benzodiazepines, and the over-the-counter cough suppressant dextromethorphan. When dextromethorphan is combined with fluoxetine or paroxetine, its plasma levels can increase significantly, which could theoretically increase the likelihood of a serotonin syndrome. Also, some SSRIs may inhibit the hepatic 2D6-mediated conversion of several prodrug-like opioids into their active analgesic metabolites, such as codeine to morphine, oxycodone to oxymorphone, and hydrocodone to hydromorphone. Clinically, this inhibition could theoretically decrease the analgesic effect of the opiates listed above. Among the SSRIs, sertraline, citalopram, and escitalopram present the least inhibition of 2D6, while mirtazapine and venlafaxine also have little effect on 2D6.
Clinicians should evaluate the probability, outcome, and risk of drug–drug interactions prior to prescribing antidepressants. In most settings, an alternative agent that does not interact can be prescribed. When patients are receiving drugs that can interact with each other, patients should be counseled on the signs and symptoms of toxicity, and clinicians should heighten monitoring techniques. Patients should be advised that using only one pharmacy allows the pharmacist to maintain a complete, comprehensive, and accurate medication profile and improves the likelihood that the pharmacist will also detect potential problematic drug–drug interactions.
Pharmacogenomics refers to the interaction of multiple genes in determining drug response. For example, genetic polymorphisms in the serotonin transporter gene have been associated with differential SSRI response rates. Some individuals have been shown to have differential activity levels of 2C19 and 2D6 isoenzymes—some patients are “extensive” metabolizers (high activity) and some are “poor” metabolizers (low enzyme activity). Of interest to researchers is that the prevalence rates of “poor metabolizers” vary by ethnicity: 30% of Asians, 10% of African Americans, and 5% of whites are poor metabolizers. From a clinical perspective, given the same dose of drug, poor metabolizers are likely to have much higher blood levels of the medication than extensive metabolizers. Why some individuals are more sensitive to lower doses of medication and/or respond better to lower doses, may be secondary to this genetically determined rate of metabolism, though how to apply this information clinically has not been clearly established.
The FDA has licensed and accredited several laboratories to provide DNA testing as well as blood tests for determination of CYP-2C9, -2C19, -2D6, and -1A2 genotypes. Although these tests are currently available, they have not yet gained widespread acceptance. The next decade will probably witness great progress in pharmacogenomics, such that testing and genomic-based medication algorithms will become part of the routine practice of medicine.
Abrupt withdrawal of SSRIs, usually within 24–48 hours may cause a discontinuation syndrome consisting of a constellation of somatic, neurologic, and psychological symptoms. These symptoms include GI complaints, headache, fever, malaise, vivid dreams, myalgias, paresthesias, “electric shock-like” sensations, worsened mood, irritability, anxiety, confusion, and forgetfulness. These symptoms can be extremely uncomfortable, even leading to emergency room visits, but they are not life threatening. The incidence of the SSRI discontinuation syndrome may be as high as 40%, but the most common and most severe withdrawal syndrome is most commonly associated with paroxetine, probably due to its short half-life (21 hours) and the absence of any active metabolites. All of the SSRIs except for fluoxetine can cause this syndrome. Fluoxetine is unlikely to cause the discontinuation syndrome because of its long half-life (4–14 days, plus its active metabolite norfluoxetine), and hence has a self-tapering discontinuation mechanism. Venlafaxine, duloxetine, trazodone, and mirtazapine have also been associated with the discontinuation syndrome. Treatment of the discontinuation syndrome consists of reinstituting the SSRI and taper more slowly, or substitute the SSRI with one or two doses of fluoxetine (10–20 mg). In summary, all known antidepressants, with the possible exception of fluoxetine and bupropion should be withdrawn very gradually to avoid the discontinuation syndrome.
Despite the absence of clear evidence, clinicians commonly observe a tolerance phenomenon or poop-out syndrome that may occur in 10–20% of patients who have successfully responded to antidepressant therapy and remain compliant. Possible mechanisms for this observed tachyphylaxis include adaptation of central nervous system receptors via upregulation and decreased receptor density, disease severity or exacerbation, loss of a placebo effect, unrecognized rapid cycling, accumulation of a less potent or competitively antagonistic metabolite, or drug interactions. Enzyme-inducing medications, such as St. John wort, phenytoin, barbiturates, carbamazepine, oxcarbazepine, rifampin, and rifabutin, may increase the hepatic metabolism of non-CYP-2D6 substrate antidepressants, thus decreasing plasma levels. For example, phenobarbital has been associated with a 25% decrease in the area under the paroxetine serum concentration–time curve; St. John wort has been associated with a 22% decrease in the area under the serum concentration–time curve of amitriptyline and a 41% decrease in its metabolite nortriptyline; and phenobarbital can decrease the plasma levels of mirtazapine by 60%. Additionally, clinicians should be suspicious of a lack of compliance in all patients with the poop-out syndrome. Management of the poop-out syndrome includes increasing antidepressant doses, switching to an alternative agent, or adding augmentation therapy.
After an antidepressant at maximal doses has produced only a partial response, with persistent residual symptoms, experts usually recommend consideration of augmentation therapy, which consists of adding another agent to the antidepressant currently in use. Quantitative assessment with the PHQ-9 can help clinicians make decisions about when to initiate augmentation therapy.
Clinicians can use the following guideline.
When a depressed patient experiences a significant clinical improvement (as manifested by a drop in PHQ-9 score by 5 points or more), but fails to reach remission (PHQ <5) within a minimum of 1 month after the dose of the initial antidepressant is raised to its maximum, then consider augmentation therapy.
The only two augmentation agents with a substantial evidence base include lithium carbonate (300–1200 mg) and triiodothyronine (T3, 25–50 μg). More commonly used agents, however, include use of a second antidepressant from a different class (e.g., bupropion, venlafaxine, and mirtazapine), buspirone (a 5-HT1A receptor agonist, approved for GAD), pindolol (beta-blocker), atypical antipsychotics (e.g., aripiprazole and olanzapine are FDA approved for augmentation), and psychostimulants (e.g., methylphenidate, dextroamphetamine, and modafinil).