Abstract
Antidepressants are among the most widely prescribed medicines in the United States, particularly in psychiatry and primary care medicine. According to the US Centers for Disease Control, approximately 13 percent of the US population aged twelve years or older were prescribed an antidepressant in a recent year. Although antidepressants may be overprescribed in some patient populations and underprescribed in others, the overall high rate of antidepressant use is almost certainly related to the high prevalence of the conditions for which antidepressants are clinically indicated and approved by the US Food and Drug Administration (FDA). These conditions include major depressive disorder, generalized anxiety disorder, panic disorder, social anxiety disorder, obsessive-compulsive disorder, and posttraumatic stress disorder. In addition, certain antidepressants are used in the treatment of pain syndromes (e.g., fibromyalgia, migraine or neuropathic pain), bulimia nervosa, binge eating disorder, premenstrual symptoms, somatic symptom disorders, irritable bowel syndrome, insomnia, and body dysmorphic disorder, as well as to help individuals quit smoking.
Antidepressants
Background
Antidepressants are among the most widely prescribed medicines in the United States, particularly in psychiatry and primary care medicine. According to the US Centers for Disease Control, approximately 13 percent of the US population aged twelve years or older were prescribed an antidepressant in a recent year. Although antidepressants may be overprescribed in some patient populations and underprescribed in others, the overall high rate of antidepressant use is almost certainly related to the high prevalence of the conditions for which antidepressants are clinically indicated and approved by the US Food and Drug Administration (FDA). These conditions include major depressive disorder, generalized anxiety disorder, panic disorder, social anxiety disorder, obsessive-compulsive disorder, and posttraumatic stress disorder. In addition, certain antidepressants are used in the treatment of pain syndromes (e.g., fibromyalgia, migraine, or neuropathic pain), bulimia nervosa, binge eating disorder, premenstrual symptoms, somatic symptom disorders, irritable bowel syndrome, insomnia, and body dysmorphic disorder, as well as to help individuals quit smoking.
The first antidepressants of the modern era – tricyclic antidepressants and monoamine oxidase (MAO) inhibitors – were discovered by Serendipity in the 1950s. In the years that followed, it became apparent that all established antidepressants shared pharmacological activity on the monoamine neurotransmitter systems, particularly those mediated by serotonin and norepinephrine and, to a lesser extent, dopamine. This recognition largely drove subsequent drug development strategies until recently. Use of the older antidepressants has been limited by problematic adverse effects, drug interactions, and potential lethality in overdose. Research in the 1970s and 1980s yielded generally safer agents that represent current first-line medications for depression and anxiety. These pharmacotherapies are used either alone (monotherapy) or in conjunction with established forms of psychotherapy, including cognitive-behavioral, dialectical-behavioral, and psychodynamic approaches. For patients with relatively severe or otherwise treatment-resistant forms of depression, medication is sometimes coupled with neurostimulation approaches as well, particularly electroconvulsive therapy (ECT) or repetitive transcranial magnetic stimulation (rTMS).
Antidepressants can have dramatic and life-saving benefits for some patients, but meta-analyses of randomized, placebo-controlled antidepressant trials consistently show relatively small or moderate effect-sizes or drug-placebo differences. The small and variable effect-sizes of antidepressants probably reflects the considerable heterogeneity among patients diagnosed with major depressive disorder. Only about 1 in 3 patients respond to the first antidepressant they receive, even with increased doses. Some may respond to a different antidepressant, and multiple trials or even drug combinations are not uncommon.
Initial benefit from an antidepressant usually is not evident for two to four weeks after achieving an adequate dose, and full effects may require six to twelve weeks of sustained treatment. Owing to the frequent need to try more than one treatment, it often takes several months to determine whether antidepressant treatment works well for a particular patient. To deal with the heterogeneity of antidepressant responses, current research aims to identify clinically useful predictors. Some promising candidate predictors include pharmacogenomic data, neuroimaging patterns, or inflammatory markers, as well as clinical phenotypes. For the most part, such efforts have had limited success, though efforts to identify reliable predictors of response to antidepressants do and should continue.
Although all FDA-approved antidepressants interact with brain monoamine systems, many complex, secondary neurobiological effects of the drugs have been identified, and precise neurobiological mechanisms through which antidepressants alleviate depression or anxiety largely remain unknown. The observation that antidepressants have immediate effects on monoamine neurotransmission, including blockade of their inactivation by neuronal uptake or transport, but delayed effects on clinical symptoms suggest that the most relevant physiological mechanisms may be “downstream” from monoamine synapses and possibly slowly evolving. Some leading hypotheses concerning antidepressant mechanisms focus on neuroplasticity, inflammation, and brain energy metabolism. In addition, a number of promising investigational antidepressants appear to interact with the glutamate, GABA, and opioid systems rather than the monoamine systems, suggesting new avenues through which depression and anxiety conditions might be helped. Indeed, as noted later in this chapter, some of these agents, such as esketamine, have rapid effects on individuals who respond to them, with relief seen within hours to days rather than weeks.
Classification
Antidepressants have traditionally been classified according to their chemical structure (e.g., tricyclics [TCAs]) or mechanisms of action (e.g., monoamine oxidase inhibitors [MAOIs], selective serotonin reuptake inhibitors [SSRIs]).
The major classes of antidepressants in current use in the United States are as follows. The generic name of each medication is followed by the initial brand name in parentheses:
Selective Serotonin Reuptake Inhibitors (SSRIs)
Citalopram (Celexa)
Escitalopram (Lexapro)
Fluoxetine (Prozac)
Fluvoxamine (Luvox; FDA-approved for anxiety disorders but not depression)
Paroxetine (Paxil)
Sertraline (Zoloft)
All of these agents (except fluvoxamine) are FDA-approved for major depressive disorder; most are also approved for different forms of anxiety, including generalized and social anxiety disorders, and some for posttraumatic stress disorder (PTSD) and bulimia or binge eating disorder. Fluvoxamine is FDA-approved only for obsessive-compulsive disorder, though it is used to treat depression in other countries. No particular SSRI appears to be more effective than another for major depressive disorder (or anxiety conditions). Nevertheless, an individual patient may respond to or tolerate one SSRI better than another. For this reason, it is not uncommon to try a second SSRI even when a first has been unsuccessful.
Serotonin and Norepinephrine Reuptake Inhibitors
Desvenlafaxine (Pristiq)
Duloxetine (Cymbalta)
Levomilnacipran (Fetzima)
Venlafaxine (Effexor)
Like the SSRIs, the SNRIs are effective for major depressive disorder and for many anxiety disorders. In addition, agents that work on both serotonin and norepinephrine appear to be more effective for pain syndromes than are agents acting on serotonin only. These serotonin and norepinephrine reuptake inhibiting agents include both the newer SNRIs and the older tricyclic antidepressants (TCAs) such as amitriptyline (Elavil). For patients with depression or anxiety that is comorbid with pain syndromes such as fibromyalgia, SNRIs, or TCAs are considered the antidepressants of choice.
Norepinephrine and Dopamine Reuptake Inhibitor (NDRI)
Bupropion (Wellbutrin, Zyban)
Among contemporary antidepressants, the only norepinephrine and dopamine reuptake inhibitor is the mild stimulant-anorexic agent bupropion. As the sole FDA-approved antidepressant devoid of serotoninergic activity bupropion is particularly well suited for individuals who have difficulty tolerating serotonin-related side effects, particularly sexual dysfunction. In addition, bupropion is the only antidepressant with demonstrated efficacy for smoking cessation. When used for this purpose, it is often prescribed in conjunction with nicotine replacement therapies and behavioral strategies. Bupropion also has some effectiveness for attention deficit hyperactivity disorder and is, therefore, one of the medication options for patients with ADHD who do not tolerate the more widely prescribed psychostimulants or whose risk for addiction may preclude the use of controlled substances. Unlike SSRIs or SNRIs, bupropion is not FDA indicated for the treatment of anxiety disorders; it is believed that serotonergic properties are required for an antidepressant to exert optimal anti-anxiety effects.
Miscellaneous Modern Antidepressants
Mirtazapine (Remeron)
Trazodone (Desyrel)
Vilazodone (Viibryd)
Vortioxetine (Trintellix)
Although these agents differ in molecular structure and pharmacological properties, they all share some effects on neurotransmission mediated by serotonin and norepinephrine. However, unlike the SSRIs and SNRIs, they have complex activities other than inhibition of neurotransmitter reuptake. At low doses, trazodone is also used as a non-addictive hypnotic agent. Another agent in this group, nefazodone (Serzone) is no longer used clinically, owing to high risk of liver toxicity.
Tricyclic Antidepressants (TCAs)
Clomipramine (Anafranil)
Desipramine (Norpramin)
Doxepin (Sinequan)
Imipramine (Tofranil)
Protriptyline (Vivactil)
Nortriptyline (Pamelor)
Trimipramine (Surmontil)
Prior to the introduction of the SSRIs in the late 1980s, the tricyclics, and particularly amitriptyline, were the most widely prescribed antidepressants. While the TCAs, like the SNRIs, block the neuronal reuptake of serotonin and norepinephrine, they also interact with other sites including adrenergic, histamine, and muscarinic receptors. These activities contribute to a variety of adverse effects, including drowsiness, dry mouth, blurred vision, constipation, weight gain, and hypotension. Notably, the TCAs also have quinidine-like depressant effects on cardiac conduction, and can induce potentially fatal arrhythmias, particularly in overdose or with preexisting cardiac conduction problems. Another unique aspect of the TCAs is that several commonly used TCAs have quite well established therapeutically optimal and safe serum concentrations that can be used for therapeutic monitoring.
Monoamine Oxidase Inhibitors (MAOIs)
Isocarboxazid (Marplan)
Phenelzine (Nardil)
Selegiline (EMSAM)
Tranylcypromine (Parnate)
MAOIs, like other antidepressants, enhance monoamine neurotransmission by interfering with monoamine metabolism, in this case by the enzyme MAO rather than blocking neuronal reuptake or by acting directly on monoamine receptors. MAO exists in two molecular forms, MAO-A and MAO-B. Type B is found in the liver and platelets, whereas MAO-A is typical of nerve terminals. At low doses, selegiline preferentially inhibits MAO-A, but at higher doses it inhibits both MAO-A and B. Blocking the catabolism of serotonin and norepinephrine appears to be relevant to its antidepressant efficacy. Other MAOIs block MAO-A and B at therapeutic doses and are more likely to induce potentially fatal hypertensive crises when taken with an indirect sympathomimetic amines such as tyramine (in cheese and other fermented foods) or neosynephrine. For this reason, MAOIs are used cautiously, with a diet that excludes tyramine and other sympathomimetic agents, and generally are reserved for individuals with severe depression unresponsive to other agents. Selegiline is available in transdermal (skin patch) form, whereas the other MAOIs are available for oral administration only.
MAOIs may be superior to TCAs for individuals with a type of depression known as “atypical depression,” characterized by carbohydrate craving, oversleeping, temporary mood improvement after positive events (“mood reactivity”), and mood decline in the setting of perceived rejection or criticism (“rejection sensitivity”). These observations support a preference for MAOIs over TCAs for atypical depression, although SSRIs and SNRIs are more often used initially for their greater safety.
Adverse Effects of Antidepressants
Adverse effects associated with antidepressant treatment are summarized in Table 15.1. Despite the efficacy of most antidepressants in the treatment of anxiety disorders, paradoxically, transient “jitteriness” or increased anxiety is a common adverse effect during the first few days of treatment. Similarly, some patients experience insomnia or interrupted sleep as well as gastrointestinal symptoms, particularly mild nausea. These symptoms are also often, but not always, temporary and self-limiting. A more persistent increase in sweating, particularly night sweats, is not uncommon, particularly with the SNRIs.
| Agents | Adverse effects |
|---|---|
| Tricyclic-type agents (TCAs) | |
| Amitriptyline, imipramine, doxepin | Anticholinergic-cognitive effects, hypotension, cardiac depressant, leukopenia |
| Amoxapine | Extrapyramidal symptoms, tardive dyskinesia, seizures (rare) |
| Clomipramine | Sedation, nausea, anticholinergic, cardiac depressant, hemolysis (rare) |
| Maprotiline | Seizures (high doses), rashes |
| Protriptyline | Agitation, photosensitivity |
| Monoamine-oxidase (MAO) inhibitors | |
| Phenelzine, tranylcypromine | Hypotension, mild hypertension, sexual dysfunction, hepatotoxicity (rare); severe hypertension with pressor amines, serotonin syndrome with serotonergic agents (SSRIs, meperidine, dextromethorphan) |
| Moclobemide | Less pressor risk, possible serotonin syndrome with other serotonergics |
| Selegiline | Less pressor risk at low doses, some risk of serotonin syndrome |
| St. John’s wort | Possible serotonin syndrome with other serotonergics |
| Serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) | |
| Citalopram, duloxetine, fluoxetine, sertraline, venlafaxine, and others |
|
Antidepressants also can be associated with mild hand tremor, which is particularly noticeable with arms outstretched or bringing a cup or spoon to one’s mouth. This kind of tremor is distinct from the Parkinsonian resting (or “pill rolling”) tremor associated with antipsychotic drugs or other antidopamine drugs. With the exception of bupropion and fluoxetine, many antidepressants are associated with modest to moderate weight gain, though with considerable variation across individual patients. Contemporary antidepressants particularly likely to cause weight gain include mirtazapine and paroxetine. TCAs and MAOIs also can cause weight gain. Drowsiness is common with some antidepressants, including mirtazapine, paroxetine, and trazodone, and most TCAs, particularly doxepin and amitriptyline.
All antidepressants with serotonergic activity can cause sexual dysfunction. Sexual side effects usually involve delayed ejaculation in men, diminished lubrication in women, and difficulty achieving orgasm. Decreased libido is also common. Since depression itself may reduce libido and sexual interest and performance, the net result of an antidepressant on sexual function may be positive as the depression lifts. The prevalence of sexual dysfunction during treatment with a serotonergic agent is as high as 30 to 60 percent. As a non-serotonergic agent, bupropion is especially unlikely to be associated with sexual dysfunction.
Anticholinergic (antimuscarinic) effects of antidepressants, particularly the TCAs, are associated with potential dry mouth, constipation, urinary retention, blurred vision, and memory impairment. These drugs should be dosed with care in older patients, particularly those with prostatic hypertrophy or mild cognitive impairment. In addition, TCAs can cause acute elevation of ocular pressure in patients with narrow-angle glaucoma.
Orthostatic hypotension can occur during treatment with trazodone or a TCA or MAOI. This is a particular concern in older patients vulnerable to falls. Clinicians often advise patients at risk to rise slowly after sitting and to dangle their feet at the edge of the bed for a few moments before standing.
When antidepressants are stopped abruptly, patients may experience discontinuation or withdrawal symptoms which, though not dangerous, can be highly distressing. Symptoms range from nausea, muscle aches, and tearfulness to unusual perceptual experiences such as sudden “zapping” sensations in one’s scalp. The SSRIs, SNRIs, and especially paroxetine are particularly prone to cause these side effects, though they may occur upon sudden discontinuation of any antidepressant. Fluoxetine, by virtue of its very long half-life, is the least likely to cause discontinuation symptoms. The risk of discontinuation symptoms can be greatly reduced by slowly reducing the dose of antidepressants or switching to fluoxetine, although for some patients, discontinuing remains difficult. These withdrawal reactions are to be distinguished from high rates of early relapse into depression that follow abrupt or rapid discontinuation of antidepressant treatment.
Antidepressant-Related Emergencies
Although newer antidepressants have a high margin of safety, even in overdose, both newer and older antidepressants are associated with rare but life-threatening emergencies that all prescribers and users of antidepressants must be aware of. They include the following:
Mania: While treating depression, antidepressants can activate manic or hypomanic behavior in predisposed individuals. Such symptoms include decreased need for sleep, increased activity, racing thoughts, intense irritability, pressured speech, impulsive behavior, grandiose thinking, and even psychotic symptoms such as paranoia or hallucinations. Prior to prescribing an antidepressant to a depressed or anxious patient, inquiry about prior symptoms suggestive of bipolar disorder as well as relevant family history is crucial. Since antidepressants may precipitate manic symptoms in patients with no previous history suggestive of bipolar disorder, it is crucial to monitor all depressed patients closely for manic symptoms during the initial weeks of treatment, and to avoid antidepressants when mixed (hypomanic with depressive) features are present. Although antidepressants may precipitate mania and are not proved to be effective for bipolar depression, they are sometimes used in the treatment of depression in bipolar disorder. However, when doing so, the bipolar disorder is first treated with adequate doses of a mood-stabilizing agent or second-generation antipsychotic drug and patients must be monitored particularly closely for exacerbation manic symptoms or increased frequency of mood episodes (rapid cycling). The actual added risk of such mood-switching during antidepressant treatment is difficult to quantify, especially as risks of spontaneous emergence of mania among bipolar disorder patients are already quite high.
Suicidal ideation: Although antidepressants generally reduce suicidal ideation along with other core depressive symptoms, a small number of patients appear to experience a paradoxical increase in suicidal thoughts, usually during the initial days or weeks of treatment. This reaction has been found most often among adolescents and young adults and may be associated with undiagnosed bipolar disorder in this age group. Since 2004, the FDA has required a so-called black box warning about this potential risk in pediatric patients and those below age twenty-five. This warning was followed by a temporary decrease in the diagnosis of major depression in juveniles and in prescribing of antidepressants, with concern about potentially increased risks of suicidal behavior due to inadequate treatment of depression. The possibility of an increase in suicidal thoughts early in antidepressant treatment warrants close monitoring, and the risk can be managed by reducing the dose of antidepressant or adding a mood stabilizer, antipsychotic, or sedative.
Cardiac arrhythmias: Among their complex pharmacological effects, the TCAs have quinidine-like effects that slow cardiac conduction (QTc prolongation >500 msec) and increase the risk of life-threatening ventricular arrhythmias such as torsades de pointes, particularly in the setting of overdose. To a lesser extent, other antidepressants including trazodone, citalopram, and escitalopram may be associated with the risk of arrhythmia at high doses.
Seizures: Most antidepressants lower the seizure threshold. This is particularly true of bupropion as well as clomipramine, which should be avoided or used with expert consultation in patients at high risk for seizures such as those with brain lesions, head trauma, active eating disorders, or prior seizures.
Priapism: Some antidepressants, most notably trazodone, have been associated with sustained, painful erection requiring emergency treatment to avoid penile damage. This uncommon adverse reaction has an incidence of approximately 1 in 6,000 men receiving trazodone.
Hypertensive crisis: Use of MAOIs with sympathomimetic agents such as amphetamines, cocaine, or even over-the-counter decongestants such as pseudoephedrine or oxymetazoline can produce an abrupt, extreme elevation of blood pressure, often accompanied by notable symptoms such as severe headache, nausea, vomiting, confusion, or nosebleeds. Hypertensive crises are a potentially life-threatening emergency requiring immediate medical attention. In addition, because the MAO enzymes exist not only in the brain but in the gastrointestinal tract and liver, ingestion of foods that contain pressor amines, such as tyramine, typically inactivated in the gut and liver, also can produce hypertensive reactions in patients taking an MAOI. This effect is sometimes referred to as the “cheese reaction” as aged and fermented products are particularly likely to contain pressor amines. These include aged cheese, smoked, pickled or cured meats, draft beer, certain soy and yeast products, and overripened fruits, including bananas. For this reason, only patients who can reliably avoid such foods and drugs are candidates for treatment with MAOIs.
Serotonin syndrome: High doses of serotonergic agents or, more commonly, combinations of highly serotonergic agents may lead to serotonin toxicity. Extreme toxicity can present clinically as “serotonin syndrome,” which is characterized by clonus (involuntary rhythmic muscle contractions, such as at the ankle or arm), agitation, confusion, tremor, and potential fatality. The symptoms of serotonin syndrome overlap with those of neuroleptic malignant syndrome (NMS), which is related to the use of antipsychotic drugs. Both can be broadly considered forms of cerebral intoxication. However, muscle rigidity and fever traditionally have been more common with NMS than serotonin syndrome. Abnormal laboratory values are also more common with NMS than serotonin syndrome, including elevated white blood cell count and increased serum concentrations of the muscle enzyme, creatine kinase (CK). However, some of the classic features of NMS (marked muscle rigidity, elevation of creatine kinase and myoglobin) may not occur with intoxications associated with some modern antipsychotic drugs such as clozapine. As with NMS, there is no definitive treatment for serotonin syndrome other than immediate cessation of the offending drugs and supportive care, often requiring an intensive medical care setting. Although most serotonergic agents have been implicated in serotonin syndrome, the combination of MAOIs with highly serotonergic agents such as SSRIs or SNRIS, is particularly dangerous and should be considered absolutely contraindicated. Furthermore, certain opioid painkillers exert serotonin activity – in particular, meperidine (Demerol) and the antitussive agent dextromethorphan – should never be combined with an MAOI due to the significant risk of serotonin syndrome-like intoxication.
Selecting an Antidepressant
Given generally indistinguishable efficacy among antidepressants, the selection of a first antidepressant usually is based on side-effect profile, co-occurring conditions, prior responses to similar agents, and cost. For most uncomplicated depression or anxiety conditions for which antidepressants are approved, the SSRIs or SNRIs are reasonable initial agents. For comorbid pain conditions, the SNRIs (and tertiary-amine TCAs) appear to be more effective than the SSRIs. With co-occurring tobacco smoking or attention disorder (ADHD), bupropion as a mild stimulant may be advantageous, though less likely to benefit anxiety disorders. Bupropion may also be a good choice for patients who have experienced sexual dysfunction when taking a serotonergic agent. Because of the greater risk of adverse effects, drug interactions, and potentially fatal overdoses, the TCAs and MAOIs are usually reserved for patients whose conditions have not responded satisfactorily to one or more modern antidepressants.
Treatment Duration
For a first time, mild to moderate episode of major depressive disorder, antidepressant treatment usually is continued for six to nine months after depression has fully remitted, so as to get past the period of risk as indicated by the typical duration of an untreated depressive episode. As it often takes at least three months to achieve remission, the full course of antidepressant treatment is often a year or more. For individuals with more severe episodes of depression, such as those associated with significant work disability, suicide attempts, or psychotic symptoms, treatment is often extended for two to three years or longer. Long-term or “maintenance” antidepressant treatment is also used for patients with repeated episodes of depression in an effort to reduce the risk of recurrence and extend periods of wellness. For patients receiving maintenance treatment, its duration becomes an individualized decision in which the prescribing clinician and patient balance adverse effects and cost against the potential consequences of recurrences. Anxiety conditions treated with antidepressants, such as generalized anxiety disorder or social phobia, or with OCD, often are persistent, and several years of treatment may be warranted, particularly if treatment is helpful and well tolerated. As with depression, decisions about the duration of antidepressant treatment for anxiety are based on an individualized risk/benefit assessment, and should be reviewed regularly. Psychotherapy such as cognitive behavior therapy (CBT), when combined with an antidepressant, typically yields better outcomes than pharmacotherapy alone and probably reduces the risk of relapses and recurrences.
Treatment Resistance
As many as two out of three depressed patients do not respond to an initial antidepressant treatment, and as many as one in three remain symptomatic despite two or more antidepressant trials. Depression that has failed to respond to several adequate trials of treatment is referred to as “treatment-resistant depression” (TRD), though the precise definition varies. For such patients, it is very important to review basic information, including the diagnosis, the presence of other psychiatric, medical, or substance abuse disorders, adequacy of dosing, and the presence of other substances that may alter the clearance of an antidepressant, and to evaluate the patient’s adherence to treatment. Repeated trials of similar medicines are unlikely to prove fruitful, but second and third trials with pharmacologically dissimilar agents may help, especially if doses are increased as tolerated. If that approach fails, it is not unusual to combine two antidepressants with complementary mechanisms, such as an SSRI with an NDRI (bupropion). Another strategy involves combining an antidepressant at an adequate dose with a potentiating agent. Some second-generation antipsychotics (notably, aripiprazole, quetiapine, and brexpiprazole) are the only agents specifically FDA-approved for antidepressant augmentation along with the combination of olanzapine and fluoxetine. However, other agents, including lithium, lamotrigine, thyroid hormone, dopamine agonists, and folic acid, have also been used as antidepressant boosters. For treatment-resistant anxiety disorders, other classes of medicines are sometimes considered, including benzodiazepines, some anticonvulsants (e.g., gabapentin, pregabalin, valproate), beta-adrenergic antagonists (e.g., propranolol), alpha-2 adrenergic agonists (e.g., clonidine), buspirone, and second-generation antipsychotics.
Rapid-Acting Antidepressants
An exciting recent development in the field of depression treatment has been the development of drugs that work through novel neural mechanisms not directly related to the potentiation of monoamine neurotransmitters; some exert remarkably rapid antidepressant effects. Two such agents were FDA-approved for depression in 2019: intranasal esketamine (Spravato) for adults with treatment-resistant depression, and brexanolone (Zulresso) for women with postpartum depression. Racemic ketamine, usually given intravenously in doses of about 0.5 mg/kg, had previously been found to have rapid antidepressant effects, and this widely used animal anesthetic agent, which acts as an antagonist of the N-methyl-D-aspartic acid (NMDA) type of excitatory glutamate receptor, has been used clinically to treat TRD on an off-label basis. An isomer of racemic R,S-ketamine, esketamine, is administered by nasal spray as it is not well absorbed through the GI tract. Racemic and esketamine can cause temporary dissociative reactions, agitation, elevated blood pressure, and, rarely, psychosis, especially at relatively high doses. In addition, esketamine has the potential for misuse as a recreational agent. For these reasons, the FDA has required that esketamine be administered only in clinical settings rather than at home and that patients be monitored closely for several hours after dosing, as is also the standard practice with racemic ketamine. Esketamine is typically administered between twice a week to every two weeks, usually along with a standard oral antidepressant. The long-term risks of repeated administration of esketamine require further study, as do suggestions from studies of racemic ketamine that the agent may reduce suicidal thinking along with improving mood.
Brexanolone is a synthetic analogue of the naturally occurring neurosteroid, allopregnanolone. Brexanolone is a modulator of the inhibitory amino acid gamma-aminobutyric acid (GABA) receptor GABA-A. As with ketamine, the gastrointestinal absorption of brexanolone is poor, leading to its administration by intravenous infusion. A typical course of brexanolone involves a 60-hour infusion in a clinical setting with close monitoring. Adverse effects include drowsiness, dizziness, and occasional loss of consciousness. For individuals who experience benefit from esketamine or brexanolone, initial relief from depressive symptoms is often experienced within hours to days compared with weeks or longer with standard antidepressants. Though complicated by side effects, the need for parenteral administration, and high cost, the availability of these agents heralds a new era of antidepressant treatment, possibly of particular value for very severe depression and TRD.
Antipsychotic Drugs
Introduction
The era of effective pharmacological treatment for mania and psychotic disorders started with the discovery of antimanic and antipsychotic properties of the phenothiazine chlorpromazine in Paris in 1952. Its clinical effects included abnormalities of posture and movement, supporting the term “neuroleptic” to imply having broad effects on the nervous system. Many corporations responded to this important discovery by developing similar compounds. Older (“typical” or “first-generation”) antipsychotics include phenothiazines (e.g., chlorpromazine, fluphenazine, perphenazine, thioridazine, trifluoperazine), thioxanthenes (e.g., thiothixene), phenylpiperidines (e.g., haloperidol, pimozide), and dibenzapines (e.g., loxapine). Most modern (“second-generation”) antipsychotics (Figure 15.1) mimic the structure or actions of the highly effective dibenzapine clozapine, including potent antagonism of central serotonin 5HT2 receptors as well as some antagonism at central dopamine D2 receptors.
Figure 15.1 Second-generation (atypical) antipsychotics
Antipsychotics are not specific for schizophrenia, and are particularly efficacious for acute psychotic disorders and mania, with some benefit in organic mental syndromes marked by agitation and psychotic features, as well as having adjunctive uses in severe depression. In addition, perhaps 60 percent or more of their usage is not FDA-approved (“off-label”) for conditions other than psychoses, indicating broad clinical utility and diagnostic nonspecificity.
Antipsychotic drugs include rapidly orally dissolving preparations (for aripiprazole, clozapine, olanzapine, risperidone) that facilitate rapid responses for patients too confused to swallow pills reliably, and short-acting injectable forms (aripiprazole, olanzapine, risperidone, ziprasidone). Half-life averages approximately twenty-four hours, but butyrophenones have much slower tissue-elimination. Long-acting injected preparations are usually given every two to four weeks. They include slowly hydrolyzed decanoate esters of fluphenazine and haloperidol, risperidone in biodegradable carbohydrate microspheres, the palmitate ester of paliperidone, a pamoate complex of olanzapine, as well as a hydrate preparation and lauroxil ester of aripiprazole. Serum assays of most antipsychotics have not proved useful to guide dosing and safety in routine clinical practice.
Antipsychotics palliate acute psychotic symptoms, hasten remission, and limit risk of future exacerbations when continued in maintenance treatment of chronic or recurring psychoses. However, improvements in overall prognosis and functional outcomes in schizophrenia are limited and inconsistent. Controlled trials yield overlapping statistical confidence-intervals of pooled response rates for most antipsychotics, making secure ranking by efficacy difficult. Combinations of antipsychotics are unlikely to provide superior benefits or safety. Differences in adverse-effect risks (tolerability) and cost can usefully guide individual treatment-selection. Risks include neurological reactions with older, especially potent neuroleptics, whereas low-potency older neuroleptics as well as clozapine, olanzapine, and quetiapine are more likely to induce excessive sedative, hypotensive, and weight gain or metabolic effects (Table 15.2).
Table 15.2 Properties of clinically employed antipsychotic drugs
| Drug | Brand | Half-life (hrs) | Doses (mg/day) | Injectable | Preferred | Adverse effect risks | |||
|---|---|---|---|---|---|---|---|---|---|
| Typical | Extreme | CYP | EPS | Sedation | Hypotension | ||||
| Phenothiazines | |||||||||
| Chlorpromazine | Thorazine | 24 | 200–600 | 30–1500 | Yes | 1A2, 2D6, 3A4 | ++ | +++ | ++/+++ |
| Fluphenazine | Prolixin | 24 | 2–20 | 0.5–30 | Yes+Depot | 2D6 | ++++ | + | + |
| Mesoridazine | Serentil | 30 | 75–300 | 30–400 | Yes | 1A2, 2D6, 3A4 | + | +++ | ++ |
| Perphenazine | Trilafon | 12 | 8–32 | 4–64 | Yes | 2D6 | ++ | ++ | + |
| Thioridazine | Mellaril | 22 | 150–600 | 20–750 | No | 1A2, 2D6 | + | +++ | +++ |
| Trifluoperazine | Stelazine | 20 | 5–20 | 2–30 | Yes | 1A2, 2D6 | +++ | + | + |
| Triflupromazine | Vesprin | ––– | 50–100 | 10–150 | Yes | ––– | ++ | +++ | ++/+++ |
| Thioxanthene | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Thiothixene | Navane | 18 | 5–30 | 2–30 | Yes | 1A2 | +++ | +/++ | ++ |
| Phenylpiperidines | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Droperidol | Inapsine | 2 | 2.5–5.0 | 1.25–10 | Yes | ––– | ++++ | ++++ | +++ |
| Haloperidol | Haldol | 20 | 4–20 | 1–50 | Yes+Depot | 3A4 | ++++ | + | + |
| Pimozide | Orap | 55 | 2–6 | 1–10 | No | 3A4 | ++++ | + | + |
| Benzepines | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Clozapine | Clozaril | 12 | 150–450 | 12.5–900 | No | 1A2, 2D6, 3A4 | +/– | +++ | +++ |
| Loxapine | Loxitane | 16 | 60–100 | 20–250 | Yes | ––– | ++/+++ | + | + |
| Olanzapine | Zyprexa | 30 | 5–20 | 2.5–30 | Yes+Depot | 1A2 | + | ++ | ++ |
| Quetiapine | Seroquel | 6.5 | 300–600 | 50–800 | No | 3A4 | +/– | +++ | ++ |
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