CHAPTER 27

Psychopharmacology^*

Stephen J. Ferrando, M.D.

James A. Owen, Ph.D.^†

James L. Levenson, M.D.

Psychopharmacology is critical to the management of all major psychiatric disorders. Since the serendipitous discovery of the psychotropic effects of antidepressants, antipsychotics, and lithium in the early 1950s, the pharmacological armamentarium and evidence for efficacy have grown dramatically, yet many of these original agents remain relevant today. Despite decades of progress, many challenges remain. Our practice of psychiatry is hampered by lack of explanatory biological specificity for the major disorders, making precise diagnosis and medication choice dependent on observation, best application of available evidence, and trial and error. Even with an appropriate diagnosis, medications have limited ability to induce remission, there is significant inter- and intraindividual difference in response, and cure is usually not possible. Further complicating treatment are psychiatric, substance use, and medical comorbidities.

In this chapter, we provide the clinician with an overview of basic psycho-pharmacological principles as well as a discussion of the major classes of psychotropic medications, including antipsychotics, antidepressants, anxiolytics and sedative-hypnotics, mood stabilizers, psychostimulants, and cognitive enhancers. Pharmacological treatment guidelines for specific disorders are covered in the respective chapters. It is implicit that psychopharmacology should be combined, when appropriate, with evidence-based psychosocial and psychotherapeutic treatments in order to enhance medication adherence, reduce symptom burden and relapse, and increase function. Finally, it is important to note that this is not an exhaustive overview of psychopharmacology and the reader is referred to one of the many comprehensive texts for more detailed review of selected topics (e.g., Ferrando et al. 2010; Schatzberg and Nemeroff 2009).

General Principles

Choice of Medication

In general, all drugs indicated for the treatment of a particular psychiatric disorder have similar therapeutic efficacy. Flowever, each patient may better respond to or tolerate one agent over another because of differences in each drug's pharmacokinetics (absorption, distribution, metabolism, and excretion), spectrum of secondary pharmacological effects, or drug interactions. A patient's personal or family history of response to and tolerance of a drug can guide future drug selection. Drug choice is further influenced by the potential for interaction with a medical condition, concurrent medications, or patient preference.

Comorbid medical conditions may influence drug choice. For example, hypotensive patients should avoid medications with substantial α₁-adrenergic blockade that exacerbate hypotension. Patients with compromised hepatic function are better able to eliminate those drugs primarily metabolized by conjugation or renal excretion. Conversely, in patients with renal impairment, drugs undergoing oxidative metabolism, with no active metabolites, are preferred. Comorbid psychiatric conditions maybe exacerbated by certain psychiatric and nonpsychiatric agents. Medically compromised patients, including those with severe nausea and vomiting, dysphagia, or malabsorption, or patients unable or unwilling to take medications by mouth may prefer a drug delivered by a nonoral route such as transdermal, sublingual, or intramuscular. Several psychotropics are available in nonoral formulations (see Owen 2010a for additional information).

Polypharmacy increases the risk of drug-drug interactions and should be minimized or avoided if possible. Drugs with less potential to cause drug interactions are preferred (see "Drug Interactions" subsection below). Often, the number of medications can be reduced by employing a drug's secondary pharmacological effects constructively. For example, a depressed patient with insomnia may benefit from a sedating antidepressant administered at bedtime rather than an additional hypnotic.

Where possible, clinicians should involve patients in medication selection. Patients may find the side effect of one drug (e.g., weight gain) preferable to that of another (e.g., sexual dysfunction). Treatment adherence is improved when the patient takes part in the treatment process. Other strategies to improve compliance are listed in Table 27-1.

Drug Interactions

A drug interaction is the alteration of the pharmacological effect of one drug by another concurrently administered drug or substance. A pharmacokinetic interaction occurs when an interacting substance alters a drug's concentration due to a change in its absorption, distribution, metabolism, or excretion. These interactions are most likely to be clinically meaningful when the drug involved has a low therapeutic index or active metabolites. Pharmacodynamic interactions alter the body's responses to a drug by altering drug binding to a receptor site, or indirectly through other mechanisms (see Owen 2010b and Wynn et al. 2008 for a more extensive review of this topic).

Pharmacokinetic Drug Interactions

Metabolism

The majority of drugs are substrates for Phase I (oxidative) metabolism by one or more cytochrome P450 (CYP) enzymes. The most common pharmacokinetic drug-drug interaction involves changes in the CYP-mediated metabolism of the substrate drug by an interacting drug. The interacting drug may be either an inducer or an inhibitor of the specific CYP enzymes involved in the substrate drug's metabolism. In the presence of an inducer, CYP enzyme activity and the rate of metabolism of the substrate are increased. Enzyme induction is not an immediate process but occurs over several weeks. Induction will decrease the amount of circulating parent drug and may reduce or abolish therapeutic efficacy. Consider a patient, stabilized on risperidone (a CYP1A2 substrate), who begins to smoke (a CYP1A2 inducer). Smoking will-increase risperidone metabolism, and unless the drug dose is suitably adjusted, risperidone levels will fall and psychotic symptoms may worsen. Metabolism of drugs which are not CYP1A2 substrates will not be affected. If the interacting drug is a metabolic inhibitor, drug metabolism mediated through the inhibited CYP isozymes will be impaired. The resulting rise in substrate drug levels may increase drug toxicity and prolong the pharmacological effect. Although enzyme inhibition is a rapid process, substrate drug levels respond more slowly, taking 5 half-lives to restabilize.

Not all combinations of substrate drug and interacting drug will result in clinically significant drug-drug interactions. For a drug eliminated by several mechanisms, including multiple CYP enzymes or non-CYP routes (e.g., renal elimination), the inhibition of a single CYP isozyme only serves to divert elimination to other pathways, with little change in overall elimination rate. Generally, for these interactions to be clinically relevant, a critical substrate drug must have a narrow therapeutic index and one primary CYP isozyme mediating its metabolism. For example, metoprolol, like all β-blockers, is primarily metabolized by the CYP2D6 isozyme. The addition of a potent CYP2D6 inhibitor, such as paroxetine, will inhibit metoprolol metabolism. Without a compensatory reduction in metoprolol dose, drug levels will rise and toxicity (hypotension) may result. When prescribing in a polypharmacy environment, it is best to avoid medications that significantly inhibit or induce CYP enzymes and to prefer those eliminated by multiple pathways and with a wide safety margin. Common drugs that are significant CYP isozyme inhibitors, inducers, and critical substrates are listed in Table 27-2.

The abundance of clinically significant pharmacokinetic interactions involving monoamine oxidase inhibitors (MAOI), especially inhibitors of MAO-A, has limited their therapeutic use. Many of these interactions involve foods containing high levels of tyramine, a pressor amine metabolized by gut MAO-A. Several drugs, including some sympathomimetics and triptan antimigraine medications, are also metabolized by MAO.

Whereas the role of Phase II (conjugative) metabolism is being increasingly recognized in clinical pharmacology, surprisingly few clinically significant drug interactions are known to involve conjugation systems.

Absorption

Many orally administered drugs, including a number of psychotropics, have poor bioavailability due to extensive first-pass metabolism. In the gut wall, drug metabolism by gut CYP3A4 and drug transport back into the gut lumen by the P-glycoprotein (P-gp) efflux transporter system form a barrier to absorption. Inhibitors of CYP3A4 and P-gp can lead to drug toxicity due to dramatic increases in the oral bioavailability of poorly bioavailable drugs. Psychotropics with poor bioavailability include buspirone, selegiline, venlafaxine, ramelteon, zaleplon, fentanyl, rivastigmine, and quetiapine. Diltiazem, a CYP3A4 and P-gp inhibitor, increases buspirone bioavailability by 5- to 10-fold and plasma levels by 4-fold (Lamberg et al. 1998). Common CYP3A4 and/or P-gp inhibitors include grapefruit juice, verapamil, diltiazem, quinidine, progestogen oral contraceptives, and proton pump inhibitors. Furthermore, CYP3A4 and P-gp inducers, such as St. John's wort, may significantly reduce the oral bioavailability of already poorly bioavailable drugs.

Distribution

Changes in drug protein binding, either disease-induced or the result of a protein-binding drug interaction, were once considered a common cause of drug toxicity because therapeutic and toxic effects increase with increasing concentrations of free drug. In the absence of changes in metabolism or excretion, these interactions are now seen as clinically significant only in very limited cases involving rapidly acting, highly protein-bound (>80%), low-therapeutic-index drugs with high hepatic extraction (possible candidates include propafenone, verapamil, and intravenous lidocaine) (Benet and Hoener 2002).

Note. Pharmacokinetic drug interactions: S=substrate; X=inhibitor; I=inducer. Only significant interactions are listed.

^a Combined properties on CYP2C8 /9 /10 and CYP2C19 isozymes.

Excretion

Drug interactions altering renal drug elimination are clinically significant only if the parent drug or its active metabolite undergoes appreciable renal excretion. By reducing renal blood flow, some drugs, including many nonsteroidal antiinflammatory agents and antihypertensive agents, decrease the glomerular filtration rate and impair renal elimination. This interaction is often responsible for lithium toxicity.

Pharmacodynamic Drug Interactions

Pharmacodynamic interactions occur when drugs with similar or opposing effects are combined. The nature of the interaction relates to the addition or antagonism of the pharmacological and toxic effects of each drug. Generally, pharmacodynamic interactions are most apparent in individuals with compromised physiological function such as cardiovascular disease or the elderly. For example, drugs with anticholinergic activity cause a degree of cognitive impairment, an effect exacerbated when several anticholinergic agents are combined. Unfortunately, anticholinergic activity is an often unrecognized property of many common drugs such as antispasmodics, antiparkinsonian agents, and antihistamines. This additive interaction is most disruptive in cognitively compromised patients, such as the elderly or those with Alzheimer's disease, and forms the basis for many cases of delirium.

Additive pharmacodynamic interactions are often employed therapeutically to enhance a drug response—this is the use of adjunctive medications. Antagonistic pharmacodynamic interactions are sometimes used deliberately to diminish a particular adverse effect. In the treatment of chronic pain syndromes psychostimulants such as amphetamine or methylphenidate are frequently combined with morphine or other opiates to reduce opiate sedation and to enhance opiate analgesia. Unintentional antagonistic interactions may be countertherapeutic, as with the erosion of asthma control in a patient who has successfully employed a (3-agonist inhaler and is subsequently prescribed a |3-blocker, or the negation of any cognitive benefit from a cholinesterase inhibitor in the presence of an anticholinergic drug like diphenhydramine.

Knowledge of a drug's therapeutic and adverse effects is essential to avoid unwanted pharmacodynamic drug interactions such as additive or synergistic toxicities, or countertherapeutic effects.

Antipsychotics

The antipsychotics (also known as neuroleptics) have as their core application the treatment of psychosis in schizophrenia; however, they play an increasing role in the treatment of bipolar and unipolar mood disorders. There are two major categories of antipsychotic medications: the first-generation antipsychotics (FGAs; also known as typical antipsychotics) and the second-generation antipsychotics (SGAs; also called atypical antipsychotics). The FGAs, most prominently the phenothiazines (e.g., chlorpromazine) and the butyrophenones (e.g., haloperidol), have heterogeneous receptor effects; however, their primary therapeutic effect is via nonspecific blockade of the dopamine D₂ receptor subtype. The SGAs (clozapine, olanzapine, risperidone, paliperidone, aripiprazole, ziprasidone, quetiapine, asenapine, lurasidone, and iloperidone) are a heterogeneous group of medications that are thought to exert more specific mesolimbic dopamine receptor blockade compared with the FGAs, combined with 5-hydroxytryptamine (5-FIT; serotonin) type 2 (5-HT₂) receptor antagonism. SGAs and FGAs appear to be equally efficacious for the treatment of schizophrenia and other psychoses, with the exception of clozapine, which has superior effects in treatment-refractory illness. The receptor profile of SGAs is thought to confer a lower risk of extrapyramidal side effects (EPS). In recent years, SGAs have played a more significant role in the treatment of bipolar disorder (mania, bipolar depression) and refractory unipolar depression, particularly as adjuncts to mood stabilizer and antidepressant medications, respectively. Generally, the SGAs have the advantage of less common EPS, including parkinsonism, neuroleptic malignant syndrome (NMS), and tardive dyskinesia; however, like many FGAs, the SGAs have significant long-term metabolic (e.g., weight gain, hyperglycemia) and other side effects (e.g., sedation, hypotension).

Indications and Efficacy

Table 27-3 outlines the U.S. Food and Drug Administration (FDA)-approved¹ indications, dosage, formulations, routes of administration and key distinguishing characteristics for currently available antipsychotic medications. As can be seen from the table, all FGAs and SGAs are approved for the acute treatment of schizophrenia, and nearly all are approved for maintenance treatment. Quetiapine is the only SGA approved for use in schizophrenia in children and adolescents; the FGAs haloperidol, trifluoperazine, and thioridazine are approved in these age groups. Clozapine is approved for patients with schizophrenia nonresponsive to two or more trials of antipsychotic medications. All SGAs, with the exception of clozapine, iloperidone, and paliperidone, are approved for use as monotherapy or in combination with mood stabilizers in the acute treatment of manic episodes and the maintenance treatment of bipolar disorder, whereas the only FGA approved in bipolar disorder is chlorpromazine. Quetiapine is the only antipsychotic approved for use as monotherapy in bipolar depression, while olanzapine is approved for use in combination with fluoxetine. Aripiprazole, quetiapine extended release, and olanzapine combined with fluoxetine are approved for use as adjunctive therapy with antidepressants for refractory major depressive disorder. The SGAs aripiprazole and risperidone are approved for the treatment of irritability in autism; the FGAs haloperidol and pimozide are approved for vocal and motor tics in children and adults with Gilles de la Tourette disorder. Finally, the FGAs haloperidol and chlorpromazine are approved for the treatment of severe hyperactivity and disruptive behavior that is not responsive to other medications or behavioral therapy in children older than 3 years.

The Clinical Antipsychotic Treatment Effectiveness Trial (CATIE) attempted to test the relative effectiveness and tolerability of four SGAs and one FGA in "real life" outpatients with schizophrenia (Lieberman et al. 2005). In this trial, 1,493 patients with chronic schizophrenia were randomized to treatment for up to 18 months with olanzapine (range=7.5-30 mg/day; mean modal dose=20.1 mg/day), quetiapine (range=200-800 mg/day; mean modal dose=543.4 mg/day), risperidone (range = 1.5-6.0 mg/day; mean modal dose=3.9 mg/day), ziprasidone (range=40-160 mg/day; mean modal dose=112.8 mg/day), or perphenazine (range=8-32 mg/day; mean modal dose=20.8 mg/day). Olanzapine was more effective than other agents (lower rates of discontinuation, shorter duration of successful treatment, and lower rates of hospitalizations) (Lieberman et al. 2005). However, olanzapine was also associated with the greatest frequency of dropouts due to adverse effects, particularly weight gain. Not surprisingly, the FGA perphenazine was associated with the greatest EPS risk.

Note. BP=bipolar disorder; CATIE=Clinical Antipsychotic Treatment Effectiveness Trial (Lieberman et al. 2005); EPS=extrapyramidal side effects; FDA=U.S. Food and Drug Administration; FGA=first-generation antipsychotic; MDD = major depressive disorder; SGA = second-generation antipsychotic; SZ = schizophrenia; SZAD=schizoaffective disorder.

^aDrug formulations: PO=oral tablets or capsules; L=liquid; ODT=oral disintegrating tablets; SL=sublingual; IM=intramuscular injection; D=decanoate; R=rectal suppository.

^bIndications: acute=acute treatment; maintenance=maintenance treatment; adjunct=adjunctive treatment.

^cRisk for prolonged QTc may be associated with fatal arrhythmias, including torsades de pointes. Obtain baseline electrocardiogram. Avoid use in patients with prolonged QTc, hypokalemia, hypomagnesemia, or concomitant use of other drugs that inhibit metabolism or themselves prolong QTc.

Source. Adapted in part from Martinez M, Marangell LB, Martinez JM: Psychopharmacology, in The American Psychiatric Publishing Textbook of Psychiatry, 5th Edition. Edited by Hales RE, Yudofsky SC, Gabbard GO. Washington, DC, American Psychiatric Publishing, 2008, pp. 1053-1131. Used with permission.

There are multiple "off label" uses for antipsychotic drugs for which there is variable evidence in the literature. These include (but are not limited to) substance-induced psychotic symptoms, agitation and psychosis in delirium, delusional disorders, severe anxiety/agitation, insomnia, psychosis and mood instability in borderline and schizotypal personality disorders, and as adjuncts in refractory obsessive-compulsive disorder. Use of antipsychotics for elderly patients with dementia-related psychosis carries an FDA black box warning for increased risk for mortality secondary to cardiovascular events and infections, particularly pneumonia. Antipsychotics are also used as antiemetics in medically ill patients due to their dopamine-blocking effects. Clinicians considering off-label use of antipsychotic medication must carefully weigh potential benefits against substantial short- and long-term side effects. The risks and benefits should be discussed thoroughly with patients and their families and carefully documented in the medical record (McKean and Monasterio 2012).

Dosage, Response, and Routes of Administration

Recommended dosages for antipsychotic medications with given indications are outlined in Table 27-3. It is important to note that treatment response may take days to weeks, and it may be tempting for clinicians to rapidly escalate doses in the hope of hastening clinical response. Rapid dosage titration and utilization of high antipsychotic doses may lead to unwanted dose-related toxicity with little or no clinical benefit.

Fortunately, multiple routes of administration are available for antipsychotics, which allow for versatility in a variety of clinical situations (e.g., emergency control of psychotic agitation, difficulty with swallowing) and serve to enhance adherence (e.g., orally dissolving and depot preparations) (see Owen 2010a for review of alternate routes of administration for all psychotropic medications). Orally dissolving formulations are available for the SGAs aripiprazole, olanzapine, and risperidone. These medications require swallowing and are absorbed enterally. Asenapine is the only antipsychotic with oral mucosal (sublingual or buccal) absorption; it has no significant enteral absorption. Liquid formulations are available for the SGAs aripiprazole and risperidone as well as the FGAs chlorpromazine, fluphenazine, perphenazine, trifluoperazine, mesoridazine, and thiothixene. The SGAs aripiprazole, olanzapine, and ziprasidone have an intramuscular formulation approved for use in acute agitation in schizophrenia and bipolar disorder. The FGAs haloperidol, chlorpromazine, fluphenazine, trifluoperazine, and mesoridazine also have intramuscular formulations. Long-acting depot formulations are available for the SGAs risperidone and paliperidone and for the FGAs haloperidol and fluphenazine. Although not FDA-approved, haloperidol is often given intravenously for the control of severe psychosis and agitation in medically hospitalized patients with delirium. This use of haloperidol carries a black box warning for QTc prolongation and torsades de pointes.

Adverse Effects

There are numerous potential adverse effects of antipsychotic medications, ranging from mild nuisance effects to severe, life-threatening conditions. These adverse effects can significantly impair quality of life, can pose potential short-and long-term health risks, and, importantly, may impede adherence, leading to relapse of the underlying psychiatric condition. These adverse effects are outlined in Table 27-4. As stated earlier, in general, SGAs as a class have a lowered risk for EPS, including acute dystonias, akathisia, and parkinsonism, as well as NMS and tardive dyskinesia. It is important to note that SGAs are not free of these effects, and risk varies based on D₂ receptor potency, which is highest for risperidone.

Extrapyramidal Side Effects

EPS include acute dystonic reactions, parkinsonian syndrome, akathisia, tardive dyskinesia, and NMS. In general, high-potency FGAs carry the greatest risk, while low-potency phenothiazines and SGAs (except risperidone) carry a significantly lower risk (Tarsy et al. 2011).

Acute dystonic reactions are perhaps the most disturbing EPS for patients, and may be life-threatening in the case of laryngeal dystonias. Patients who have experienced acute dystonias are at risk for medication nonadherence. These reactions can be treated acutely with intravenous or intramuscular medication, followed by oral maintenance. Patients who have a history of dystonia or who are perceived to be at risk may be treated prophylactically. This approach is generally averted by SGA use. Medications used to treat EPS are outlined in Table 27-5. Most EPS are responsive to anticholinergic agents or amantadine, with the exception of akathisia, which is responsive to propranolol (Blaisdell 1994).

Tardive Dyskinesia

Tardive dyskinesia is a disorder characterized by involuntary choreoathetoid movements of the face, trunk, or extremities, as well as tardive akathisia, dystonias, and tics. Tardive dyskinesia is associated with prolonged exposure to high-potency FGAs; however, the disorder has been reported with SGAs (with the exception of clozapine) as well as dopamine antagonist antiemetics (especially metoclopramide). (Tarsy et al. 2011). Tardive dyskinesia often emerges abruptly after antipsychotic discontinuation and is mitigated or masked by resumption of the same or an alternative antipsychotic. Elevated oxidative load (free radicals) and glutamatergic neurotoxicity have been implicated in the disorder (Tsai et al. 1998). Risk factors include older age, female gender, EPS early in the treatment, history of drug holidays, presence of other brain disorders, diabetes mellitus, and a diagnosis of a mood disorder. Cumulative prevalence is 5% per year of exposure in young adults and 30% per year in the elderly (American Psychiatric Association 1992).

The Abnormal Involuntary Movement Scale (AIMS; Guy 1976) may be used to assess and monitor patients at risk for tardive dyskinesia. An evaluation for abnormal movements should be conducted before treatment begins and every 6 or 12 months thereafter. Patients often tend to minimize or be unaware of tardive dyskinesia symptoms.

No definitive treatment for tardive dyskinesia has been identified to date. Although tardive dyskinesia will often resolve within weeks or months of antipsychotic discontinuation, it may persist indefinitely. A meta-analysis of α-tocopherol (vitamin E) treatment for tardive dyskinesia indicated no clear benefit over placebo, but α-tocopherol-treated patients showed less deterioration in tardive dyskinesia over time (Soares-Weiser et al. 2011). Clozapine is a desirable agent for patients with tardive dyskinesia who need an antipsychotic medication (Lieberman et al. 1991; van Harten and Tenback 2011).

Note. DA=dopamine; ECG=electrocardiogram; ECT=electroconvulsive therapy; SGA=second-generation antipsychotic; WBC=white blood cell.

^a Most adverse effects listed will respond to dosage reduction or discontinuation of medication and switch to an alternative agent with less propensity to cause this effect. Therefore, this strategy is not listed for each adverse effect. If the adverse effect is not dose-related, that circumstance is indicated.

^b Highest risk associated with thioridazine, chlorpromazine, quetiapine, ziprasidone, intravenous haloperidol, pimozide. Risk increased with coadministration of metabolic inhibitors of antipsychotics. Lowest-risk agent is aripiprazole. (This Note b is not found from the original Textbook.)

Note. po=oral administration of tablets or capsules; bid=twice daily; iv=intravenous; tid=three times a day; im=intramuscular.

^a Follow with oral medication.

Source. Adapted from Martinez M, Marangell LB, Martinez JM: Psychopharmacology, in The American Psychiatric Publishing Textbook of Psychiatry, 5th Edition. Edited by Hales RE, Yudofsky SC, Gabbard GO. Washington, DC, American Psychiatric Publishing, 2008, pp. 1053-1131. Used with permission.

Neuroleptic Malignant Syndrome

The incidence of NMS is about 0.02% among patients treated with antipsychotic drugs (Caroff 2003b; Strawn et al. 2007). Classic signs are hyperthermia, generalized rigidity with tremors, altered consciousness with catatonia, and autonomic instability. Laboratory findings include muscle enzyme elevations (primarily creatine phosphokinase, median elevations 1,000 IU/L; Gurrera et al. 2011), myoglobinuria, leukocytosis, metabolic acidosis, hypoxia, and low serum iron levels. Risk factors include dehydration, exhaustion, agitation, catatonia, previous episodes, and large doses of high-potency drugs given parenterally at a rapid rate of titration. NMS may develop within hours but usually evolves over days, with two-thirds of cases occurring during the first 1-2 weeks after drug initiation. Several lines of evidence implicate drug-induced dopamine blockade as the primary triggering mechanism in the pathogenesis of NMS. Once dopamine-blocking drugs are withheld, two-thirds of NMS cases resolve within 1-2 weeks, with an average duration of 7-10 days (Caroff 2003b). Patients may experience more prolonged symptoms (4 weeks) if injectable long-acting drugs are implicated. Occasional patients develop a residual catatonic and parkinsonian state that can last for weeks unless electroconvulsive therapy (ECT) is administered (Caroff et al. 2000). NMS is potentially fatal in some cases due to renal failure, cardiorespiratory arrest, disseminated intravascular coagulation, pulmonary emboli, or aspiration pneumonia.

Treatment consists of early diagnosis, discontinuing dopamine antagonists, and supportive medical care. Benzodiazepines, dopamine agonists, dantrolene, and ECT have been advocated in clinical reports, but randomized controlled trials comparing these agents with supportive care have not been done. These agents may be considered empirically in individual cases, based on symptoms, severity, and duration of the episode (Strawn et al. 2007). For additional information about the diagnosis and management of NMS, access the Neuroleptic Malignant Syndrome Information Service (888-667-8367 or www.nmsis.org).

Endocrinological Effects

Metabolic Syndrome

Most antipsychotics are associated with metabolic syndrome (American Diabetes Association et al. 2004). Metabolic syndrome is defined by five criteria: abdominal obesity, triglycerides >150 mg/dL (>1.7 mmol/L), high-density lipoprotein (HDL) <40 mg/dL (<1.03 mmol/L) for men or <50 mg/dL (<1.28 mmol/L) for women, blood pressure >130/85 mm Hg, and fasting glucose >110 mg/dL (>6.0 mmol/L) (Expert Panel 2001). Metabolic syndrome is an independent risk factor for diabetes (including ketoacidosis) and for cardiovascular, cerebrovascular, and peripheral vascular disease (Wilson et al. 2002). The extent to which metabolic syndrome is solely a function of antipsychotic treatment is controversial. Compared with the general population, medication-naive patients with schizophrenia, bipolar disorder, or schizoaffective disorder have been found to have impaired glucose tolerance (D. Cohen et al. 2006; Ryan et al. 2003). Generally antipsychotic-induced metabolic changes are proportional to weight gain, which has been related to blockade of histamine H-, and 5-HT_2C receptors and to increased levels of insulin and leptin (Nasrallah 2003). Weight gain is common with SGAs; clozapine and olanzapine cause the greatest weight gain (3-12 kg), whereas quetiapine, risperidone, and aripiprazole cause mild to moderate weight gain (2-4 kg) (Gentile 2006). Ziprasidone appears to be the only SGA that is weight neutral. Elevations in serum triglycerides and low-density lipoprotein (LDL) cholesterol as well as diminished HDL cholesterol usually occur in parallel, but these changes may exist in the absence of weight gain. Patients taking antipsychotics should be monitored for weight gain, hypertension, glucose in~ tolerance, and lipid derangements. Guidelines for patient monitoring are summarized in Table 27-6.

Treatment of metabolic syndrome begins with dosage adjustment when feasible or cross-tapering to a more weight-neutral medication (e.g., aripiprazole, ziprasidone). Techniques including dietary education, exercise, and cognitive-behavioral interventions have been found in randomized controlled trials to be effective for either maintaining or losing weight in patients treated with atypical antipsychotics. Several randomized controlled trials have documented small benefits from the addition of metformin (500-850 mg/day in divided doses) to an antipsychotic regimen for reducing or preventing weight gain and insulin resistance (Baptista et al. 2007; Klein et al. 2006; Wu et al. 2008).

Hyperprolactinemia may cause impotence, menstrual dysregulation, infertility, and sexual dysfunction (Bostwick et al. 2009). Elevated prolactin may also give rise to galactorrhea and gynecomastia (Windgassen et al. 1996). Emerging evidence suggests long-term sequelae, including loss of bone mineral density and osteoporosis (O'Keane and Meaney 2005), breast cancer (Tworoger and Hankinson 2006), and cardiovascular disease (Serri et al. 2006). Risk factors for drug-induced hyperprolactinemia include increased potency of D₂ blockade, female sex, and increased age (Kinon et al. 2003). Additionally, an increased risk is identified in those with the CYP2D6*10 allele (Ozdemir et al. 2007). Hyperprolactinemia is most likely to occur with risperidone and high-potency FGAs, and least likely with aripiprazole. Current American Psychiatric Association guidelines recommend routine monitoring of prolactin serum levels only in symptomatic patients (Lehman et al. 2004). Treatment strategies include 1) decreasing the dosage of the offending agent, 2) changing medication to an agent less likely to affect prolactin, 3) using a dopamine partial agonist such as aripiprazole (Mir et al. 2008), and 4) preventing long-term complications such as bone demineralization.

Cardiac Effects

All antipsychotics may prolong the QT interval, with the possible exception of aripiprazole. Haloperidol, droperidol, thioridazine, sertindole, and ziprasidone tend to produce greater magnitude QT prolongation than other agents (Glassman and Bigger 2001; Stöllberger et al. 2005). QT interval prolongation corrected for heart rate (QTc) greater than 500 msec is associated with increased risk of polymorphic sustained ventricular tachycardia (torsades de pointes), which can degenerate into ventricular fibrillation. Women, patients with chronic heavy alcohol consumption, and patients with anorexia nervosa are at increased risk. Other noted risk factors for torsades de pointes include familial long QT syndrome, severe heart disease, hypokalemia, hypomagnesemia, and concurrent treatment with other drugs that prolong the QT interval or that inhibit antipsychotic metabolism (Justo et al. 2005; Stöllberger et al. 2005).

Note. BMI=body mass index (weight in kg/[height in m²]); CVD=cardiovascular disease; DM=diabetes mellitus.

Source. Adapted from American Diabetes Association et al. 2004.

Based on Danish registry data, the risk of sudden death associated with antipsychotic medication is estimated to be only about 2-4 per 10,000 person-years of exposure in otherwise medically healthy subjects (Glassman and Bigger 2001). However, reviews of treatment studies addressing use of both first- and second-generation antipsychotic medications inbehaviorally disturbed elderly patients have concluded that antipsychotic medications are associated with about a 1.9% absolute increase in short-term mortality in this patient population (4.5% vs. 2.6%, or about a 70% increase in adjusted relative risk), due mostly to cardiovascular events and infections. This resulted in an FDA-mandated black-box warning about off-label treatment of agitation and psychotic symptoms in behaviorally disturbed elderly patients with dementia (Kuehn 2008; Rochon et al. 2008). A review of Tennessee Medicaid data found that nonusers of antipsychotic drugs had a sudden death rate of 0.0014 deaths per person-year, whereas antipsychotic drug users had a sudden death rate of 0.0028-0.0029 deaths per person-year (Ray et al. 2009). Thus, antipsychotic drugs were associated with an approximate doubling of risk for sudden death, but the absolute risk was only about 0.0015 deaths per person-year, yielding a number needed to treat to cause one additional sudden death in 1 year of 666 persons. The degree to which these findings apply in the treatment of delirium and acute psychotic symptoms in patients with cardiac disease is unknown.

Clozapine is associated with a risk of myocarditis, which has been variously estimated to develop in between 0.01% and 1% of exposed patients (Merrill et al. 2005), generally within the first few weeks of treatment. An immune hypersensitivity reaction is suspected. Patients exposed to clozapine also have an increased incidence of cardiomyopathy, even in the absence of an acute myocarditis process; onset may occur months to a few years after starting treatment (Mackin 2008).

Drug Interactions (See also "General Principles" Section)

Most antipsychotics are metabolized by the hepatic CYP2D6 isoenzyme. Exceptions include ziprasidone and quetiapine, which are metabolized mainly by the CYP3A4 enzyme. Thus, metabolism may be affected by inhibition or induction of these enzymes. For example, the addition of fluoxetine increased serum haloperidol concentrations significantly (Avenoso et al. 1997). Two categories of potential drug-drug interactions are of particular concern. The first includes interactions that can increase serum concentrations of antipsychotics to dangerous levels. For example, clozapine is metabolized by the CYP2D6, CYP3A4, and CYP1A2 isoenzymes. Coadministration of potent inhibitors erythromycin or fluvoxamine can lead to toxic serum clozapine concentrations (Wetzel et al. 1998). Conversely, reductions in serum clozapine and haloperidol concentrations have been reported with the addition of enzyme inducers such as carbamazepine, phenobarbital, and phenytoin (Arana et al. 1986; Byerly and DeVane 1996). Cigarette smoking can affect antipsychotic metabolism; serum concentrations of clozapine in particular are reduced with smoking and increased after smoking cessation (Byerly and DeVane 1996; Haring et al. 1989).

Clozapine

Clozapine, the first and a uniquely important SGA, is discussed in detail here. Clozapine has been shown in multiple clinical trials, including CATIE, to be efficacious for treatment-resistant schizophrenia, to significantly reduce negative symptoms of schizophrenia, and to reduce suicidal ideation and attempts in patients with schizophrenia and related disorders. Clozapine rarely causes EPS and does not produce tardive dyskinesia. This clinical profile is thought to be due to clozapine's selective blockade of mesolimbic dopamine pathways, with minimal effects on the tuberoinfundibular and nigrostriatal dopamine tracts.

Because clozapine is associated with a risk for agranulocytosis, its use is restricted to patients who have not adequately responded to or who have not tolerated treatment with two other anti-psychotics (Lewis et al. 2006). Several studies have confirmed clozapine's efficacy in patients with a history of nonresponse to previous antipsychotic treatment, with up to 30% of such patients responding (Lewis et al. 2006; McEvoy et al. 2006).

Clozapine shows a high in vitro receptor affinity for the D₄, 5-HT₂, α₁-adrenergic, muscarinic, and receptors and a relatively weak affinity for D₁ D₂, and D₃ receptors. The high 5-HT₂-to-D₂ ratio is hypothesized to be responsible for many of clozapine's advantages (Meltzer 1994). Clozapine may also increase norepinephrine release (Breier et al. 1994) and may reduce glutamatergic N-methyl-D-aspartate (NMDA) receptor-mediated neurotoxicity (Goff and Coyle 2001).

Clozapine therapy is usually cross-titrated with a previous agent with insufficient efficacy. It is initiated at a dosage of 12.5 mg/day, with a rapid increase to 12.5 mg twice a day. The dose is then increased as tolerated, generally in 25- or 50-mg increments every day or every other day. It is important to monitor for orthostatic hypotension and sedation. Clozapine doses can be increased much more rapidly in an inpatient setting, with monitoring of vital signs. The typical target dose is 300-500 mg/day in divided doses. Although routine blood-level monitoring is not recommended, a serum level greater than 350 ng/mL is associated with a higher response rate (Perry et al. 1991). Serum levels should be ascertained in nonresponders. The duration of treatment required to assess response is longer than for most medications, typically 3-6 months (Meltzer 1994). Gradual titration up to 900 mg/day may be necessary for patients who do not respond to clozapine after 6 months and who have no other viable options.

Agranulocytosis was previously estimated to occur in 0.8% of the patients receiving clozapine during the first year of treatment, with a peak incidence at 3 months. A system of hematological monitoring, the Clozaril National Registry (www.clozapineregistry.com), has reduced agranulocytosis-related fatalities to less than half of previous levels. In this system, clozapine dispensing is linked to weekly white blood cell (WBC) counts during the first 6 months of treatment and biweekly counts thereafter. Strict guidelines for management based on WBC and absolute neutrophil counts have been set (Table 27-7).

If agranulocytosis develops, prompt consultation with a hematologist is indicated. Reverse isolation and prophylactic antibiotics may be used to prevent infection. Granulocyte colony-stimulating factors may be used to shorten the duration and reduce the morbidity of agranulocytosis (Gerson 1994). Once a patient has developed agranulocytosis while taking clozapine, he or she should not be rechallenged with this medication, although cautious rechallenge may be considered after neutropenia (Manu et al. 2012).

Source. Adapted from Martinez M, Marangell LB, Martinez JM: "Psychopharmacology," in The American Psychiatric Publishing Textbook of Psychiatry, 5th Edition. Edited by Hales RE, Yudofsky SC, Gabbard

GO. Washington, DC, American Psychiatric Publishing, 2008, pp. 1053-1131. Used with permission.

Clozapine is relatively contraindicated in patients who have myeloproliferative disorders and/or who are immunocompromised, because of their increased risk for agranulocytosis. Concomitant administration of medications that are associated with bone marrow suppression, such as carbamazepine, is also relatively contraindicated.

Clozapine is associated with a dose-dependent risk of seizures, most often tonic-clonic. Dosages less than 300 mg/day are associated with a l%-3% risk of seizures; dosages of 300-600 mg/day carry a 2.7% risk; and dosages greater than 600 mg/day are associated with a 4.4% risk (Devinsky et al. 1991). Clozapine dosages greater than 600 mg/day are not recommended unless the patient's symptoms have not responded at lower doses. Once a seizure has occurred, determining whether to continue using clozapine requires clinical judgment. Carbamazepine use should be avoided in patients taking clozapine because of the additive risk of bone marrow suppression. At present, valproate appears to be the safest anticonvulsant for patients taking clozapine.

Mood Stabilizers

Three primary classes of medications have documented efficacy in the treatment of mania associated with bipolar disorder: 1) lithium and 2) the anticonvulsants valproic acid, lamotrigine, and carbamazepine, covered in this section; and 3) the antipsychotics, covered previously. The cornerstone of mood stabilization is treatment of acute mania; however, the approved indications and documented efficacy of these drugs vary for other aspects of bipolar disorder, including maintenance treatment (prevention of mania and depression relapse), mixed manic states, and bipolar depression. Table 27-8 outlines the indications, dosing, serum drug level monitoring (as applicable), and adverse effects of the approved mood stabilizers.

Lithium

The tranquilizing properties of lithium have been known for millennia; however, its toxicity with unregulated use limited its application in medicine. The modern use of lithium for the treatment of mania was described by Cade in 1949, after his serendipitous observation that lithium calmed rodents when used in his experiments on uric acid (Cole and Parker 2012). He and others studied the pharmacological use of lithium in manic-depressive patients during the 1950s and 1960s, and the FDA approved lithium for the treatment of mania in 1970. It remains the gold standard medication in the treatment of this condition.

Lithium has multiple proposed mechanisms. It influences several intracellular properties, including phosphoinositide metabolism, G proteins, and protein kinase activity, and it stimulates neurogenesis.

Lithium is approved for acute mania and maintenance treatment for prophylaxis against mania and depression in bipolar disorder (American Psychiatric Association 2002, 2006), and is considered to be a first-line choice for treatment of bipolar depression. Patients with rapid-cycling bipolar disorder and mixed manic states may respond less well to lithium treatment (Dunner and Fieve 1974). Lithium is also effective as an adjunct to antidepressant therapy in treatment refractory unipolar depression (American Psychiatric Association 2002, 2006) and may be useful in maintaining remission of depression after ECT (Sackeim et al. 2001).

Clinical Use

Lithium carbonate is completely absorbed in the gastrointestinal tract, reaches peak plasma levels in 1-2 hours, has an elimination half-life of approximately 24 hours, and reaches steady state in approximately 5 days. It is excreted unaltered through the urine. Lithium is dosed according to clinical response, side effects, and serum level. During acute treatment, lithium is generally started at 900-1,200 mg/day in divided doses, and may be raised as high as 1,500-1,800 mg/day. A serum level of 0.8-1.5 mEq/L is generally necessary for treatment of acute mania; however, side effects must be monitored closely at the higher end of the range. During the initiation phases of lithium treatment, it is often combined with an antipsychotic and/or benzodiazepine until lithium has a chance to take effect (American Psychiatric Association 2002, 2006). Once sustained remission of mania is achieved, adjunctive medications are tapered if possible.

Serum concentrations required for maintenance treatment in bipolar disorder are not precisely known. A study comparing low serum lithium levels (0.4-0.6 mEq/L) versus standard serum levels (0.8-1.0 mEq/L) in patients receiving maintenance therapy found fewer relapses in the standard-dose group (Gelenberg et al. 1989). A relapse may be more likely to be triggered by a sudden rather than a gradual drop in lithium level (Perlis et al. 2002).

Lithium is often given in divided doses at the initiation of treatment; however, once stability is achieved and side effects have been assessed, it may be helpful to give lithium once daily in the evening or at bedtime. This helps to increase adherence and to minimize adverse effects, such as daytime polyuria and polydipsia (see "Lithium and the Kidney" subsection below).

Note. Table excludes antipsychotics that are U.S. Food and Drug Administration (FDA) approved for use in bipolar disorder (aripiprazole, asenapine, olanzapine, quetiapine, risperidone, and ziprasidone). See Table 27-3 for details regarding use of antipsychotics in bipolar disorder. DRESS=drug reaction with eosinophilia and systemic symptoms; N/A=not applicable.

Lithium levels should be determined about 12 hours after the last lithium dose. After therapeutic lithium levels have been established, levels should be measured every month for the first 3 months and every 3-6 months thereafter. Renal function should be determined before lithium therapy and every 3-6 months during therapy if tolerated, and more frequently if adverse effects increase or if there are signs of renal insufficiency.

Lithium is almost entirely excreted by the kidneys. It is contraindicated in patients with acute renal failure, but not in those with chronic renal failure. For patients with stable partial renal insufficiency, clinicians should dose conservatively and monitor renal function frequently. For patients on dialysis, lithium is completely dialyzed and may be given as a single oral dose (300-600 mg) following hemodialysis treatment. Lithium levels should not be checked until at least 2-3 hours after dialysis, because reequilibration from tissue stores occurs in the immediate post-dialysis period. For patients on peritoneal dialysis, lithium can be given in the dialysate. Lithium prolongs the QT interval and may increase the risk of cardiac arrhythmias in patients with electrolyte disturbances.

Adverse Effects

Lithium has a number of serum level-dependent side effects that, if present, can be a significant impediment to adherence and at worst may cause severe toxicity. Lithium has a low therapeutic index, with a narrow difference between therapeutic and toxic levels. Fluid and electrolyte disturbances as well as concurrent medications that modify renal function (particularly nonsteroidal antiinflammatory drugs, thiazide diuretics, angiotensin-converting-enzyme inhibitors) may reduce elimination and increase adverse effects. Children, the elderly, and patients with medical and neurological comorbidity are at heightened risk. Table 27-9 outlines the adverse effects of lithium according to serum level in adults. Common adverse effects in the therapeutic range include gastrointestinal disturbances (nausea, vomiting), fine motor tremor, cognitive slowing, weight gain, cardiac effects (benign flattening of T wave, QTc prolongation), benign leukocytosis, and dermatological complications including acne, folliculitis, psoriasis, and hair loss. Fine motor tremor is successfully treated with propranolol up to 80 mg daily in divided doses (Zubenko et al. 1984). Patients often complain of impaired cognitive and psychomotor slowing while on lithium, which may precipitate nonadherence in those who are accustomed to the rapid thoughts and perceived clarity associated with mania. It is important to note that bipolar disorder itself is associated with neuropsychological impairment, independent of medication treatment.

Acute lithium toxicity occurs at serum levels above 1.5 mEq/L, and can involve moderate to severe gastrointestinal, neurological, and cardiovascular effects, outlined in Table 27-9. Management of lithium toxicity (Table 27-10) includes discontinuation of lithium, supportive hospital care, and, in severe cases, hemodialysis. A rare severe encephalopathic syndrome has also been reported in patients treated with lithium and haloperidol, suggesting synergistic toxic effects (Caroff 2003a). The manifestations of this neurotoxicity are similar to those of lithium. toxicity; however, the symptoms may occur at nontoxic serum lithium levels.

Lithium and the Kidney

Lithium causes water and sodium diuresis and may precipitate nephrogenic diabetes insipidus (NDI) (see Table 27-10). Most patients receiving lithium have polydipsia and polyuria, reflecting mild benign NDI. Lithium-induced NDI sometimes has persisted long after lithium discontinuation, and varies from mild polyuria to hyperosmolar coma. Amiloride is considered the treatment of choice for lithium-induced NDI (Grünfeld and Rossier 2009).

The effects of lithium on renal function are controversial; some studies report that longer duration of lithium therapy is predictive of a decrease in estimated glomerular filtration ("creeping creatinine"), whereas others do not. Although chronic lithium use may result in altered kidney morphology, including interstitial fibrosis, tubular atrophy, urinary casts, and occasionally glomerular sclerosis, in 10%-20% of patients (Bendz et al. 1996), these changes are not generally associated with impaired renal function. A meta-analysis concluded that lithium-induced effects on renal function are quantitatively small and probably clinically insignificant (Paul et al. 2010). Although long-term lithium treatment is the only well-established factor associated with lithium-induced nephropathy, changes in renal function are often associated with other factors, including age, episodes of lithium toxicity, other medications (analgesics, substance abuse), and the presence of comorbid disorders (hypertension, diabetes). Lithium dosage is not strongly related to nephrotoxic effects (Freeman and Freeman 2006). The progression of lithium nephrotoxicity to end-stage renal disease is rare (0.2%-0.7%) and requires lithium use for several decades (Presne et al. 2003). With yearly monitoring of renal function, the benefits of long-term lithium maintenance for bipolar disorder far outweigh the risks to renal function.

Note. BUN=blood urea nitrogen; CR=creatinine; K⁺=potassium; T₃=triiodothyronine; T₄=thyroxine; TSH=thyroid-stimulating hormone.

Source. Adapted from Saxena S, Fieve RR: "Managing Adverse Effects of Mood Stabilizers." Primary Psychiatry 14:59-67, 2007.

Lithium-Induced Thyroid Disorders

Lithium-induced hypothyroidism is common (see Table 27-10), developing in 5%-35% of patients treated for bipolar disorder. It presents with varying degrees of severity from subclinical effects to myxedema. Women have three times higher risk than men of developing lithium-induced hypothyroidism within 2 years of initiating therapy (14% for women vs. 4.5% for men) (Johnston and Eagles 1999). Women who were 40-59 years of age had the highest risk (20%). Subclinical hypothyroidism (i.e., elevated thyroid-stimulating hormone (TSH) with normal thyroxine (T₄) and no symptoms) is more prevalent than clinical hypothyroidism. Among outpatients receiving lithium therapy 39% had subclinical hypothyroidism and only 3% had clinical hypothyroidism (Deodhar et al. 1999).

Risk factors for the development of lithium-induced hypothyroidism include female sex (Ahmadi-Abhari et al. 2003), preexisting vulnerability to autoimmune thyroiditis (Baethge et al. 2005), first-degree relatives with thyroid anomalies (Kusalic and Engelsmann 1999), increased duration of treatment, age older than 50 years (Ozpoyraz et al. 2002), and weight gain of more than 5 kg while receiving treatment (Caykoylu et al. 2002). Screening for thyroid dysfunction via measurement of TSH should occur prior to initiating lithium therapy. TSH should be reassessed 3 months into treatment. If TSH is normal, follow-up every 6-12 months is suggested while the patient is undergoing lithium therapy. A mild increase in TSH and a decrease in T₄ may be seen during the first few months of treatment; these effects are usually selflimited, and T₄ replacement is unwarranted (Maarbjerg et al. 1987). If clinically significant hypothyroidism develops or subclinical effects persist after 4 months of lithium treatment, T₄ replacement or a switch to an alternative mood stabilizer (e.g., valproate) is recommended (Kleiner et al. 1999).

Approximately l%-2% of lithium-treated patients develop hyperthyroidism (Bogazzi et al. 1999). Lithium-induced hyperthyroidism may be missed because it is often transient, asymptomatic, and followed by hypothyroidism (Stow-ell and Barnhill 2005). Lithium-induced or exacerbated autoimmune thyroiditis is the likely mechanism, although, because lithium is concentrated within the thyroid, it is postulated that lithium might directly damage thyroid follicular cells, triggering release of thyroglobulin into the circulation (Mizukami et al. 1995). Although no treatment guidelines are available for lithium-induced thyrotoxicosis, a switch to an alternative mood stabilizer is generally necessary.

Lithium and Hyperparathyroidism

Hyperparathyroidism is an underrecognized side effect of long-term lithium therapy, and it is prudent to screen patients undergoing chronic lithium therapy for hypercalcemia (Saunders et al. 2009). Cessation of lithium often does not correct the hyperparathyroidism, necessitating parathyroidectomy. Although hyperparathyroidism is a risk factor for osteoporosis, patients taking lithium who have normal calcium and parathyroid hormone levels do not have an increased risk of osteoporosis. One study even found that maintenance therapy with lithium carbonate may actually preserve or enhance bone mass (Zamani et al. 2009).

Valproate

Divalproex sodium is approved for the treatment of acute mania. Valproic acid binds to and inhibits γ-aminobutyric acid (GABA) transaminase, resulting in increased brain concentrations of GABA, an inhibitory neurotransmitter. Valproic acid may also work by suppressing repetitive neuronal firing through inhibition of voltage-sensitive sodium channels.

Clinical Use

Several valproate preparations are available in the United States, including valproic acid, sodium valproate, divalproex sodium, and an XL preparation of divalproex sodium (slightly reduced bioavailability). Divalproex sodium, a dimer of sodium valproate and valproic acid with an enteric coating, is the best-tolerated of the valproate preparations. The half-life of valproate is 9-16 hours.

There are two primary strategies for initiation of valproate: gradual dosage titration and valproate loading. The former is appropriate for patients with hypomania or mild manic symptoms, with treatment initiated at 250 mg three times daily, then adjusted upward every 3-4 days to a target range of 1,000-2,000 mg. For acute mania, valproate treatment can be initiated at a dose of 20 mg per kilogram of body weight (Keck et al. 1993). Plasma levels of 85-125 μg/mL are recommended for the treatment of acute mania (see Table 27-8); however, dosing should be based on clinical response and side-effect burden.

Adverse Effects

The most common adverse effects of valproate are gastrointestinal, including indigestion, nausea, and vomiting. Sedation, mild ataxia, benign tremor, and weight gain are also common. Weight gain does not appear to be dose dependent, and diet and exercise should always be recommended. Valproate treatment can also cause alopecia, which is generally but not always reversible.

Valproate has been associated with rare hepatic failure and is considered to be relatively contraindicated for patients with severe liver disease. No cases have occurred in patients older than 10 years who were receiving valproate monotherapy. Prior to initiation of valproate, baseline liver function tests are indicated. Monitoring of liver function tests while on valproate may yield elevations of liver enzymes 2-3 times normal that do not necessitate discontinuation if they remain stable and are not associated with clinical signs of liver toxicity (Pellock and Willmore 1991). Serum ammonia and y-glutamyltransferase levels may also be transiently elevated and of no clinical significance.

Rarely, valproate can cause pancreatitis (Pellock et al. 2002). If vomiting and severe abdominal pain develop during valproate therapy, serum amylase levels should be determined immediately and valproate discontinued.

Valproate has also been associated with thrombocytopenia and should be given with caution in patients requiring anticoagulation.

Polycystic ovarian syndrome is characterized by menstrual irregularity and hyperandrogenism, including hirsutism. In the Systematic Treatment Enhancement Program for Bipolar Disorders (STEP-BD), women taking valproate had a 10.5% rate of oligomenorrhea with hyperandrogenism, compared with 1.4% of the women with bipolar disorder who were taking other agents (Joffe et al. 2006).

Valproate overdose results in sedation, confusion, and ultimately coma. The patient also may manifest hyperreflexia or hyporeflexia, seizures, respiratory suppression, and supraventricular tachycardia. Treatment should include gastric lavage, electrocardiographic monitoring, treatment of emergent seizures, and respiratory support.

Drug Interactions (See also "General Principles" Section)

Valproate can inhibit hepatic enzymes, resulting in increased levels of other medications, particularly lamotrigine, resulting in increased risk of rash (current lamotrigine product labeling provides specific lamotrigine dosing guidelines for patients who are taking valproate). Valproate may increase concentrations of phenobarbital, ethosuximide, and the active 10,11-epoxide metabolite of carbamazepine, increasing the risk of toxicity. Valproate is also highly bound to plasma proteins and may displace other highly bound drugs from protein-binding sites, which may lead to toxicity with low-therapeutic-index drugs. Drugs that may increase valproate levels include cimetidine, macrolide antibiotics (e.g., erythromycin), and felbamate. Valproate metabolism may be induced by other anticonvulsants, including carbamazepine, phenytoin, primidone, and phenobarbital, resulting in an increased total clearance of valproate and perhaps decreased efficacy.

Carbamazepine

Carbamazepine extended release (Equetro) is approved for the treatment of acute mania, although all formulations have been found to be effective for acute and maintenance treatment of mania (Weisler et al. 2004, 2005).

Carbamazepine should be initiated at a dosage of 200 mg twice a day, with increments of 200 mg/day every 3-5 days to a maximum of 1,600 mg/day. Medication dosage should balance clinical response with side effects. A therapeutic serum level of 4-12 mg/L is documented in patients with epilepsy, but the upper limit is more useful for monitoring toxicity in bipolar patients. During the titration phase, patients may experience sedation, dizziness, and ataxia, necessitating more gradual titration. Carbamazepine induces its own metabolism, which may cause downward fluctuations in serum levels and clinical response in the early stages of treatment, necessitating careful upward dose adjustment.

Adverse Effects

Gastrointestinal (nausea, vomiting) and mild neurological (dizziness, drowsiness, or ataxia) side effects are common with carbamazepine, particularly early in treatment. The most serious toxic hematological side effects of carbamazepine are agranulocytosis and aplastic anemia, which can be fatal. Fortunately, these are rare (Fuller et al. 2006), and other hematological effects, such as leukopenia (total WBC count<3,000 cells/mm³), thrombocytopenia, and mild anemia may occur more frequently. When carbamazepine-induced agranulocytosis occurs, the onset is rapid, making periodic hematological monitoring of limited benefit. Therefore, it is important to educate the patient regarding early signs and symptoms of agranulocytosis and thrombocytopenia and to inform their physician immediately if these occur.

Carbamazepine may also cause hepatic toxicity (Horowitz et al. 1988), usually a hypersensitivity hepatitis that appears after several weeks and involves increases in alanine transaminase (ALT), aspartate transaminase (AST), and lactate dehydrogenase levels. Cholestasis is also possible, with increases in bilirubin and alkaline phosphatase concentrations. Mild transient increases in transaminase levels generally do not necessitate discontinuation of carbamazepine. If ALT or AST levels increase more than three times the upper limit of normal, carbamazepine should be discontinued.

Rash is a common side effect of carbamazepine, occurring in 3%-17% of patients within the first 6 months of treatment. If rash develops, dermatological consultation and cessation of carbamazepine should be considered because of the risk of Stevens-Johnson syndrome and other serious dermatological reactions (Gau et al 2008).

Carbamazepine can cause the syndrome of inappropriate antidiuretic hormone secretion (SIADH), with resultant hyponatremia. The elderly, alcoholic individuals, and patients on selective serotonin reuptake inhibitors (SSRIs) may be at greater risk. Carbamazepine may also cause reduction in circulating thyroid hormones (Simko and Horacek 2007).

Carbamazepine overdose presents with neuromuscular disturbances, such as nystagmus, myoclonus, and hyperreflexia and may progress to seizures and coma. Cardiac conduction changes, nausea, vomiting, and urinary retention also may occur. After a serious overdose, blood pressure and respiratory and kidney function should be monitored for several days.

Drug Interactions (See also "General Principles" Section)

Carbamazepine induces hepatic CYP enzymes, which may reduce levels of other medications, including itself (autoinduction), and oral contraceptives. Therefore, women initiating carbamazepine should be advised to consider alternative forms of birth control. Use of medications or substances that inhibit CYP3A3/4 may result in significant increases in plasma carbamazepine levels (Owen 2010b).

Oxcarbazepine

Oxcarbazepine is a keto derivative of carbamazepine that is often used as an alternative to carbamazepine because of a milder side-effect profile, although it is not FDA approved for use in bipolar disorder and evidence for its efficacy is lacking (Vasudev et al. 2011). Nonetheless, oxcarbazepine is an attractive alternative to carbamazepine because it does not require blood cell count, hepatic, or serum drug level monitoring; causes less CYP enzyme induction than does carbamazepine (may still decrease oral contraceptive levels); and does not induce its own metabolism. Like carbamazepine, oxcarbazepine has been associated with hyponatremia and severe dermatological reactions, including Stevens-Johnson syndrome (Trileptal 2013).

Lamotrigine

Lamotrigine is approved by the FDA for the prevention of mania and depression in patients with bipolar disorder, and is considered a first-line option for bipolar depression. It is an anticonvulsant that decreases sustained high-frequency repetitive firing of the voltage-dependent sodium channel, which may then decrease glutamate release (Lees and Leach 1993). Two randomized controlled trials showed a greater time to intervention for any mood episode for both lamotrigine and lithium compared with placebo (Bowden et al. 2003; Calabrese et al. 2003). Lamotrigine has not shown efficacy as a monotherapy treatment for acute mania. Lamotrigine has shown efficacy in a double-blind, placebo-controlled trial for the treatment of bipolar depression, although it is not FDA approved for acute use (Calabrese et al. 1999).

Clinical Use

Lamotrigine treatment is usually initiated at 25 mg once a day. Because the risk of a serious rash increases with rapid titration, it is essential to follow the recommended titration schedule. After 2 weeks, the dosage is increased to 50 mg/day for another 2 weeks. At week 5, the dosage can be increased to 100 mg/day, and at week 6 to 200 mg/day. In patients who are taking valproate or other medications that decrease the clearance of lamotrigine, the dosing schedule and target dose are halved. Conversely, the titration schedule and dose are increased in those taking carbamazepine. In the absence of carbamazepine or other enzyme inducers, doses higher than 200 mg are typically not recommended.

Adverse Effects

Lamotrigine is well tolerated and is not associated with hepatotoxicity, weight gain, or significant sedation. Common early side effects include headache, dizziness, gastrointestinal distress, and blurred or double vision.

Lamotrigine has been associated with both benign and severe rashes. A maculopapular rash develops in 5%-10% of patients taking lamotrigine, usually in the first 8 weeks of treatment. Calabrese et al. (2002) analyzed data from 12 multicenter trials of lamotrigine in patients with mood disorders and reported an 8.3% rate of benign rashes with lamotrigine therapy. Lamotrigine also has been associated with severe, life-threatening rashes, including Stevens-Johnson syndrome, in approximately 0.3% of adults receiving adjunctive treatment for epilepsy, 0.13% of adults receiving adjunctive therapy in mood disorder clinical trials, and 0.08% of adults receiving lamotrigine as initial monotherapy in mood disorder clinical trials (Lamictal 2012). Before initiating lamotrigine, patients must be advised of the potential risk of developing a serious rash and the need to call the clinician immediately if a rash emerges, especially when accompanied by systemic symptoms. Ketter et al. (2005) reported a decreased incidence of lamotrigine-associated rash when patients were advised to avoid other new medicines, new foods, cosmetics, conditioners, deodorants, detergents, and fabric softeners, as well as sunburn and exposure to poison ivy and poison oak.

Drug Interactions (See also "General Principles" Section)

Concurrent treatment with valproate will increase lamotrigine levels, and carbamazepine will decrease lamotrigine levels. Many other anticonvulsants interact with lamotrigine as well. Oral contraceptives can result in decreases in lamotrigine concentrations, but lamotrigine does not affect the availability of oral contraceptives.

Antidepressants

Antidepressants include several different types of medications, categorized largely by their neurotransmitter effects. To date, all antidepressants appear to be similarly effective for treating major depression, but individual patients may respond preferentially to one agent or another. There are significant differences between them with regard to side effects, lethality in overdose, pharmacokinetics, drug-drug interactions, and the ability to treat comorbid disorders.

All antidepressants are effective and FDA approved for treatment of major depression. Additionally, some antidepressants are effective in obsessive-compulsive disorder (OCD; SSRIs and clomipramine), panic disorder (tricyclic antidepressants [TCAs] and SSRIs), generalized anxiety disorder (venlafaxine and SSRIs), bulimia (TCAs, SSRIs, and MAOIs), dysthymia (SSRIs), bipolar depression (with treatment with a mood stabilizer), social phobia (SSRIs, venlafaxine, MAOIs), post-traumatic stress disorder (SSRIs), irritable bowel syndrome (TCAs for diarrhea predominant, SSRIs for constipation predominant), enuresis (TCAs), neuropathic pain (TCAs, duloxetine), migraine headaches (TCAs), attention-deficit/hyperactivity disorder (bupropion), autism (SSRIs), late luteal phase dysphoric disorder (SSRIs), borderline personality disorder (SSRIs), and smoking cessation (bupropion). However, the FDA has not evaluated or approved the use of antidepressants to treat many of these conditions. We refer the reader to current product labeling to determine the indications for uses approved by the FDA for a specific medication.

Information on dosing is summarized in Table 27-11, and a list of key features and side effects is presented in Table 27-12. The choice of a specific antidepressant medication is based on several factors, including the patient's psychiatric symptoms, history of previous treatment response and tolerability, family members' history of response, medication side-effect profiles, drug-drug interaction potentials, and the presence of co-morbid disorders that may respond to (or preclude the use of) specific antidepressants. In general, SSRIs and other newer antidepressants are preferred as initial treatment options because they are better tolerated and safer than TCAs and MAOIs, although many patients benefit from treatment with the older drugs.

Selective Serotonin Reuptake Inhibitors and Novel/Mixed-Action Agents

Mechanisms of Action

SSRIs selectively inhibit serotonin reuptake and are largely devoid of other major pharmacological properties, resulting in relatively few serious side effects. Duloxetine, venlafaxine, and desvenlafaxine selectively inhibit uptake of both serotonin and norepinephrine (i.e., they are serotonin-norepinephrine reuptake inhibitors [SNRIs]). Bupropion is a relatively weak reuptake inhibitor of dopamine and norepinephrine. Mirtazapine modulates the actions of norepinephrine and serotonin, whereas trazodone modulates serotonin. Vilazodone is supposed to be both an SSRI and a partial 5-HT_1A receptor agonist.

Indications and Efficacy

Despite their highly selective pharmacological activity, SSRIs have a broad spectrum of action. They are efficacious in the treatment of depression and many other psychiatric disorders, including many anxiety disorders. All the SSRIs have similar spectrums of efficacy and side-effect profiles. However, they are structurally distinct, and response or nonresponse to one SSRI does not necessarily predict a similar reaction to another SSRI. Allergy or intolerance to one SSRI does not necessarily predict allergy or intolerance to another. SSRIs also have distinct pharmacokinetic properties, including differences in half-life, and drug-drug interaction potential. SNRIs have similar indications, and in addition are effective in some forms of chronic pain. Bupropion is the one antidepressant that is generally ineffective for treatment of anxiety disorders. Because of their sedating properties, trazodone and mirtazapine are often used in place of hypnotics, especially if a more activating antidepressant has aggravated insomnia.

Adverse Effects

Adverse effects of SSRIs and novel/mixed-action agents are common, but they are usually mild and dose related, and most abate over time. However, serotonergic agents, especially when used in combination, can induce the potentially fatal serotonin syndrome (see "Serotonin Syndrome" later in this section).

Note. L=liquid; NA=not applicable; CR=controlled release; XL or XR=extended release; SolTab=orally disintegrating tablets; SR=sustained release.

^a Lower starting doses are recommended for elderly patients and patients with panic disorder, significant anxiety or hepatic disease.

^b Mean half-lives of active metabolites are given in parentheses.

^c Not available in the United States due to incidents of severe hepatotoxicity.

^d Dose varies with diagnosis. See text for specific guidelines.

^e Generic only.

Data Sources. Dosing information from American Psychiatric Association 2010. Half-life data from Physicians' Desk Reference, 59th Edition, 2005. Dosing and half-life information for transdermal selegiline system from EMSAM product information, 2006. Desvenlafaxine information from product monograph 2013.

Source. Adapted from Martinez M, Marangell LB, Martinez JM: Psychopharmacology, in The American Psychiatric Publishing Textbook of Psychiatry, 5th Edition. Edited by Hales RE, Yudofsky SC, Gabbard GO. Washington, DC, American Psychiatric Publishing, 2008, pp. 1053-1131. Used with permission.

Note. XL or XR=extended release; CHF=congestive heart failure.

Source. Adapted from Martinez M, Marangell LB, Martinez JM: Psychopharmacology, in The American Psychiatric Publishing Textbook of Psychiatry, 5th Edition. Edited by Hales RE, Yudofsky SC, Gabbard GO. Washington, DC, American Psychiatric Publishing, 2008, pp. 1053-1131. Used with permission.

Common short-term side effects with SSRIs and SNRIs include nausea, vomiting, anxiety, headache, sedation, tremors, and anorexia. Common long-term side effects include sexual dysfunction, dry mouth, sweating, impaired sleep, and potential weight gain. Trazodone, mirtazapine, and bupropion do not disrupt sexual function. Trazodone causes sedation in 20%-50% of patients and is often used for its sedating properties. It also rarely causes priapism. Trazodone can cause orthostatic hypotension.

Frequent SNRI side effects are nausea, dry mouth, fatigue, dizziness, constipation, somnolence, decreased appetite, and increased sweating. Mirtazapine is associated with a high incidence of sedation, increased appetite, and weight gain. Common adverse effects of bupropion include agitation, insomnia, anxiety, dry mouth, constipation, postural hypotension, and tachycardia. Nausea and vomiting are much less common with bupropion than with SSRIs. Patients treated with reboxetine (used only in Europe) often report dry mouth, insomnia, constipation, sweating and hypotension. Milnacipran, an SNRI approved for depression in Europe and Japan and approved by the FDA in the United States for fibromyalgia, is associated with the same side effects as other SNRIs.

Central Nervous System

In May 2007, the FDA concluded that all antidepressants increase the risk of suicidal thinking and behavior in young adults (age <24 years) during initial treatment and required manufacturers to include in their labeling a warning statement that recommends close observation of young adult and pediatric patients treated with these agents for worsening depression or the emergence of suicidality (Bridge et al. 2007; Stone et al. 2009). There is no evidence that antidepressants increase the risk of completed suicide in children or adults.

Bupropion causes a dose-related lowering of the seizure threshold and may precipitate seizures in susceptible patients receiving dosages above 450 mg/day. The incidence of seizure rises with increasing dosage, from 0.1% at 100-300 mg/day through 0.4% at 300-450 mg/day. The seizure risk reported for other antidepressants ranges from 0.04% for mirtazapine to 0.5% for clomipramine. Given that the annual incidence of first unprovoked seizure is 0.06% in the general population, seizure risk for patients taking most antidepressants is not elevated. However, it is clear that certain antidepressants, including bupropion, clomipramine, maprotiline, and venlafaxine, are associated with a greater seizure risk than are other antidepressants (Harden and Goldstein 2002; Whyte et al. 2003), but this is rarely significant except at toxic doses.

Potential side effects of SSRIs include SSRI-induced EPS, likely resulting from serotonergic antagonism of dopaminergic pathways in the central nervous system (CNS). Akathisia, dystonia, parkinsonism, and tardive dyskinesia-like states have been infrequently reported, with akathisia being the most common effect and tardive dyskinesia-like states being the least common. Certain patients appear to be at increased risk, such as the elderly, patients with Parkinson's disease, and patients concurrently treated with dopamine antagonists.

Serotonin syndrome. Serotonin syndrome is an uncommon but potentially life-threatening complication of treatment with serotonergic agents (Boyer and Shannon 2005; Sternbach 1991). Overall, there is considerable heterogeneity in the reported clinical features of serotonin syndrome (Table 27-13), reflecting the variation in the degree of severity of the syndrome. The incidence of the syndrome is unknown, in part because many physicians are unaware of the syndrome as a clinical diagnosis, and because uniform diagnostic criteria are lacking. Virtually all medications that potentiate serotonergic neurotransmission in the CNS have been reported in association with serotonin syndrome. The antidepressant combinations most commonly implicated have been monoamine oxidase inhibitors (MAOIs; reversible and irreversible) and TCAs, MAOIs and SSRIs, and MAOIs and venlafaxine. Table 27-14 lists other selected serotonergic drugs.

Currently there is no formal consensus regarding diagnostic criteria for serotonin syndrome. The first operationalized criteria were proposed by Sternbach (1991) but were found to have low specificity. The Hunter Serotonin Toxicity Criteria have subsequently gained acceptance as a simple set of highly sensitive and specific decision rules; these criteria are listed in Table 27-15 (Dunkley et al. 2003). Laboratory findings have not been commonly reported in cases of serotonin syndrome, but some reports have noted leukocytosis, rhabdomyolysis with elevated creatine phosphokinase (CPK), serum hepatic transaminase elevations, electrolyte abnormalities (hyponatremia, hypomagnesemia, hypercalcemia), and disseminated intravascular coagulopathy. The differential diagnosis includes CNS infection, delirium tremens, poisoning with anticholinergic or adrenergic agents, NMS, and malignant hyperthermia. Differentiating serotonin syndrome from NMS can be very difficult in patients receiving both serotonergic and antipsychotic medications (see "Neuroleptic Malignant Syndrome" under "Antipsychotics" earlier in this chapter).

Serotonin syndrome is often selflimited and usually resolves quickly after discontinuation of serotonergic agents. Management includes the following basic principles: 1) discontinue all serotonergic agents, 2) provide necessary supportive care, 3) anticipate potential complications, 4) consider administering antiserotonergic agents, and 5) reassess the need for psychopharmacological therapy before reinstituting drug therapy (Boyer and Shannon 2005). Some patients will require admission to an intensive care unit, but most will show some improvement within 24 hours with supportive care alone. There are no specific antidotes available for the treatment of serotonin syndrome. The antihistamine cyproheptadine is the most consistently effective serotonin antagonist reported. The recommended adult dose is 4-8 mg and may be repeated every 1-4 hours up to a maximum daily dose of 32 mg. There is limited information on drug rechallenge in patients who have developed serotonin syndrome. General guidelines include reevaluating the necessity for drug therapy, considering a switch to a nonserotonergic medication, using single-drug therapy when serotonergic medications are required, and considering an extended (6-week) serotonin "drug-free" period before restarting a serotonergic agent (Mills 1997).

Autonomic and Cardiovascular

The SSRIs and the novel/mixed-action antidepressants have a much safer cardiovascular profile than the TCAs and MAOIs. In general, the SSRIs have little effect on blood pressure or cardiac conduction (Shapiro 2010). SSRIs have been reported to rarely cause mild bradycardia in elderly patients with preexisting cardiac arrhythmias. In 2011, the FDA announced that there had been reports of citalopram causing dose-dependent QTc interval prolongation and torsades de pointes (Vieweg et al. 2012). The FDA advised that citalopram should no longer be prescribed at doses greater than 40 mg per day, and no greater than 20 mg per day for patients with hepatic impairment, who are greater than 60 years of age, who are CYP2C19 poor metabolizers, or who are taking concomitant cimetidine. Citalopram should not be prescribed in patients with the congenital long QT syndrome. Caution is also advised in patients with other risk factors for QTc prolongation (e.g., hypocalcemia, hypomagnesemia, or with other QTc prolonging drugs).

Source. Compiled in part from Boyer and Shannon 2005; Dunkley et al. 2003.

Note. MAOIs=monoamine oxidase inhibitors; MDMA=3,4-methylenedioxymethamphetamine; SSRIs=selective serotonin reuptake inhibitors; TCAs=tricyclic antidepressants.

Source. Compiled from Boyer and Shannon 2005; Dunkley et al. 2003.

The novel/mixed-action agents venlafaxine, desvenlafaxine, duloxetine, bupropion, mirtazapine, trazodone, vilazo-done, and reboxetine have little effect on cardiac conduction but may affect blood pressure or heart rate. Venlafaxine exhibits dose-related increases in heart rate and blood pressure, typically at doses of more than 300 mg/day. Similar effects would be expected for desvenlafaxine. Duloxetine and bupropion may also cause elevation in blood pressure. Trazodone lacks significant effects on cardiac conduction but in rare cases was reported to cause ventricular ectopy and ventricular tachycardia. The most frequent cardiovascular adverse effect of trazodone is postural hypotension, which may be associated with syncope. Mirtazapine does not have significant effects on cardiac conduction, but because of its moderate alpha₁-antagonist activity, it has a 7% incidence of orthostatic hypotension. Hypotension and elevated heart rate have been observed in patients receiving reboxetine. Vilazo-done has minimal effects on cardiac conduction and blood pressure.

SNRIs frequently cause sweating.

Gastrointestinal

Nausea is the most common adverse effect associated with the serotonergic antidepressants. Nausea is most likely to occur in 30%-40% of patients receiving fluvoxamine, venlafaxine, and duloxetine at a starting dose of 60 mg/day. Other serotonergic antidepressants have a lower incidence (20%-25%) of nausea, but these incidences are still much higher than those seen with placebo (9%-12%). Loose stool and diarrhea are also common with SSRIs.

Although most adverse gastrointestinal effects of serotonergic antidepressants are dose related and generally decrease with continued treatment, sometimes severe side effects require antidepressant discontinuation. Potential severe hepatotoxicity with nefazodone has led to its removal from the market in a number of countries, and it should not be used in patients with preexisting liver disease (Stewart 2002). Duloxetine-related hepatotoxicity in 1% of patients has prompted product monograph warnings; however, a review of duloxetine hepatic safety suggested no increase in hepatotoxicity compared with other conventional antidepressants (McIntyre et al. 2008). Pancreatitis has also rarely been reported with mirtazapine (Hussain and Burke 2008).

Hematological

SSRIs have hemorrhagic potential by interfering with serotonin-induced platelet aggregation through depletion of platelet serotonin stores (Andrade et al. 2010). The absolute effects are modest and about equal to low-dose ibuprofen. The relative risk of gastrointestinal bleeding increases if patients are receiving an SSRI and a nonsteroidal anti-inflammatory drug (NSAID), and even more so if in conjunction with a third drug interfering with platelet function (e.g., clopidogrel) or coagulation (warfarin), but the absolute risk remains low in patients not otherwise at increased risk for gastrointestinal bleeding. Increased risk would be expected in patients with thrombocytopenia or clotting disorders, which predispose to prolonged bleeding time (e.g., von Willebrand's disease).

Weight Gain or Loss

Weight gain is a relatively common problem during both acute and long-term treatment with antidepressants. Mirtazapine and TCAs are most likely to cause significant weight gain. Although SSRIs are weight-neutral in most patients, they can cause considerable weight gain in a minority of patients. Bupropion is the only antidepressant that does not cause weight gain.

Sexual Dysfunction

Most antidepressants have been reported to cause sexual dysfunction. Delayed orgasm/anorgasmia is most common with SSRIs, SNRIs, and TCAs, with diminished libido less so (Schweitzer et al. 2009). Sildenafil may reverse SSRI-related sexual side effects in men and women (Nurnberg et al. 2008). Other strategies, such as dosage reduction and drug holidays, must be approached with caution, given the risk for depression relapse. Trazodone causes priapism in about 1 in 5,000 men. Bupropion and mirtazapine do not cause sexual side effects.

Serotonin Reuptake Inhibitor Discontinuation Syndrome

Abrupt discontinuation of SSRIs or SNRIs, especially those with short half-lives (e.g., fluvoxamine, paroxetine, venlafaxine), may give rise to a discontinuation syndrome characterized by a wide variety of symptoms, including psychiatric, neurological, and flulike symptoms (nausea, vomiting, sweats); sleep disturbances; and headache, usually resolving within 3 weeks (Schatzberg et al. 1997). Some patients experience the symptoms even with very gradual withdrawal over months. Antidepressants, like all psychoactive medications, should be gradually withdrawn when possible. Discontinuation symptoms can cause misdiagnosis and inappropriate treatment, particularly in a patient with an active medical illness, as well as erode future compliance.

Tricyclic Antidepressants

TCAs are now viewed as second-line treatments for depression because their adverse-effect profile is less benign than that of SSRIs and novel/mixed-action agents. Death from TCA-induced cardiac conduction abnormalities was not uncommon in overdose.

Adverse Effects

Many adverse effects of TCAs are due not to their effects on serotonin or norepinephrine reuptake inhibition but rather to secondary pharmacological actions. TCAs are antagonists at histamine H₁, α₁-adrenergic, and muscarinic receptors and have class Ia antiarrhythmic (quinidine-like) effects (Shapiro 2010). Adverse effects of TCAs include sedation, anticholinergic effects (dry mouth, dry eyes, constipation, urinary retention, decreased sweating, confusion, memory impairment, tachycardia, blurred vision), and postural hypotension. Tolerance to these effects usually develops over time. TCAs at or just above therapeutic plasma levels frequently prolong PR, QRS, and QTc intervals, but rarely to a clinically significant degree in patients without preexisting cardiac disease or conduction defects. TCAs can cause heart block, arrhythmias, palpitations, tachycardia, syncope, and heart failure and should be used with caution in patients with preexisting cardiovascular disease or at risk of suicide. Following the discovery that class I antiarrhythmic drugs can increase mortality in patients after myocardial infarction, it is prudent to assume that TCAs may carry the same risk.

Toxicity/Overdose

TCA overdose carries a risk of death from cardiac conduction abnormalities that result in malignant ventricular arrhythmias. Initial symptoms of overdose involve CNS stimulation, in part due to anticholinergic effects, and include hyperpyrexia, delirium, hypertension, hallucinations, seizure, agitation, hyperreflexia, and parkinsonian symptoms. The initial stimulation phase is typically followed by CNS depression with drowsiness, areflexia, hypothermia, respiratory depression, severe hypotension, and coma. Risk of cardiotoxicity is high if the QRS interval is 100 msec or more or if the total TCA plasma concentration is greater than 1,000 ng/mL; concentrations greater than 2,500 ng/mL are often fatal.

Treatment for overdose includes activated charcoal to reduce absorption of any unabsorbed medication from the stomach, followed by supportive therapy and close monitoring (Rasimas 2011). Gastric lavage with the aim of removing unabsorbed compounds is rarely indicated and should be considered only when a patient is seen less than an hour after ingestion. Cardiac conduction abnormalities, arrhythmias, and hypotension may be treated with administration of intravenous sodium bicarbonate to produce a serum pH of 7.4-7.5. Life-threatening anticholinergic effects may be managed with physostigmine. Because of their large volumes of distribution and extensive protein binding, TCAs are not removed by dialysis.

Abrupt discontinuation of TCAs may give rise to a discontinuation syndrome characterized by dizziness, lethargy, headache, nightmares, and symptoms of anticholinergic rebound, including gastrointestinal upset, nausea, vomiting, diarrhea, excessive salivation, sweating, anxiety, restlessness, piloerection, and delirium. This syndrome can be avoided by gradual withdrawal.

Monoamine Oxidase Inhibitors

MAOIs, with the possible exception of moclobemide (not available in the United States), are seen as third-line antidepressants because of their significant drug interactions and the dietary restrictions that are required with their use. Phenelzine and tranylcypromine are irreversible inhibitors of MAO-A and MAO-B. Hypertensive crisis can occur in patients taking MAOIs who take sympathomimetic drugs, including over-the-counter decongestants, other agents (e.g., meperidine), or foods containing tyramine. Common adverse effects of MAOIs include orthostatic hypotension, dizziness, headache, sedation, insomnia or hypersomnia, tremor, and hyperreflexia. Interactions between MAOIs and direct- or indirect-acting sympathomimetics or dopaminergic agonists may cause a hypertensive crisis. MAOIs may trigger serotonin syndrome when combined with other medications (see "Serotonin Syndrome" subsection earlier in chapter). Moclobemide shares the potential to cause hypertensive crises and serotonin syndrome with the irreversible agents. MAOIs may greatly potentiate the hypotensive effects of antihypertensive agents, including diuretics.

Selegiline, a semiselective MAO-B inhibitor used to treat Parkinson's disease, and now as a transdermal patch indicated for depression, may also contribute to serotonin syndrome (Robinson and Amsterdam 2008). At oral dosages greater than 10 mg/day, and with patch strengths greater than 6 mg/24 hours, selegiline also inhibits MAO-A and thus shares risk for the adverse effects and drug-food interactions, including hypertensive crisis, of the antidepressant MAOIs. Moclobemide, a short-half-life reversible inhibitor of MAO-A, is less susceptible to dietary interactions provided that it is taken after meals.

Treatment for MAOI hypertensive crisis involves discontinuing the MAOI and slowly administering intravenous phentolamine (typical adult dose =5 mg). Beta-blockers should never be used; beta-blockade allows unrestrained alpha-adrenergic stimulation, which further exacerbates the hypertension.

Anxiolytics and Sedative-Hypnotics

Many psychotropic drugs have antianxiety properties and sedative effects that promote sleep. In early years of use, the antipsychotics were frequently called major tranquilizers, owing to these properties, and were often prescribed for anxiety states. Nonetheless, these drugs are seldom used as monotherapy for anxiety disorders today because of their risk for adverse effects. Drugs that primarily treat anxiety symptoms and disorders include the benzodiazepines, buspirone, and many antidepressants, which are covered in the previous section. Drugs that are indicated for the treatment of insomnia include the nonbenzodiazepine GABA receptor agonist hypnotics and the melatonin MT_t and MT₂ receptor agonists. The benzodiazepines, buspirone, and the above-mentioned hypnotics are discussed in this section and are summarized in Table 27-16.

Benzodiazepines

The benzodiazepines continue to be among the most widely prescribed psychotropic drugs. In psychiatry, they are utilized to treat both short-term and long-term anxiety and insomnia. Although these medications may provide rapid relief of anxiety symptoms, their use is limited by the development of tolerance and withdrawal, as well as by their abuse liability and propensity to impair judgment, cognition, and motor performance (Lader 2011). In general, benzodiazepines are best in short-term clinical situations, such as episodic stress-related anxiety and insomnia. They are often utilized to quell anxiety symptoms in the early stages of SSRI or SNRI treatment for panic, generalized anxiety, OCD, or posttraumatic stress disorders, while awaiting the therapeutic effect of the antidepressant. Despite these provisos, many patients receive chronic benzodiazepine therapy and do not experience deleterious effects. Patients should be counseled regarding the liabilities of chronic benzodiazepine use and monitored closely.

Note. tid=three-times~per-day dosing; N/A=not applicable; qid=four-tim.es-per-day dosing; bid = twice-daily dosing; qd=once-daily dosing; CR=extended release; SD=single dose; T-tab=T-shaped tablet; GABA=γ-aminobutyric acid.

^a Lower doses maybe required in special populations, such as elderly, debilitated, or hepatically or renally impaired patients; use of certain agents may also be precluded in such patients.

^b Not available in the United States.

Source. Adapted from Martinez M, Marangell LB, Martinez JM: Psychopharmacology, in The American Psychiatric Publishing Textbook of Psychiatry, 5th Edition. Edited by Hales RE, Yudofsky SC, Gabbard GO. Washington, DC, American Psychiatric Publishing, 2008, pp. 1053-1131. Used with permission.

Benzodiazepines act by binding to a modulatory site on the "A" subtype of the GABA receptor (Sankar 2012). GABA is the major inhibitory neurotransmitter in the CNS. By potentiating the GABA-mediated activation of the GABA_A receptor, benzodiazepines enhance the opening of chloride ion channels and decrease neuronal excitability.

Benzodiazepine choice is based primarily on pharmacokinetic properties, including half-life, rapidity of onset, metabolism, and potency. In general, longer acting agents possess active metabolites and tend to produce a steady serum drug concentration and few rebound effects between doses, whereas shorter acting agents are prone to emergence of symptoms between doses. All benzodiazepines are metabolized by the liver, increasing the risk of sedation, confusion, and frank hepatic encephalopathy in patients with hepatic failure. In patients with liver failure, lorazepam, temazepam, and oxazepam may be preferred because they undergo hepatic conjugation and renal excretion and have no active metabolites, whereas other benzodiazepines undergo hepatic microsomal metabolism and may have long-acting active metabolites.

Adverse effects of benzodiazepines are dose-dependent and include sedation, impaired cognitive function and judgment, amnesia, impaired motor performance, and disinhibition. Abuse liability is a significant concern. Benzodiazepines also cause respiratory suppression and may produce respiratory arrest in overdose, especially when combined with other sedative drugs and alcohol. Abrupt cessation of benzodiazepine use after long-term administration may result in withdrawal symptoms including anxiety, agitation, tremor, autonomic hyperactivity, insomnia, nausea and vomiting, seizure, and delirium. Benzodiazepine withdrawal is best managed by resumption of an intermediate- to long-acting benzodiazepine to stabilize the patient, followed by gradual taper under supervision.

Buspirone

Buspirone is a 5-HT_1A receptor partial agonist. Because it does not affect GABA receptors or chloride ion channels, buspirone does not possess many of the major liabilities of benzodiazepines—namely, the potential for abuse, tolerance, and withdrawal. Buspirone is not cross-tolerant with benzodiazepines; thus, a rapid switch from a benzodiazepine to buspirone is likely to precipitate benzodiazepine withdrawal and therefore is not indicated.

Buspirone is indicated for the treatment of generalized anxiety disorder. Limited literature supports its use as augmentation in refractory depression and OCD (Trivedi et al. 2006).

Buspirone is administered in divided doses three times daily. It has a very short half-life and may precipitate a discontinuation reaction much like that of SSRIs if abruptly stopped. Buspirone has a relatively slow onset of therapeutic action, much like antidepressants. Buspirone works best for benzodiazepine-naive patients. Adverse effects include nausea, headache, nervousness, and insomnia. Buspirone is not lethal in overdose. Its metabolism is decreased by CYP3A4 inhibitors.

Eszopiclone, Zopiclone, Zolpidem, and Zaleplon

Eszopiclone, zopiclone, zolpidem, and zaleplon are selective agonists at the omega-1 modulatory site of the GABA_A receptor complex, producing sedation (Terzano et al. 2003). This selectivity is hypothesized to be associated with a low risk of dependence compared with benzodiazepines, but a small number of patients have developed dependence and abuse. Zolpidem and zaleplon do not have significant anxiolytic, muscle relaxant, or anticonvulsant properties.

Eszopiclone and zopiclone (not available in the United States) are well tolerated short-half-life hypnotics with very few dose-related adverse effects. Adverse effects of eszopiclone and zopiclone include bitter taste, dry mouth, difficulty arising in the morning, sleepiness, nausea, and nightmares. Zolpidem is a shortacting hypnotic with established efficacy in inducing and maintaining sleep. Because of the short half-life of this drug, most patients taking zolpidem report minimal daytime sedation. Zolpidem is available in an extended-release form to assist with sleeping through the night, as well as a sublingual formulation for middle insomnia. Zaleplon is an ultra-shortacting hypnotic with minimal residual sedative effects. Short-term or intermittent use of both agents is recommended to avoid tolerance.

Side effects of zopiclone, eszopiclone, zolpidem, and zaleplon are similar to those of benzodiazepines. Daytime sedation, impaired cognitive performance, amnesia, and nocturnal activity such as wandering, eating, and driving that is not recalled the next day have been reported. Elderly patients are at increased risk for amnesia and falls with zolpidem. Because of these side effects, the FDA has recommended reducing by half the dose of products containing zolpidem, especially in women and the elderly (U.S. Food and Drug Administration 2013a, 2013b). Caution is also advised in patients with hepatic dysfunction. These agents may be abused. These agents do not appear to be fatal in overdose, unless combined with other drugs or alcohol.

Ramelteon

Ramelteon is a melatonin agonist FDA-approved for insomnia. It has demonstrated efficacy for insomnia with no next-morning residual effects, similar adverse effects to placebo, and minimal withdrawal symptoms upon discontinuation (Liu and Wang 2012).

Psychostimulants

Psychostimulants are used for treatment of attention-deficit/hyperactivity disorder (ADHD) and excessive sleepiness due to narcolepsy, shift work sleep disorder, and obstructive sleep apnea. Off-label, they are used to augment treatments for depression, apathy, and analgesia. Classification of psychostimulants is confusing. Although all psychostimulants have CNS stimulant properties, they are often subclassified as stimulant or nonstimulant agents based roughly on the degree of stimulation and the time to onset of effect. Stimulants have strong effects with rapid onset (hours) and include the well-established agents methylphenidate, dexmethylphenidate, and amphetamines (amphetamine salts and dextroamphetamine) as well as the amphetamine prodrug lisdexamfetamine. Grouped as nonstimulants are atomoxetine (a specific norepinephrine reuptake inhibitor) and the α₂-adrenergic agonists clonidine and guanfacine, which have a slow onset of psychostimulant effect over several weeks, and modafinil and armodafinil, which are acutely effective but less stimulating (Table 27-17). Nonstimulants have less abuse potential than do stimulants.

Prefrontal norepinephrine and dopamine neurotransmission modulates attention and behavior and is impaired in patients with ADHD. Most, if not all, effective treatments for ADHD enhance norepinephrine and/or dopamine neurotransmission in this area. Amphetamine, methylphenidate, and atomoxetine increase synaptic concentrations of catecholamines in the prefrontal cortex by one or more mechanisms including inhibition of presynaptic norepinephrine reuptake (amphetamine, methylphenidate, atomoxetine) and dopamine reuptake (methylphenidate and amphetamine). Amphetamine also increases presynaptic dopamine release by reversing the action of the dopamine reuptake transporters.

The α₂-adrenergic agonists clonidine and guanfacine are believed to reduce ADHD symptoms by directly stimulating postsynaptic α_2A-adrenergic receptors in noradrenergic pathways that activate the prefrontal cortex (Sallee and Eaton 2010). Guanfacine is a more specific agonist of α_2A-adrenergic receptors than clonidine.

Modafinil and its purified R-enantiomer armodafinil are also reported to inhibit the dopamine reuptake transporter, but in a manner different from classical stimulants such as methylphenidate and amphetamines (Schmitt and Reith 2011). This may account for their milder activating effects.

Stimulants: Methylphenidate, Dexmethylphenidate, Amphetamines, and Lisdexamfetamine

All stimulant formulations are indicated as first-line treatments for ADHD, but only short- and intermediate-duration formulations (4-10 hours) are indicated for treatment of narcolepsy. Meta-analyses of the response in children and adolescents with ADHD provide strong evidence of efficacy for short- and long-acting stimulants. Compared with stimulants, nonstimulant medications have a positive but less robust effect (Hodgkins et al. 2012).

Stimulants, except for lisdexamfetamine, are available in a variety of formulations, providing a range of drug-release profiles differing in speed of onset of action (0.5-2 hours) and duration of action (4-12 hours). Specific formulations are described in Table 27-17. Because of variations in drug-release profiles, different formulations are generally not interchangeable.

Medication selection involves choice of both agent and drug release profile (formulation). Although studies suggest a similar overall response to methylphenidate or amphetamine-based stimulants, individual response may differ considerably between the two drug classes and a switch to the alternate agent may improve an inadequate response. Short-acting formulations have a limited duration of effect (only 4-6 hours), requiring two- or three-times-a-day dosing to maintain therapeutic effect over the school (working) day. Repeat dosing not only is inconvenient and increases the stigma of medication use and the chances for drug diversion but also can increase the possibility of lapses in therapeutic coverage by impairing medication adherence in patients with organizational and attentional deficits. Long-acting formulations have been developed based on controlled drug release (delayed or bimodal [immediate and delayed]), transdermal absorption, and metabolic delivery of active drug from a prodrug. Delayed-release preparations provide an extended duration of therapeutic effect but have a slower onset of effect. In this situation, addition of an immediate-release preparation improves the speed of onset of effect. Bi-modal drug-release formulations provide an immediate initial dose for rapid onset of action followed by delayed release of the remaining capsule contents for extended effect. Long-acting formulations with once-a-day dosing are more convenient and provide more consistent blood levels and therapeutic effect, improved medication compliance, and reduced potential for abuse.

Note. C=child; T=adolescent; A=adult; ADHD=attention-deficit/hyperactivity disorder; OSA=obstructive sleep apnea; SWD=shift work disorder.

^a Approximate duration of single dose in ADHD.

^b Unless otherwise noted, bid dosing is morning and noon; tid dosing is morning, noon, and 4 pm.

^c Therapeutic effect builds over several weeks of treatment. (This Note c is not found from the original Textbook.)

Source. Product monographs (Adler et al. 2009; Brams et al. 2008; Czeisler et al. 2009; Hodgkins et al. 2012; May and Kratochvil 2010; Pelham et al. 1990; Sallee et al. 2009; Schachar et al. 2008).

In the United States, methylphenidate is available in a long-acting transdermal patch. The patch is worn for 9 hours but provides therapeutic effect through 12 hours, although the duration of effect can be modified by early removal of the patch. A placebo-controlled comparison of transdermal methylphenidate and Concerta osmotic-release oral methylphenidate in children observed similar treatment efficacy for the active formulations but a higher incidence of tics and anorexia for the transdermal preparation (Findling et al. 2008).

Lisdexamfetamine is a prodrug slowly metabolized by enzymatic hydrolysis in blood to dextroamphetamine. Because the drug must first undergo oral absorption and subsequent metabolism to dextroamphetamine, lisdexamfetamine has a slow onset (1.5-2 hours) but long duration (13-14 hours) of effect.

Common adverse effects of stimulant agents include CNS (insomnia, headache, nervousness, and social withdrawal) and gastrointestinal (stomach ache and anorexia) symptoms. Adverse effects are generally mild and diminish with continued treatment, adjustment of dose, or change of dose timing. Rebound hyperactivity and irritability may occur with falling blood levels after the last daily dose.

Stimulants can cause elevated heart rate and blood pressure, palpitations, hypertension, hypotension, and cardiac arrhythmias when taken at higher doses. However, large retrospective database studies have found no increased cardiac risk in children and adults taking prescribed stimulants (Cooper et al. 2011; Habel et al. 2011). Stimulants may exacerbate motor or phonic tics or psychotic symptoms. Adverse effects increase in incidence and severity with short-duration-of-action formulations and with increasing dose.

All stimulants may interact with sympathomimetics and MAOIs (including selegiline), resulting in headache, arrhythmias, hypertensive crisis, and hyperpyrexia. Stimulants should not be administered with MAOIs or within 14 days of MAOI discontinuation. Methylphenidate may interact pharmacodynamically with TCAs to cause increased anxiety, irritability, agitation, and aggression. Higher doses of stimulants may also reduce the therapeutic effectiveness of antihypertensive medications. When stimulants are used concurrently with beta-blockers, the excessive alpha-adrenergic activity may cause hypertension, reflex bradycardia, and possible heart block.

Nonstimulants

Atomoxetine

Atomoxetine is indicated for treatment of ADHD. In trials comparing atomoxetine versus stimulants for treatment of ADHD, atomoxetine was superior to placebo but was generally less effective than stimulants (May and Kratochvil 2010). Unlike the rapid response to stimulants (a few hours), the therapeutic effect of atomoxetine builds gradually over several weeks. Elimination of atomoxetine is reduced in patients with hepatic impairment.

Atomoxetine side effects reported in clinical trials included nausea, decreased appetite, fatigue, abdominal pain, increased heart rate and blood pressure, insomnia, irritability, and urinary retention. Nausea is worse with once-daily versus twice-daily dosing. Atomoxetine may increase suicidality, so patients should be monitored for adverse mood and behavioral changes during therapy. Symptoms of overdose include tachycardia, gastrointestinal symptoms, agitation, QT prolongation, increased blood pressure, somnolence, dizziness, tremor, and dry mouth. Treatment is primarily supportive.

Atomoxetine may interact with sympathomimetics and MAOIs (including selegiline), resulting in hyperthermia, rigidity, myoclonus, autonomic instability and agitation. It should not be administered with MAOIs or within 14 days of MAOI discontinuation. Atomoxetine is metabolized by CYP2D6 and is a mild inhibitor of CYP2D6. Potent CYP2D6 inhibitors (e.g., paroxetine, quinidine) may increase the plasma levels and toxicity of atomoxetine (see Table 27-2). Atomoxetine may increase the toxicity of other coadministered narrow-therapeutic-index medications primarily metabolized by CYP2D6 such as albuterol and other beta agonists.

Clonidine and Guanfacine

Clonidine and guanfacine are available in extended-release formulations indicated for monotherapy or adjunctive therapy of ADHD. Immediate-release preparations of clonidine and guanfacine, and a clonidine weekly transdermal patch, are also available for the treatment of hypertension; these forms are not indicated for treatment of ADHD.

In comparison with stimulants for treatment of ADHD, trials of guanfacine or clonidine monotherapy suggest superiority to placebo but generally less effect than stimulants (May and Kratochvil 2010). Tic symptoms appear responsive to guanfacine or clonidine, whereas they are often worsened by stimulants. In patients with suboptimal response to stimulant monotherapy, the combination of a stimulant and an a₂ agonist (clonidine or guanfacine) is significantly more effective than a stimulant alone (Kollins et al. 2011; Spencer et al. 2009). Unlike the rapid response to stimulants (a few hours), the therapeutic effect of guanfacine and clonidine on ADHD symptoms builds gradually over several weeks.

Because of their hypotensive effects, guanfacine and clonidine should be used with caution in patients receiving cardiovascular drugs and in those at risk of hypotension, bradycardia, heart block, and syncope. Blood pressure and heart rate should be measured before and during treatment.

Guanfacine's adverse effects include dose-dependent somnolence, headache, fatigue, upper abdominal pain, hypotension, and dizziness. Clonidine's adverse effects include somnolence, upper respiratory tract infection, fatigue, irritability, insomnia, nightmares, hypotension, and emotional dysregulation.

Overdose of clonidine or guanfacine may cause initial hypertension followed by hypotension, bradycardia, respiratory depression, hypothermia, lethargy, and impaired consciousness. Large overdoses may cause reversible cardiac conduction defects or dysrhythmias, apnea, coma, and seizures. Treatment is primarily supportive. Guanfacine and clonidine may exacerbate the hypotensive and bradycardic effects of other medications. Caution is warranted in patients receiving other antihypertensive agents or drugs known to affect sinus node function or atrioventricular node conduction such as digitalis, calcium channel blockers, and beta-blockers.

Modafinil and Armodafinil

Modafinil and armodafinil are indicated for promotion of wakefulness in patients with narcolepsy, shift work disorder, and obstructive sleep apnea. These agents were well tolerated and significantly improved wakefulness (increased sleep latency) in controlled trials (Kumar 2008). Modafinil and armodafinil have similar therapeutic and adverse effects, but armodafinil has a longer duration of action due to slower metabolism.

Adverse effects of modafinil and armodafinil include headache, nausea, anxiety, dizziness, insomnia, and rhinitis. Serious skin rash and possible Stevens-Johnson syndrome have been observed in modafinil trials and may occur with armodafinil. To date, there are no reports of fatal overdose with modafinil or armodafinil.

Modafinil and armodafinil are moderate inducers of CYP3A4 and moderate inhibitors of CYP2C19. Significant metabolic drug interactions are most likely from decreased levels of drugs that undergo significant CYP3A4-mediated first-pass metabolism such as cyclosporine, ethinylestradiol, and triazolam. Modafinil and armodafinil should not be administered to patients receiving MAOIs or within 14 days of MAOI withdrawal.

Cognitive Enhancers

Cognitive enhancers may provide symptomatic improvement for cognitive (memory, visual-spatial function, motor skills) and functional (personality and behavior) symptoms of dementia. There is no evidence they alter the course of the underlying disease process. Currently approved agents for the treatment of Alzheimer's disease (AD) include the cholinesterase inhibitors donepezil, galantamine, and rivastigmine and the NMDA receptor antagonist memantine (Table 27-18).

Cholinesterase Inhibitors

The cognitive impairment associated with AD has been suggested to be due to a loss of CNS cholinergic neurons in the nucleus basalis of Meynert. Cholinesterase inhibitors increase acetylcholine availability and enhance cholinergic neurotransmission by decreasing the cholinesterase-mediated degradation of acetylcholine in the synaptic cleft.

Donepezil, galantamine, and rivastigmine are indicated for treatment of mild to moderate AD; donepezil is also approved for treating severe AD. Rivastigmine is additionally indicated for mild to moderate dementia associated with Parkinson's disease. A meta-analysis of 10 randomized, double-blind, placebo-controlled 6-month trials of donepezil, galantamine, or rivastigmine in patients with mild to severe AD reported similar efficacy among the three agents in regard to improvement in cognitive function, global clinical state, activities of daily living, and behavior compared with placebo (Birks 2006), with the improvements occurring in a subset of the subjects. Similar results were observed in a meta-analysis of six randomized trials of cholinesterase inhibitors for dementia associated with Parkinson's disease (Rolinski et al. 2012).

Patients with hepatic or renal impairment may require dosage reduction for galantamine and rivastigmine. Initial dosage titration should be slow and according to patient tolerability. Galanfamine should not be prescribed in severe hepatic or renal impairment or exceed 16 mg/day in moderate hepatic or renal impairment.

Note. AD=Alzheimer's disease; NMDA=N-methyl-D-aspartate. Drug dosage forms: L=oral liquid; Q=oral tablet or capsule; ODT=oral dissolving tablet; TD=transdermal patch.

Cholinesterase inhibitors are generally well tolerated; most of their adverse effects are mild, dose-related, and gastrointestinal in nature (nausea, vomiting, diarrhea, reduced appetite, and anorexia), as expected from procholinergic agents. Rivastigmine tends to cause the worst gastrointestinal side effects. Gastrointestinal side effects lessen over time and can be minimized by slow dose titration and administration with food. Adequate hydration reduces nausea. The procholinergic properties of cholinesterase inhibitors may also cause muscle cramps, insomnia, and vivid dreams and increase vagotonic (e.g., bradycardia) and bronchoconstrictor effects. These agents should be used with caution in patients with cardiac conduction abnormalities or a history of asthma or obstructive pulmonary disease. Procholinergic agents may promote seizures.

Overdose of cholinesterase inhibitors can cause a potentially fatal cholinergic crisis, with bradycardia, hypotension, muscle weakness, nausea, vomiting, respiratory depression, sialorrhea, diaphoresis, and seizures. Treatment is with atropine (0.5-2.0 mg intravenously, repeated as required) and supportive care.

Donepezil and galantamine are metabolized by CYP2D6 and CYP3A4 isozymes but are not associated with any clinically important CYP-mediated pharmacokinetic interactions. Rivastigmine is unaffected by drugs that interact with CYP isozymes.

Cholinesterase inhibitors may exacerbate the effects of other cholinesterase inhibitors (e.g., physostigmine) or cholinomimetic agents (e.g., bethanechol). Cholinesterase inhibitors should be discontinued several weeks before surgery. These agents prolong the duration of action of the depolarizing neuromuscular blocking agent succinylcholine (suxamethonium) by inhibiting its metabolism. In contrast, cholinesterase inhibitor-mediated increase in acetylcholine levels antagonizes the actions of nondepolarizing neuromuscular blockers (e.g., atracurium, mivacurium).

Many psychotropic drugs have anticholinergic properties that may antagonize the effect of cognitive enhancers. The use of anticholinergic agents in a patient with compromised cognitive function should be minimized. A partial listing of drugs with significant CNS anticholinergic effects is presented in Table 27-19. Conversely, cholinesterase inhibitors may have a countertherapeutic effect in those patients receiving anticholinergic medication for medical conditions such as asthma or obstructive pulmonary disease.

N-Methyl-D-Aspartate Receptor Antagonists

Chronic activation of CNS NMD A receptors leading to neuronal excitotoxicity has been suggested to be partially responsible for the neurodegeneration and symptoms of AD. Memantine is proposed to reduce chronic activation by acting as an NMDA receptor antagonist. Although memantine may provide symptomatic improvement for symptoms of AD, there is no evidence that it prevents or slows neurodegeneration or alters the course of the underlying disease process.

Memantine has been shown in a review of three randomized 6-month clinical trials to deliver a small improvement in cognition, behavior, and clinical impression of change in patients with moderate to severe AD (McShane et al. 2006).

Because of their different mechanisms of action, the use of cholinesterase inhibitors in combination with memantine has been suggested in patients with moderate to severe AD. A systematic review of pooled data from three 6-month trials in patients with moderate to severe AD receiving memantine plus a cholinesterase inhibitor (mainly donepezil) suggests that combination therapy results in a small improvement of cognition, global impression, and behavior, but not of function or activities of daily living (Farrimond et al. 2012). Memantine has no effect on the pharmacokinetics of cholinesterase inhibitors and may be used in combination with these agents without dosage adjustment.

Memantine undergoes primarily renal elimination. Patients with severe renal impairment should not exceed a dosage of 5 mg bid for the immediate-release form, or 14 mg/day for the extended-release form.

Memantine has been shown in a metaanalysis of controlled long-term trials in patients with Alzheimer's disease to be well tolerated, with an adverse-effect profile similar to that of placebo (McShane et al. 2006). Memantine has no effect on respiration and is generally benign in patients with cardiovascular disease.

Memantine overdose has been reported with symptoms of agitation, confusion, psychosis, bradycardia, and coma, followed by full recovery. No fatalities have occurred with memantine alone. Treatment is with supportive care. Urine acidification enhances memantine elimination.

Memantine has no significant CYP interactions with other drugs. Drugs that alkalinize urine may reduce memantine elimination by up to 80%, whereas urine acidifiers enhance memantine elimination.

Note. TCAs=tricyclic antidepressants. Risk of anticholinergic adverse effects at therapeutic doses: +++=high; ++=medium; += low. Risk is increased in the elderly and with multiple agents with anticholinergic activity.

Psychotropic Drugs in Pregnancy

Management of any psychiatric disorder during pregnancy and lactation is complicated by the need to consider the effects of psychiatric medication on the fetus and newborn as well as the potential effects of untreated illness on fetal development (Altemus and Occhiogrosso 2010). Most psychotropic medications are Category C medications, indicating that risk is unknown and cannot be ruled out (Armstrong 2008). Several medications, however, are designated Category D, indicating evidence of risk. These include several benzodiazepines, carbamazepine, lithium, and valproate. Interestingly, clozapine, bupropion, buspirone, and zolpidem are designated Category B: no evidence of risk in humans. Pregnant and lactating women should use the minimal number of medications at the lowest effective dosage. Updated reviews for reproductive toxicity of specific drugs are available on the Internet through the U.S. National Library of Medicine's Developmental and Reproductive Toxicology (DART) Database (www.nlm.nih.gov/pubs/fact-sheets/dartfs.html) and Motherisk (www.motherisk.org).

Recent prospective studies found that 68% of pregnant women who discontinued antidepressant use because of pregnancy relapsed during the first or second trimester (L.S. Cohen et al. 2006), and 80% of women who discontinued mood stabilizers relapsed during pregnancy (Viguera et al. 2007). In women with severe psychiatric disorder, the decision of whether to continue the mood stabilizer or antidepressant treatments during the first trimester and throughout pregnancy should be carefully balanced against the risks of discontinuation and should be discussed with the patient, her psychiatrist, and her obstetrician. In women with mild disease and low relapse risk, the mood stabilizer or antidepressant may be tapered off or continued during efforts to conceive, and the patient can be monitored closely for relapse of mood symptoms. Abrupt cessation of mood stabilizers greatly increases the risk of relapse (50% within 2 weeks) compared with a gradual taper (Viguera et al. 2007). In women with moderate disease and/or relapse risk who respond best to lithium, which has teratogenic risk, one option is to slowly discontinue lithium before conception and then restart lithium at 12 weeks, after the structural development of the fetus's heart is complete. Monitoring of maternal serum levels and dosage adjustment of medication is advised as pregnancy progresses and during the early postpartum period, because serum levels of lithium, TCAs, lamotrigine, and other psychotropics fall with pregnancy-related increases in volume of distribution, metabolic capacity, and renal filtration. These changes reverse in the postpartum period, but timing is variable, so monitoring is needed to guide dosage adjustments postpartum.

Antipsychotics

Large national registry studies of nonpsychiatrically ill women taking the phenothiazines dixyrazine or prochlorperazine for nausea and 570 women taking other antipsychotics revealed no increased risk for teratogenicity compared with women not taking these agents (Reis and Kallen 2008). Data from women using exclusively atypical antipsychotic drugs during pregnancy are limited (data are primarily for olanzapine, clozapine, and risperidone, with fewer data on birth outcomes for ziprasidone, quetiapine, and aripiprazole) but do not point toward an increased risk of teratogenesis (Coppola et al. 2007; Diav-Citrin et al. 2005; Ernst and Goldberg 2002; McKenna et al. 2005). A small study found that although all atypical antipsychotics examined passed into the placental circulation, quetiapine had the least and olanzapine the most placental transfer (Newport et al. 2007).

Mood Stabilizers

Use of lithium in the pregnant patient has been associated with an overall 1.2- to 7.7-fold increase in fetal cardiac defects (Yonkers et al. 2004), most of which are correctable and many of which resolve spontaneously. The risk of Ebstein's anomaly is increased 20-fold but is still low (1 in 1,000 infants) (Giles and Banni-gan 2006). With fetal exposure to lithium in the first trimester, ultrasonography or fetal echocardiography to assess fetal cardiac development is advised. Use of sustained-release lithium preparations minimizes peak lithium levels, which may be protective (Yonkers et al. 2004). Use of antiepileptic agents in pregnancy has been studied mainly in patients with epilepsy. Valproic acid is associated with a significantly increased risk of incomplete neural tube closure (l%-4%), cardiac defects, craniofacial abnormalities, and limb defects. Valproate exposure increases the rate of any congenital malformation to 11%, versus 3.2% in nonexposed infants (Meador et al. 2008). Risk increases with dosage and with combined anticonvulsant therapy. Carbamazepine is also teratogenic, increasing the risk of neural tube defects, facial dysmorphism, and fingernail hypoplasia, but the risk of malformations is much lower than with valproate. The risk of any major malformation at birth is 4.6% with carbamazepine, compared with 3.2% in unexposed infants (Meador et al. 2008). Folate supplementation decreases the incidence of neural tube defects in carbamazepine-exposed pregnancies (Hernandez-Diaz et al. 2001) but not in valproate-exposed pregnancies (Wyszynski et al. 2005). Overall, lamotrigine registry data to date indicate no increased risk of congenital malformations (Holmes et al. 2008). Topiramate was not associated with any structural abnormalities in a small prospective study (Ornoy et al. 2008). Insufficient data are available to assess oxcarbazepine's teratogenicity.

Newborns exposed to lithium prior to delivery may experience symptoms of neonatal lithium toxicity including flaccidity, lethargy, and poor reflexes, especially when serum lithium levels are above 0.64 mEq/L (Newport et al. 2005). If clinically feasible, consideration should be given to holding lithium 24-48 hours prior to delivery.

Antidepressants

SSRIs are not associated with an increased rate of stillbirths or major physical malformations (Wisner et al. 2009). Concerns of increased risk of cardiac defects following paroxetine use during pregnancy, which prompted the FDA to issue a product warning, have not been confirmed (Einarson et al. 2009). Risk of cardiac malformations may be increased if SSRIs are combined with benzodiazepines (Oberlander et al. 2008; Wikner et al. 2007). An early report of increased rates of minor physical malformations after fluoxetine exposure (Chambers et al. 1996) was not confirmed by several more recent studies (Wisner et al. 2009). Teratogenic effects have not been found for venlafaxine, nefazodone, trazodone, mirtazapine (Einarson et al. 2009), or bupropion (Cole et al. 2007). Although less formally studied, TCAs do not seem to be associated with birth defects. Increased risks for premature birth, small-for-gestational-age birth, pre-eclampsia, and persistent pulmonary hypertension in the newborn have been reported with SSRI exposure during pregnancy; however, study results have conflicted, and the risk of one or more of these conditions with SSRI exposure may be no worse than the risk of untreated depression in pregnancy (Altemus and Occhiogrosso 2010).

A neonatal syndrome has been associated with SSRI exposure in the third trimester. Symptoms include difficulty feeding, tremor, high-pitched cry, irritability, muscle rigidity or low muscle tone, respiratory distress, tachypnea, jitteriness, and convulsions. This syndrome, most common with paroxetine and fluoxetine, occurs in approximately 20% of SSRI-exposed infants, but usually lasts only a few days (Moses-Kolko et al. 2005; Oberlander et al. 2006).

Anxiolytics and Sedative-Hypnotics

Retrospective case-control studies, which are prone to recall bias, observed a threefold increased risk of oral cleft (Dolovich et al. 1998). More recent large national birth registry studies have not found evidence of teratogenic risk when benzodiazepines are used as monotherapy, although two studies suggested a twofold increased risk of congenital heart defects if an SSRI was also administered during pregnancy (Oberlander et al. 2008; Wikner et al. 2007). Several studies suggest an increased, but still very rare, risk of pyloric stenosis or alimentary tract atresia with first-trimester benzodiazepine exposure (Bonnot et al. 2003; Juric et al. 2009; Wikner et al. 2007). If benzodiazepines are used late in pregnancy, infants should be closely monitored for neonatal adverse effects, including irritability, tremor, withdrawal seizures, floppy baby syndrome, and apnea and other respiratory difficulties.

Psychostimulants

Insufficient data are available to evaluate the teratogenic effects of the therapeutic use of amphetamine, methylphenidate, modafinil, or atomoxetine during pregnancy. Two cohort studies of amphetamine administration for weight control during pregnancy did not show an increase in the rate of malformations. Animal studies, however, suggest the neuro-developmental toxicity of amphetamine exposure; stimulant medications should be avoided during pregnancy, and behavioral and organizational therapeutic approaches for ADHD should be emphasized (U.S. Department of Health and Human Services 2005).

Conclusion

In this chapter, we have attempted to provide a useful clinical overview of the major psychotropic drug classes and their uses. We hope that the reader has gained an understanding of the strengths and liabilities of the available armamentarium. As research into the biological mechanisms of psychiatric disorders progresses, inevitably our medication treatments will be further refined to target these specific derangements, resulting in increased efficacy, reduced adverse effects, and improved patient outcomes.

Key Clinical Points

• The use of psychopharmacological agents for given psychiatric disorders should be based on the best available clinical evidence.
• Psychopharmacology should be combined, when appropriate, with evidence-based psychosocial and psychotherapeutic modalities in order to enhance medication adherence, reduce symptom burden and relapse, and increase function.
• The choice of psychopharmacological agent is based on multiple factors, including evidence for efficacy, side effects, desirable secondary pharmacodynamics effects, routes of administration, drug-drug interactions, medical and psychiatric comorbidities, and personal and family history of medication response.
• There is tremendous inter- and intraindividual variation in response to psychotropic medications.
• If a patient does not respond to one drug in a given class, it does not mean that they will not respond to another drug from the same class.
• In general, drugs that are approved for specific disorders are equally efficacious, and differ primarily in terms of pharmacokinetics, adverse-effect profiles, and drug-drug interactions. The most notable exception to this rule is clozapine, which has unique efficacy for treatment-refractory schizophrenia.
• When possible, minimize polypharmacy, which increases the risk for medication toxicity and drug-drug interactions.

^† We would like to dedicate this chapter to our friend and colleague Jim Owen, who died on Tuesday, October 5th, 2013. Jim was a profoundly dedicated and generous man whose immense knowledge, intellectual curiosity, and academic enthusiasm continue to be an inspiration to us.

^* The authors wish to acknowledge and thank Melissa Martinez, M.D., Lauren B. Marangell, M.D., and James M. Martinez, M.D., who were coauthors on the previous version of this chapter (Martinez M, Marangell LB, Martinez JM: ''Psychopharmacology," in The American Psychiatric Publishing Textbook of Psychiatry, 5th Edition. Arlington, VA, American Psychiatric Publishing, 2008, pp. 1053-1131).

¹ It is important to note that the presence of an FDA-approved indication for a given disorder is not synonymous with superiority, and lack of indication is not necessarily proof of inferiority, especially for drugs that have long been generic. Many of the FGAs have been used for years for conditions in which the SGAs have received FDA approval (e.g., bipolar mania), but have never been FDA-approved for these uses.

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Online Resources

Drug Interactions

http://reference.medscape.com/drug-inter-actionchecker

http://hivinsite.ucsf.edu/

https://online.epocrates.com/

Neuroleptic Malignant Syndrome: Information Service (NMSIS): http://www.nmsis.org

Serotonin Syndrome: http://www.nlm.nih.gov/medlineplus/ency/article/007272.htm

U.S. Food and Drug Administration Postmarketing Information on Drug Safety for Patients and Providers: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetylnformationforPatientsandProviders/default.htm

Drugs in Pregnancy and Lactation

Developmental and Reproductive Toxicology/Environmental Teratology Information Center (DARTO/ETIC) Database: http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?DARTETIC

American College of Obstetrics and Gynecology Guidelines: http://www.aafp.org/afp/2008/0915/p772.html

Antipsychotic Dosing: International Consensus Study of Antipsychotic Dosing: http://ajp.psychiatryonline.org/article.aspx?articleid=102312

Clozapine Registry: https://www.clozapine-registry.com/registry/default.aspx

Lithium and the Kidney: http://www.bmj.com/content/339/bmj.b2452

Motherisk: http://www.motherisk.org