Milder forms of depression usually do not require medication therapy and can be managed by psychotherapy and the passage of time. In severe cases—particularly when vegetative signs are significant and symptoms have persisted for more than a few weeks—antidepressant medication therapy is often effective. Medication therapy is also suggested by a family history of major depression in first-degree relatives or a past history of prior episodes.
The antidepressant medications may be classified into four groups: (1) the newer antidepressants, including the SSRIs, SNRIs, and bupropion, vilazodone, vortioxetine, and mirtazapine, (2) the TCAs and clinically similar medications, (3) the MAO inhibitors (Table 25–7), and (4) stimulants. ECT and repetitive transcranial magnetic stimulation are procedural treatments for depression. These modalities are described in greater detail below.
Table 25–7.Commonly used antidepressant medications (listed in alphabetical order within classes). ||Download (.pdf) Table 25–7. Commonly used antidepressant medications (listed in alphabetical order within classes).
|Medication ||Usual Daily Oral Dose (mg) ||Usual Daily Maximum Dose (mg) ||Sedative Effects1 ||Anticholinergic Effects1 ||Cost per Unit ||Cost for 30 Days of Treatment Based on Maximum Dosage2 |
|Citalopram (Celexa) ||20 ||40 ||< 1 ||1 ||$0.14/40 mg ||$4.20 |
|Escitalopram (Lexapro) ||10 ||20 ||< 1 ||1 ||$0.13/20 mg ||$3.90 |
|Fluoxetine (Prozac, Sarafem) ||5–40 ||80 ||< 1 ||< 1 ||$4.20/20 mg ||$504.00 |
|Fluvoxamine (Luvox) ||100–300 ||300 ||1 ||< 1 ||$2.63/100 mg ||$236.70 |
|Paroxetine (Paxil) ||20–30 ||50 ||1 ||1 ||$2.64/20 mg ||$161.10 |
|Sertraline (Zoloft) ||50–150 ||200 ||< 1 ||< 1 ||$2.70/100 mg ||$162.00 |
|Desvenlafaxine (Pristiq) ||50 ||100 ||1 ||< 1 ||$5.80/100 mg ||$179.00 |
|Duloxetine (Cymbalta) ||40 ||60 ||2 ||3 ||$1.92/60 mg ||$57.60 |
|Levomilnacipran (Fetzima) ||40 ||120 ||1 ||1 ||$16.50/80 mg ||$495.00 |
|Milnacipran (Savella) ||100 ||200 ||1 ||1 ||$8.02/100 mg ||$481.20 |
|Venlafaxine XR (Effexor) ||150–225 ||225 ||1 ||< 1 ||$0.63/75 mg ||$56.70 |
|Tricyclic and Clinically Similar Compounds |
|Amitriptyline (Elavil) ||150–250 ||300 ||4 ||4 ||$2.14/150 mg ||$128.40 |
|Amoxapine (Asendin) ||150–200 ||400 ||2 ||2 ||$1.98/100 mg ||$237.60 |
|Clomipramine (Anafranil) ||100 ||250 ||3 ||3 ||$9.70/75 mg ||$1164.00 |
|Desipramine (Norpramin) ||100–250 ||300 ||1 ||1 ||$4.48/100 mg ||$403.20 |
|Doxepin (Sinequan) ||150–200 ||300 ||4 ||3 ||$1.97/100 mg ||$177.30 |
|Imipramine (Tofranil) ||150–200 ||300 ||3 ||3 ||$1.16/50 mg ||$219.60 |
|Maprotiline (Ludiomil) ||100–200 ||300 ||4 ||2 ||$2.34/75 mg ||$280.80 |
|Nortriptyline (Aventyl, Pamelor) ||100–150 ||150 ||2 ||2 ||$0.29/75 mg ||$17.40 |
|Protriptyline (Vivactil) ||15–40 ||60 ||1 ||3 ||$3.30/10 mg ||$594.00 |
|Trimipramine (Surmontil) ||75–200 ||200 ||4 ||4 ||$9.44/100 mg ||$566.40 |
|Monoamine Oxidase Inhibitors |
|Phenelzine (Nardil) ||45–60 ||90 ||… ||… ||$0.84/15 mg ||$151.20 |
|Selegiline transdermal (Emsam) ||6 (skin patch) ||12 ||… ||… ||$70.27/6 mg patch ||$2018.10 |
|Tranylcypromine (Parnate) ||20–30 ||50 ||… ||… ||$3.60/10 mg ||$540.00 |
|Other Compounds |
|Bupropion SR (Wellbutrin SR) ||300 ||4003 ||< 1 ||< 1 ||$3.38/200 mg ||$202.80 |
|Bupropion XL (Wellbutrin XL) ||3004 ||4504 ||< 1 ||< 1 ||$0.55/300 mg ||$32.10 |
|Mirtazapine (Remeron) ||15–45 ||45 ||4 ||2 ||$2.77/30 mg ||$84.90 |
|Nefazodone (Serzone) ||150–600 ||600 ||3 ||1 ||$4.98/200 mg ||$448.20 |
|Trazodone (Desyrel) ||100–300 ||400 ||4 ||< 1 ||$0.21/100 mg ||$25.60 |
|Vilazodone (Viibryd) ||10–40 ||40 ||1 ||1 ||$11.43/40 mg ||$342,90 |
|Vortioxetine (Brintellix) ||10 ||20 ||< 1 ||< 1 ||$16.11/20 mg ||$483.30 |
Hospitalization is necessary if suicide is a major consideration or if complex treatment modalities are required.
Medication selection is influenced by the history of previous response or lack thereof if that information is available. There is mixed and inconclusive evidence about the utility and cost-effectiveness of genetic testing to choose an antidepressant treatment strategy. A positive family history of response to a particular medication may suggest that the patient will respond similarly. If no background information is available, a medication such as sertraline, 25 mg orally daily and increasing gradually up to 200 mg depending on response and side effects, or venlafaxine at 37.5 mg/day and titrated gradually as indicated to a maximum dose of 225 mg/day can be selected and a full trial instituted. The medication trial should be monitored for worsening mood or suicidal ideation with patient assessments every 1–2 weeks until week 6. The STAR*D trial suggests that if there is no response to the first medication, the best alternatives are to switch to a second agent that may be from the same or different class of antidepressant; another option if there is partial response is to try augmenting the first agent with bupropion (150–450 mg/day), lithium (eg, 300–900 mg/day orally), thyroid medication (eg, liothyronine, 25–50 mcg/day orally), or a second-generation antipsychotic (eg, aripiprazole [5–15 mg/day]). The Agency for Health Care Policy and Research has produced clinical practice guidelines that outline one algorithm of treatment decisions (Figure 25–2).
Overview of treatment for depression. (Reproduced from Agency for Health Care Policy and Research: Depression in Primary Care. Vol. 2: Treatment of Major Depression. United States Department of Health and Human Services, 1993.)
Cognitive issues such as concentration and memory problems are common to depression; the evidence shows that these issues sometimes persist even after depression has remitted, with a higher risk in those individuals who have had more depressive episodes.
Psychotic depression should be treated with a combination of an antipsychotic such as olanzapine and an antidepressant such as an SSRI at their usual doses. Mifepristone may have specific and early activity against psychotic depression. ECT is generally regarded as the single most effective treatment for psychotic depression, with remission rates between 60% and 90%.
Major depression with atypical features or seasonal onset can be treated with bupropion or an SSRI with good results. MAO inhibitors appear more effective than TCAs, and a MAO inhibitor may be used if more benign antidepressant strategies prove unsuccessful.
Melancholic depression may respond to ECT, TCAs, and SNRIs, which are preferable to SSRIs. However, SSRIs are often used in the treatment of melancholic depression and are effective in many cases.
Caution: Depressed patients often have suicidal thoughts, and the amount of medication dispensed should be appropriately controlled particularly if prescribing a MAO inhibitor, TCA, and to a lesser extent, venlafaxine. At the same time, adults with untreated depression are at higher risk for suicide than those who are treated sufficiently to reduce symptoms. It has been thought that in children and adolescent populations, antidepressants may be associated with some slightly increased risk of suicidality. One meta-analysis indicates that suicidality persists even after symptoms of depression are treated, suggesting other causes such as increased impulsivity among younger patients. After age 25, antidepressants may have neutral or possibly protective effects until age 65 years or older. The older TCAs have a narrow therapeutic index. One advantage of the newer medications is their wider margin of safety. Nonetheless, even with newer agents, because of the possibility of suicidality early in antidepressant treatment, close follow-up is indicated. In all cases of pharmacologic management of depressed states, caution is indicated until the risk of suicide is considered minimal.
1. SSRIs, SNRIs, and atypical antidepressants
SSRIs include fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram and its enantiomer escitalopram (Table 25–7). The chief advantages of these agents are that they are generally well tolerated, the starting dose is typically a therapeutic dose for most patients, and they have much lower lethality in overdose compared to TCAs or MAO inhibitors. (Notably, citalopram carries a warning regarding QT prolongation in doses above 40 mg, and 20 mg is considered the maximum dose for patients older than 60 years. There is no similar FDA warning for escitalopram.) The SNRIs include venlafaxine, desvenlafaxine, duloxetine, milnacipran, and levomilnacipran. In addition to possessing the strong serotonin reuptake blocking properties of the SSRIs, the SNRIs are also norepinephrine reuptake blockers. The combined serotonergic-noradrenergic properties of these medications may provide benefits in pain conditions such as neuropathy and fibromyalgia as well as conditions such as stress incontinence. The atypical antidepressants are bupropion, nefazodone, trazodone, vilazodone, vortioxetine, and mirtazapine (Table 25–7). All of these antidepressants are effective in the treatment of depression, both typical and atypical. The SSRI medications have been effective in the treatment of panic disorder, bulimia, GAD, OCD, and PTSD.
Most of the medications in this group tend to be activating and are given in the morning so as not to interfere with sleep. Some patients, however, may have sedation, requiring that the medication be given at bedtime. This reaction occurs most commonly with paroxetine, fluvoxamine, and mirtazapine. The SSRIs can be given in once-daily dosage. Nefazodone and trazodone are usually given twice daily. Bupropion and venlafaxine are available in extended-release formulations and can be given once daily. There is usually some delay in response; fluoxetine, for example, requires 2–6 weeks to act in depression, 4–8 weeks to be effective in panic disorder, and 6–12 weeks in treatment of OCD. The starting dose (10 mg) is given for 1 week before increasing to the average daily oral dose of 20 mg for depression, while OCD may require up to 80 mg daily. Some patients, particularly the elderly, may tolerate and benefit from as little as 10 mg/day or every other day. The other SSRIs have shorter half-lives and a lesser effect on hepatic enzymes, which reduces their impact on the metabolism of other medications (thus not increasing significantly the serum concentrations of other medications as much as fluoxetine). The shorter half-lives also allow for more rapid clearing if adverse side effects appear. Venlafaxine appears to be more effective with doses greater than 200 mg/day orally, although some individuals respond to doses as low as 75 mg/day.
The side effects common to these medications are headache, nausea, tinnitus, insomnia, and nervousness. Akathisia has been common with the SSRIs; other extrapyramidal symptoms (eg, dystonias) have occurred infrequently but particularly in withdrawal states. Because SSRIs affect platelet serotonin levels, abnormal bleeding can occur. Sertraline and citalopram appear to be the safest agents in this class when used with warfarin. Sexual side effects of erectile dysfunction, retrograde ejaculation, and dysorgasmia are very common with the SSRIs. Oral phosphodiesterase-5 inhibitors (such as sildenafil, 25–50 mg; tadalafil, 5-20 mg; or vardenafil, 10–20 mg taken 1 hour prior to sexual activity) can improve erectile dysfunction in some patients and have been shown to improve other SSRI-induced sexual dysfunction in both men and women. Adjunctive bupropion (75–150 mg orally daily) may also enhance sexual arousal. Cyproheptadine, 4 mg orally prior to sexual activity, may be helpful in countering drug-induced anorgasmia but also is quite sedating and may counter the therapeutic benefits of SSRIs as well. Taking a “drug holiday,” ie, skipping a day of medication periodically when sexual activity is anticipated, can also decrease sexual side effects. The SSRIs are strong serotonin uptake blockers and may in high dosage or in combination with MAO inhibitors, including the antiparkinsonian drug selegiline, cause a “serotonin syndrome.” This syndrome is manifested by rigidity, hyperthermia, autonomic instability, myoclonus, confusion, delirium, and coma. This syndrome can be a particularly troublesome problem in the elderly. Research indicates that SSRIs are safer agents to use than TCAs in patients with cardiac disease; the SSRI sertraline is a safe and effective antidepressant treatment in patients with acute myocardial infarction or unstable angina.
Withdrawal symptoms, including dizziness, paresthesias, dysphoric mood, agitation, and a flu-like state, have been reported for the shorter-acting SSRIs and SNRIs but may occur with other classes including the TCAs and MAO inhibitors. These medications should be discontinued gradually over a period of weeks or months to reduce the risk of withdrawal phenomena.
Most studies show that SSRIs are not associated with birth defects. Paroxetine has some association with a fetal heart defect and should be avoided in favor of other SSRIs during pregnancy. Untreated depression in the mother can contribute substantially to deficits in the verbal, intellectual and motor development of a newborn. Peripartum effects may be a concern and are documented anecdotally in the literature. Maternal major mood disorder in pregnancy by itself carries its own risks to the mother and fetus and has been linked to low birth weight and preterm delivery. Postpartum effects of prenatal depression have not been studied. The decision to use SSRIs and other psychotropic agents during pregnancy and postpartum must be a collaborative decision based on a thorough risk-benefit analysis for each individual.
Venlafaxine lacks significant anticholinergic side effects. Nausea, nervousness, and profuse sweating appear to be the major side effects. Venlafaxine appears to have few drug-drug interactions. It does require monitoring of blood pressure because dose-related hypertension may develop in some individuals. Venlafaxine prescribing in the United Kingdom has been restricted to psychiatrists. Venlafaxine appears to carry a greater risk of lethal arrhythmias in instances of overdose relative to the SSRIs, but less risk than with the TCAs. Desvenlafaxine, a newer form of the medication, is started at its target dose of 50 mg/day orally and does not require upward titration although higher doses have been well studied and some patients benefit from 100 mg/day. Duloxetine may also result in small increases in blood pressure. Common side effects include dry mouth, dizziness, and fatigue. Inhibitors of 1A2 and 2D6 may increase duloxetine levels with a risk of toxicity. Milnacipran, approved for the treatment of fibromyalgia, and levomilnacipran, approved for the treatment of major depression, carry many of the side effects common to other SNRIs including a mild tachycardia, hypertension, sexual side effects, mydriasis, urinary constriction, and occasional abnormal bleeding. Levomilnacipran is started at 20 mg/day orally then increased to 40 mg/day after 2–3 days. The target dose is 40–120 mg given once daily. Milnacipran is typically started at 12.5 mg/day orally, titrated to 12.5 mg twice daily after 2 days, and then to 25 mg twice daily after 7 days. The target dose is typically 100–200 mg/day given in in two divided doses. While not approved for the treatment of major depression, the evidence suggests that milnacipran, like levomilnacipran, is an effective antidepressant agent.
Nefazodone appears to lack the anticholinergic effects of the TCAs and the agitation sometimes induced by SSRIs. Nefazodone should not be given with terfenadine, astemizole, or cisapride, which are not commercially available in the United States. Because nefazodone inhibits the liver’s cytochrome P450 3A4 isoenzymes, concurrent use of these medications can lead to serious QT prolongation, ventricular tachycardia, or death. Through the same mechanism of enzyme inhibition, nefazodone can elevate cyclosporine levels sixfold to tenfold. Nefazodone carries an FDA warning given its association with liver failure in rare cases. Pretreatment and ongoing monitoring of liver biochemical enzymes are indicated.
Mirtazapine is thought to enhance central noradrenergic and serotonergic activity with minimal sexual side effects compared with the SSRIs. Its action as a potent antagonist of histaminergic receptors may make it a useful agent for patients with depression and insomnia. It is also an effective antiemetic due to its antagonism of the 5-HT3 receptor. Its most common adverse side effects include somnolence, increased appetite, weight gain, lipid abnormalities, and dizziness. The labeling for mirtazapine indicated that agranulocytosis was seen in 2 of 2796 patients in premarketing studies. An association of agranulocytosis or a clinically significant neutropenia with the medication appears to be modest. Although it is metabolized by P450 isoenzymes, it is not an inhibitor of this system. It is given in a single oral dose at bedtime starting at 15 mg and titrated up to 45 mg.
Vortioxetine is an antidepressant that blocks serotonin reuptake, is a partial agonist of the 5-HT1A receptor, and effects a variety of other serotonin receptor sites. The side effects attributed to its serotonergic effects include gastrointestinal upset and sexual dysfunction. Vortioxetine has demonstrated efficacy in improving cognitive symptoms of depression and received regulatory approval for this indication in Europe. Vortioxetine is typically dosed at 10 mg/day orally and may be increased to 20 mg/day.
2. Tricyclic antidepressants (TCAs) and clinically similar medications
TCAs were the mainstay of medication therapy for depression for many years. They have also been effective in panic disorder, pain syndromes, and anxiety states. Specific ones have been studied and found to be effective in OCD (clomipramine), enuresis (imipramine), psychotic depression (amoxapine), and reduction of craving in cocaine withdrawal (desipramine).
TCAs are characterized more by their similarities than by their differences. They tend to affect both serotonin and norepinephrine reuptake; some medications act mainly on the former and others principally on the latter neurotransmitter system. Individuals receiving the same dosages vary markedly in therapeutic drug levels achieved (elderly patients require smaller doses), and determination of plasma drug levels is helpful when clinical response has been disappointing. Nortriptyline is usually effective when plasma levels are between 50 and 150 ng/mL; imipramine at plasma levels of 200–250 ng/mL; and desipramine at plasma levels of 100–250 ng/mL. High blood levels are not more effective than moderate levels and may be counterproductive (eg, delirium, seizures). Patients with gastrointestinal side effects benefit from plasma level monitoring to assess absorption of the drug. Most TCAs can be given in a single dose at bedtime, starting at fairly low doses (eg, nortriptyline 25 mg orally) and increasing by 25 mg every several days as tolerated until the therapeutic response is achieved (eg, nortriptyline, 100–150 mg) or to maximum dose if necessary (eg, nortriptyline, 150 mg). The most common cause of treatment failure is an inadequate trial. A full trial consists of giving a therapeutic daily dosage for at least 6 weeks. Because of marked anticholinergic and sedating side effects, clomipramine is started at a low dose (25 mg/day orally) and increased slowly in divided doses up to 100 mg/day, held at that level for several days, and then gradually increased as necessary up to 250 mg/day. The TCAs have anticholinergic side effects to varying degrees (amitriptyline 100 mg is equivalent to atropine 5 mg). One must be particularly wary of the effect in elderly men with prostatic hyperplasia. The anticholinergic effects also predispose to other medical problems such as constipation, confusion, heat stroke, or dental problems from xerostomia. Orthostatic hypotension is fairly common, is not dose-dependent, and may not remit with time on medication; this may predispose to falls and hip fractures in the elderly.
Cardiac effects of the TCAs are functions of the anticholinergic effect, direct myocardial depression, quinidine-like effect, and interference with adrenergic neurons. These factors may produce altered rate, rhythm, and contractility, particularly in patients with preexisting cardiac disease, such as bundle-branch or bifascicular block. Even relatively small overdoses (eg, 1500 mg of imipramine) have resulted in lethal arrhythmias. Electrocardiographic changes range from benign ST segment and T wave changes and sinus tachycardia to a variety of complex and serious arrhythmias, the latter requiring a change in medication. Because TCAs have class I antiarrhythmic effects, they should be used with caution in patients with ischemic heart disease, arrhythmias, or conduction disturbances. SSRIs or the atypical antidepressants are better initial choices for this population.
TCAs lower the seizure threshold, so this is of particular concern in patients with a propensity for seizures. Loss of libido and erectile, ejaculatory, and orgasmic dysfunction are common and can compromise compliance. Trazodone rarely causes priapism (1 in 9000), but when it occurs, it requires treatment within 12 hours (epinephrine 1:1000 injected into the corpus cavernosum). Delirium, agitation, and mania are infrequent complications of the TCAs but can occur. Sudden discontinuation of some of these medications can produce “cholinergic rebound,” manifested by headaches and nausea with abdominal cramps. Overdoses of TCAs are often serious because of the narrow therapeutic index and quinidine-like effects (see Chapter 38).
3. Monoamine oxidase inhibitors
The MAO inhibitors are generally used as third-line medications for depression (after a failure of SSRIs, SNRIs, TCAs, or the atypical antidepressants) because of the dietary and other restrictions required (Table 25–8). They should be considered third-line medications for refractory panic disorder as well as depression; however, this hierarchy has become more flexible since MAO inhibitor skin patches (selegiline) have become available. They deliver the MAO inhibitor to the bloodstream bypassing the gastrointestinal tract so that dietary restrictions are not necessary in the lowest dosage strength (6 mg/24 h).
Table 25–8.Principal dietary restrictions in MAOI use. ||Download (.pdf) Table 25–8. Principal dietary restrictions in MAOI use.
Cheese, except cream cheese and cottage cheese and fresh yogurt
Fermented or aged meats such as bologna, salami
Broad bean pods such as Chinese bean pods
Liver of all types
Meat and yeast extracts
Red wine, sherry, vermouth, cognac, beer, ale
Soy sauce, shrimp paste, sauerkraut
Oral MAO inhibitors are administered in gradual stepwise dosage and may be given in the morning or evening, depending upon their effect on sleep. They tend to take effect in a fairly low dosage range (Table 25–7). Blood levels are not congruent with therapeutic response.
The MAO inhibitors commonly cause symptoms of orthostatic hypotension (which may persist) and sympathomimetic effects of tachycardia, sweating, and tremor. Nausea, insomnia (often associated with intense afternoon drowsiness), and sexual dysfunction are common. Zolpidem 5–10 mg orally at bedtime can ameliorate MAO-induced insomnia. Central nervous system effects include agitation and toxic psychoses. Dietary limitations (see Table 25–8) and abstinence from medication products containing phenylpropanolamine, phenylephrine, meperidine, dextromethorphan, and pseudoephedrine are mandatory for MAO-A type inhibitors (those marketed for treatment of depression), since the reduction of available MAO leaves the patient vulnerable to exogenous amines (eg, tyramine in foodstuffs).
Treatment for a resultant hypertensive crisis has been the same as for pheochromocytoma (see Chapter 26), but there have been reports of success with nifedipine, 10 mg chewed and placed under the tongue, normalizing blood pressure in 1–5 minutes. The restrictions on the proscribed foodstuffs and sympathomimetic medications are in effect during treatment and for 2–3 weeks after cessation of therapy. Termination of therapy with MAO inhibitors may be associated with anxiety, agitation, cognitive slowing, and headache. Very gradual withdrawal and short-term benzodiazepine therapy will ameliorate symptoms.
4. Other medications and those under investigation
Dextroamphetamine (5–30 mg/day orally) and methylphenidate (10–45 mg/day orally) may be effective for the short-term treatment of some depressive symptoms in medically ill and geriatric patients. The stimulants are notable for rapid onset of action (hours) and a paucity of side effects (tachycardia, agitation) in most patients. They are usually given in two divided doses early in the day (eg, 7 am and noon) so as to avoid interfering with sleep. These agents may also be useful as adjunctive agents in refractory depression. Intravenous infusion of the dissociative anesthetic ketamine has been shown to lead to a rapid improvement in depressive symptoms in 50–70% of patients with depression. The effects of a single treatment are short-lived (about 3–7 days). Ketamine acts both through the glutamate system as well as the opioid system. Other NMDA antagonists and opioid system agents continue to be evaluated in the treatment of resistant depression. Esketamine nasal spray has been approved by the FDA for the treatment of depression for patients who have been inadequately treated by two other antidepressant medications. However, there are ongoing concerns about long-term use of esketamine or ketamine, including the risk of abuse and longer-term impacts on mood and suicidality.
Allopregnanolone, a neurosteroid, is an allosteric modulator of GABA-a receptors and was approved in 2019 for the treatment of postpartum depression. Like ketamine, allopregnanolone is administered intravenously, and the antidepressant effects are rapid. An allopregnanolone infusion is given over 60 hours in a healthcare facility and was significantly more effective than placebo in treating postpartum depression by the end of the 2.5-day infusion, and benefits were sustained for the 30 days of the study period in three registration trials. The most common side effects of allopregnanolone are headache, dizziness, and somnolence. There is a rare side effect of loss of consciousness that requires the infusion be monitored in a healthcare facility. There is good reason to believe that GABA-a modulators will be useful in other types of depression, including for addressing anxiety and insomnia in patients with more severe depression. Several orally active GABA-a modulators are in development.
5. Switching and combination therapy
If the therapeutic response has been poor after an adequate trial with the chosen medication, the diagnosis should be reassessed. Assuming that the trial has been adequate and the diagnosis is correct, a trial with a second medication is appropriate. In switching from one group to another, an adequate “washout time” must be allowed. This is critical in certain situations—eg, in switching from a MAO inhibitor to a TCA, allow 2–3 weeks between stopping one medication and starting another; in switching from an SSRI to a MAO inhibitor, allow 4–5 weeks for fluoxetine and at least 2 weeks for other SSRIs. In switching within groups—eg, from one TCA to another (amitriptyline to desipramine, etc)—no washout time is needed, and one can rapidly decrease the dosage of one medication while increasing the other. In clinical practice, adjunctive treatment with lithium, buspirone, or thyroid hormone may be helpful in depression. The adjunctive use of low-dose atypical antipsychotics such as aripiprazole, olanzapine, and quetiapine in the treatment of patients with refractory depression is supported by research. The side effect risk is the same as when treating psychosis. Adding an atypical agent requires monitoring body mass index, lipids, and glucose. Combining two antidepressants, or adding an antipsychotic to an antidepressant, requires caution and is usually reserved for clinicians who feel comfortable managing this or after psychiatric consultation.
6. Maintenance and tapering
When clinical relief of symptoms is obtained, medication is continued for 12 months in the effective maintenance dosage, which is the dosage required in the acute stage. The full dosage should be continued indefinitely when the individual has a first episode before age 20 or after age 50, is over age 40 with two episodes, has at least one episode after age 50, or has had three episodes at any age. Major depression generally should be considered a chronic/intermittent disease with most patients having relapses in time and some patients never fully recovering from a depressive episode. If the medication is being tapered, it should be done gradually over several months, monitoring closely for relapse.
Interactions with other medications are listed in Table 25–9.
Table 25–9.Antidepressant drug interactions with other medications (listed in alphabetical order within classes). ||Download (.pdf) Table 25–9. Antidepressant drug interactions with other medications (listed in alphabetical order within classes).
|Medication ||Effects |
|Tricyclic and Other Non-MAOI Antidepressants |
|Antacids ||Decreased absorption of antidepressants |
|Anticoagulants ||Increased hypoprothrombinemic effect |
|Cimetidine ||Increased antidepressant blood levels and psychosis |
|Clonidine ||Decreased antihypertensive effect |
|Digitalis ||Increased incidence of heart block |
|Disulfiram ||Increased antidepressant blood levels |
|Haloperidol ||Increased antidepressant levels |
|Insulin ||Decreased blood sugar |
|Lithium ||Increased lithium levels with fluoxetine |
|Methyldopa ||Decreased antihypertensive effect |
|Other anticholinergic medications ||Marked anticholinergic responses |
|Phenytoin ||Increased blood levels |
|Procainamide ||Decreased ventricular conduction |
|Procarbazine ||Hypertensive crisis |
|Propranolol ||Increased hypotension |
|Quinidine ||Decreased ventricular conduction |
|Rauwolfia derivatives ||Increased stimulation |
|Sedatives ||Increased sedation |
|Sympathomimetic medications ||Increased vasopressor effect |
|Terfenadine,1 astemizole,1 cisapride1 ||Torsades de pointes |
|Antihistamines ||Increased sedation |
|Belladonna-like medications ||Increased blood pressure |
|Dextromethorphan ||Same as meperidine |
|Guanethidine ||Decreased blood pressure |
|Insulin ||Decreased blood sugar |
|Levodopa ||Increased blood pressure |
|Meperidine ||Increased agitation, serotonin syndrome, death |
|Methyldopa ||Decreased blood pressure |
|Pseudoephedrine ||Hypertensive crisis (increased blood pressure) |
|Reserpine ||Increased blood pressure/hypertensive crisis |
|Succinylcholine ||Increased neuromuscular blockade |
|Sulfonylureas ||Decreased blood sugar |
|Sympathomimetic medications ||Increased blood pressure/hypertensive crisis |
|SSRIs, SNRIs, triptans ||Serotonin syndrome, death |
8. Electroconvulsive therapy
ECT causes a generalized central nervous system seizure (peripheral convulsion is not necessary) by means of electric current. The key objective is to exceed the seizure threshold, which can be accomplished by a variety of means. The mechanism of action is not known, but it is thought to involve major neurotransmitter responses at the cell membrane.
ECT is the most effective (about 45–85% remission rate) treatment of severe depression. In more treatment-resistant depression, remission rates from ECT are lower (around 48%). It is particularly effective for the delusions and agitation commonly seen with depression in the elderly. It is indicated when medical conditions preclude the use of antidepressants, nonresponsiveness to these medications, and extreme suicidality. Comparative controlled studies of ECT in severe depression show that it is more effective than pharmacotherapy. It is also effective in the treatment of mania and catatonia. It has also been shown to be helpful in chronic schizophrenic disorders when clozapine alone is not fully effective.
The most common side effects of ECT are memory disturbance and headache. Memory loss or confusion is usually related to the number and frequency of ECT treatments and proper oxygenation during treatment. Unilateral ECT is associated with less memory loss than bilateral ECT. Both anterograde and retrograde memory loss may occur, but short-term anterograde memory loss is more common. While some memory deficits may persist, memory loss tends to improve in a few weeks after the last ECT treatment.
Increased intracranial pressure is a contraindication. Other problems such as cardiac disorders, aortic aneurysms, bronchopulmonary disease, and venous thrombosis must be evaluated in light of the severity of the medical problem versus the need for ECT. Serious complications arising from ECT occur in less than 1 in 1000 cases. Most of these problems are cardiovascular or respiratory in nature (eg, aspiration of gastric contents, arrhythmias, myocardial infarction). Poor patient understanding and lack of acceptance of the technique by the public are some of the biggest obstacles to the use of ECT.
Phototherapy is used in major depression with seasonal onset. It consists of indirect eye exposure to a light source of greater than 2500 lux for 2 hours daily or 10,000 lux for 20 minutes daily to increase the photoperiod of the day. Light visors are an adaptation that provides greater mobility and an adjustable light intensity but may not be as effective. The dosage varies, with some patients requiring morning and night exposure. One effect is alteration of biorhythm through melatonin mechanisms.
10. Repetitive transcranial magnetic stimulation
Repetitive transcranial magnetic stimulation (rTMS) is used to treat nonpsychotic treatment-resistant depression and involves the application of electromagnetic pulses to the dorsolateral prefrontal cortex. Its use in depression is approved by the FDA for individuals who have not tolerated or responded to at least one or more standard antidepressant medications. It is usually delivered in a course of 30 sessions over 6 weeks. rTMS neither requires general anesthesia nor is it associated with cognitive side effects. Several meta-analyses have demonstrated that in nonpsychotic depression, rTMS is noninferior to ECT. There is a small risk of seizure (1:30,000 in post market research), and this is due primarily to operator error. The most common side effects are scalp sensitivity under the coil and transient headache.
Vagus nerve stimulation has shown promise in about one-third of extremely refractory cases and is approved by the FDA but has not been approved by insurers. Data have demonstrated that the effects plateau around 18 months to 2 years and are durable at 5 years. Deep brain stimulation continues to be explored for the treatment of refractory depression but two multisite randomized controlled studies in two separate targets (subgenual cingulate and ventral capsule/ventral striatum) have not shown success to date. There has been one successful trial but the study methodology was a derivation of the traditional randomized controlled trial. This is still considered an experimental approach, and the appropriate target and methodology are unknown.
It is often challenging to engage an individual in penetrating psychotherapeutic endeavors during the acute stage of a severe depression. While medications may be taking effect, a supportive and behavioral approach to strengthen existing coping mechanisms and appropriate consideration of the patient’s continuing need to function at work, to engage in recreational activities, etc, are necessary as the severity of the depression lessens. Therapy during or just after the acute stage may focus on coping techniques, with some practice of alternative choices. Depression-specific psychotherapies help improve self-esteem, increase assertiveness, and lessen dependency. Interpersonal psychotherapy for depression has shown efficacy in the treatment of acute depression, helping patients master interpersonal stresses and develop new coping strategies. Cognitive behavioral therapy for depression addresses patients’ patterns of negative thoughts, called cognitive distortions, which lead to feelings of depression and anxiety. Treatment usually includes homework assignments such as keeping a journal of cognitive distortions and of positive responses to them. The combination of medication therapy plus interpersonal psychotherapy or cognitive behavioral therapy is generally more effective than either modality alone. It is sometimes helpful to involve the spouse or other significant family members early in treatment. Mindfulness-based cognitive therapy has reduced relapse rates in several randomized controlled trials. In two studies, it was as effective as maintenance medication in preventing relapse. This therapy incorporates meditation and teaches patients to distance themselves from depressive thinking.
Flexible use of appropriate social services can be of major importance in the treatment of depression. Since alcohol abuse is often associated with depression, early involvement in alcohol treatment programs such as Alcoholics Anonymous can be important to future success (see Alcohol Use Disorder [Alcoholism]). The structuring of daily activities during severe depression is often quite difficult for the patient, and loneliness is often a major factor. The help of family, employer, or friends is often necessary to mobilize the patient who experiences no joy in daily activities and tends to remain uninvolved and to deteriorate. Insistence on sharing activities will help involve the patient in simple but important daily functions. In some severe cases, the use of day treatment centers or support groups of a specific type (eg, mastectomy groups) is indicated. It is not unusual for a patient to have multiple legal, financial, and vocational problems requiring legal and vocational assistance.
When depression is a function of self-defeating coping techniques such as passivity, the role-playing approach can be useful. Behavioral techniques, including desensitization, may be used in problems such as phobias where depression is a by-product. When depression is a regularly used interpersonal style, behavioral counseling to family members or others can help in extinguishing the behavior in the patient. Behavioral activation, a technique of motivating depressed patients to begin engaging in pleasurable activities, has been shown to be a useful depression-specific psychotherapy. Exercise, especially aerobic and supervised by exercise professionals, has evidence in improving depressive symptoms.