Pharmacology_Katzung

Pharmacology_Katzung. Psychotic symptoms associated with Parkinson’s disease represent a clinical challenge. Medications such as levodopa that treat the symptoms of Parkinson’s disease can also exacerbate psychotic symptoms. Likewise, antipsychotics that can treat the psychotic symptoms can significantly worsen the other symptoms of Parkinson’s disease. In 2016, a new type of antipsychotic was approved for the treatment of psychosis in Parkinson’s disease. Pimavanserin is a selective serotonin inverse agonist. As such, it has no dopamine antagonist properties and is not associated with EPS. Pimavanserin is currently being investigated as an adjunctive treatment in schizophrenia. B. Nonpsychiatric Indications


Pharmacology_Katzung

Pharmacology_Katzung. B. Nonpsychiatric Indications Most older first-generation antipsychotic drugs, with the exception of thioridazine, have a strong antiemetic effect. This action is due to dopamine-receptor blockade, both centrally (in the chemoreceptor trigger zone of the medulla) and peripherally (on receptors in the stomach). Some drugs, such as prochlorperazine and benzquinamide, are promoted solely as antiemetics. Phenothiazines with shorter side chains have considerable H1-receptor-blocking action and have been used for relief of pruritus or, in the case of promethazine, as preoperative sedatives. The butyrophenone droperidol is used in combination with the opioid fentanyl in neuroleptanesthesia. Droperidol has dose-associated risk of QT prolongation and has been removed from some markets. The use of these drugs in anesthesia practice is described in Chapter 25.


Pharmacology_Katzung

Pharmacology_Katzung. Choice among antipsychotic drugs is based mainly on differences in adverse effects and possible differences in efficacy. In addition, cost and the availability of a given agent on drug formularies also influence the choice of a specific antipsychotic. Because use of the older drugs is still widespread, especially for patients treated in the public sector, knowledge of such agents as chlorpromazine and haloperidol remains relevant. Thus, one should be familiar with one member of each of the three subfamilies of phenothiazines, a member of the thioxanthene and butyrophenone group, and all of the newer compounds—clozapine, risperidone, olanzapine, quetiapine, ziprasidone, lurasidone, iloperidone, asenapine, cariprazine, and aripiprazole. Each may have special advantages for selected patients. A representative group of antipsychotic drugs is presented in Table 29–3.


Pharmacology_Katzung

Pharmacology_Katzung. For approximately 70% of patients with schizophrenia, and probably for a similar proportion of patients with bipolar disorder with psychotic features, firstand second-generation antipsychotic drugs are of equal efficacy for treating positive symptoms. TABLE 29–3 Some representative antipsychotic drugs. 1Other aliphatic phenothiazines: promazine, triflupromazine. 2Other piperidine phenothiazines: piperacetazine, mesoridazine. 3Other piperazine phenothiazines: acetophenazine, perphenazine, carphenazine, prochlorperazine, trifluoperazine. However, the evidence favors second-generation drugs for benefit for negative symptoms and cognition, for diminished risk of tar-dive dyskinesia and other forms of EPS, and for lesser increases in prolactin levels.


Pharmacology_Katzung

Pharmacology_Katzung. Some of the second-generation antipsychotic drugs produce more weight gain and increases in lipids than some first-generation drugs. A small percentage of patients develop diabetes mellitus, most often seen with clozapine and olanzapine. Ziprasidone is the second-generation drug causing the least weight gain. Risperidone, lurasidone, brexpiprazole, paliperidone, and aripiprazole usually produce small increases in weight and lipids. Asenapine and quetiapine have an intermediate effect. Clozapine and olanzapine frequently result in large increases in weight and lipids. Thus, these drugs should be considered as second-line drugs unless there is a specific indication. That is the case with clozapine, which at high doses (300–900 mg/d) is effective in the majority of patients with schizophrenia refractory to other drugs, provided that treatment is continued for up to 6 months. Case reports and several clinical trials suggest that high-dose olanzapine, ie, doses of 30–45 mg/d, may also be


Pharmacology_Katzung

Pharmacology_Katzung. refractory to other drugs, provided that treatment is continued for up to 6 months. Case reports and several clinical trials suggest that high-dose olanzapine, ie, doses of 30–45 mg/d, may also be efficacious in refractory schizophrenia when given over a 6-month period. Clozapine is the only second-generation antipsychotic drug approved to reduce the risk of suicide in patients with history of schizophrenia. Patients with schizophrenia who have made life-threatening suicide attempts should be seriously evaluated for switching to clozapine.


Pharmacology_Katzung

Pharmacology_Katzung. New antipsychotic drugs have been shown in some trials to be more effective than older ones for treating negative symptoms. The floridly psychotic form of the illness accompanied by uncontrollable behavior probably responds equally well to all potent antipsychotics but is still frequently treated with older drugs that offer intramuscular formulations for acute and chronic treatment. Moreover, the low cost of the older drugs contributes to their widespread use despite their risk of adverse EPS effects. Several of the newer antipsychotics, including clozapine, risperidone, and olanzapine, show superiority over haloperidol in terms of overall response in some controlled trials. More comparative studies with aripiprazole are needed to evaluate its relative efficacy. Moreover, the superior adverse-effect profile of the newer agents and low to absent risk of tardive dyskinesia suggest that these should provide the first line of treatment. Generic forms of many second-generation drugs


Pharmacology_Katzung

Pharmacology_Katzung. adverse-effect profile of the newer agents and low to absent risk of tardive dyskinesia suggest that these should provide the first line of treatment. Generic forms of many second-generation drugs including clozapine, olanzapine, aripiprazole, risperidone, and quetiapine have become available, and cost of these drugs is much less of a consideration than it once was.


Pharmacology_Katzung

Pharmacology_Katzung. The best guide for selecting a drug for an individual patient is the patient history of past responses to drugs. At present, clozapine is limited to those patients who have failed to respond to substantial doses of conventional antipsychotic drugs. The agranulocytosis and seizures associated with this drug prevent more widespread use. Risperidone’s improved adverse-effect profile (compared with that of haloperidol) at dosages of 6 mg/d or less and the apparently lower risk of tardive dyskinesia have contributed to its widespread use. Olanzapine and quetiapine may have even lower risks and have also achieved widespread use. At this writing, aripiprazole is the most commonly prescribed second-generation antipsychotic in the USA due to a relatively favorable side effect profile and aggressive marketing.


Pharmacology_Katzung

Pharmacology_Katzung. The range of effective dosages among various antipsychotic agents is broad. Therapeutic margins are substantial. At appropriate dosages, antipsychotics—with the exception of clozapine and perhaps olanzapine—are of equal efficacy in broadly selected groups of patients. However, some patients who fail to respond to one drug may respond to another; for this reason, several drugs may have to be tried to find the one most effective for an individual patient. Patients who have become refractory to two or three antipsychotic agents given in substantial doses become candidates for treatment with clozapine or high-dose olanzapine. Thirty to fifty percent of patients previously refractory to standard doses of other antipsychotic drugs respond to these drugs. In such cases, the increased risk of clozapine can well be justified. Some dosage relationships between various antipsychotic drugs, as well as possible therapeutic ranges, are shown in Table 29–4.


Pharmacology_Katzung

Pharmacology_Katzung. Some dosage relationships between various antipsychotic drugs, as well as possible therapeutic ranges, are shown in Table 29–4. Well-tolerated parenteral forms of the high-potency older drugs haloperidol and fluphenazine are available for rapid initiation of treatment as well as for maintenance treatment in noncom-pliant patients. Since the parenterally administered drugs may have much greater bioavailability than the oral forms, doses should be only a fraction of what might be given orally, and TABLE 29–4 Dose relationships of antipsychotics.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 29–4 Dose relationships of antipsychotics. the manufacturer’s literature should be consulted. Fluphenazine decanoate and haloperidol decanoate are suitable for long-term parenteral maintenance therapy in patients who cannot or will not take oral medication. In addition, newer long-acting injectable (LAI) second-generation antipsychotics are now available, including formulations of risperidone, olanzapine, aripiprazole, and paliperidone. For some patients, the newer LAI drugs may be better tolerated than the older depot injectables.


Pharmacology_Katzung

Pharmacology_Katzung. Antipsychotic drugs are often given in divided daily doses, titrating to an effective dosage. The low end of the dosage range in Table 29–4 should be tried for at least several weeks. After an effective daily dosage has been defined for an individual patient, doses can be given less frequently. Once-daily doses, usually given at night, are feasible for many patients during chronic maintenance treatment. Simplification of dosage schedules leads to better compliance. A very small minority of schizophrenic patients may recover from an acute episode and require no further drug therapy for prolonged periods. In most cases, the choice is between “as needed” increased doses or the addition of other drugs for exacerbations versus continual maintenance treatment with full therapeutic dosage. The choice depends on social factors such as the availability of family or friends familiar with the early symptoms of relapse and ready access to care.


Pharmacology_Katzung

Pharmacology_Katzung. Combining antipsychotic drugs confounds evaluation of the efficacy of the drugs being used. Use of combinations, however, is widespread, with more emerging experimental data supporting such practices. Tricyclic antidepressants or, more often, selective serotonin reuptake inhibitors (SSRIs) are often used with anti-psychotic agents for symptoms of depression complicating schizophrenia. The evidence for the usefulness of this polypharmacy is minimal. Electroconvulsive therapy (ECT) is a useful adjunct for antipsychotic drugs, not only for treating mood symptoms, but for positive symptom control as well. Electroconvulsive therapy can augment clozapine when maximum doses of clozapine are ineffective. In contrast, adding risperidone to clozapine is not beneficial. Lithium or valproic acid is sometimes added to antipsychotic agents with benefit to patients who do not respond to the latter drugs alone. There is some evidence that lamotrigine is more effective than any of the other mood


Pharmacology_Katzung

Pharmacology_Katzung. is sometimes added to antipsychotic agents with benefit to patients who do not respond to the latter drugs alone. There is some evidence that lamotrigine is more effective than any of the other mood stabilizers for this indication (see below). It is uncertain whether instances of successful combination therapy represent misdiagnosed cases of mania or schizoaffective disorder. Benzodiazepines may be useful for patients with anxiety symptoms or insomnia not controlled by antipsychotics.


Pharmacology_Katzung

Pharmacology_Katzung. Most of the unwanted effects of antipsychotic drugs are extensions of their known pharmacologic actions (Tables 29–1 and 29–2), but a few effects are allergic in nature, and some are idiosyncratic. A. Behavioral Effects The older typical antipsychotic drugs are unpleasant to take. Many patients stop taking these drugs because of the adverse effects, which may be mitigated by giving small doses during the day and the major portion at bedtime. A “pseudodepression” that may be due to drug-induced akinesia usually responds to cautious treatment with antiparkinsonism drugs. Other pseudodepressions may be due to higher doses than needed in a partially remitted patient, in which case decreasing the dose may relieve the symptoms. Toxic-confusional states may occur with very high doses of drugs that have prominent antimuscarinic actions. B. Neurologic Effects


Pharmacology_Katzung

Pharmacology_Katzung. B. Neurologic Effects Extrapyramidal reactions occurring early during treatment with older agents include typical Parkinson’s syndrome, akathisia (uncontrollable restlessness), and acute dystonic reactions (spastic retrocollis or torticollis). Parkinsonism can be treated, when necessary, with conventional antiparkinsonism drugs of the antimuscarinic type or, in rare cases, with amantadine. (Levodopa should never be used in these patients.) Parkinsonism may be self-limiting, so that an attempt to withdraw antiparkinsonism drugs should be made every 3–4 months. Akathisia and dystonic reactions also respond to such treatment, but many clinicians prefer to use a sedative antihistamine with anticholinergic properties, eg, diphenhydramine, which can be given either parenterally or orally.


Pharmacology_Katzung

Pharmacology_Katzung. Tardive dyskinesia, as the name implies, is a late-occurring syndrome of abnormal choreoathetoid movements. It is the most important unwanted effect of antipsychotic drugs. It has been proposed that it is caused by a relative cholinergic deficiency secondary to supersensitivity of dopamine receptors in the caudate-putamen. The prevalence varies enormously, but tardive dyskinesia is estimated to have occurred in 20–40% of chronically treated patients before the introduction of the newer atypical antipsychotics. Early recognition is important, since advanced cases may be difficult to reverse. Any patient with tardive dyskinesia treated with a typical antipsychotic drug or possibly risperidone or paliperidone should be switched to quetiapine or clozapine, the atypical agents with the least likelihood of causing tardive dyskinesia. Many treatments have been proposed, but their evaluation is confounded by the fact that the course of the disorder is variable and sometimes self-limited.


Pharmacology_Katzung

Pharmacology_Katzung. likelihood of causing tardive dyskinesia. Many treatments have been proposed, but their evaluation is confounded by the fact that the course of the disorder is variable and sometimes self-limited. Reduction in dosage may also be considered. Most authorities agree that the first step should be to discontinue or reduce the dose of the current antipsychotic agent or switch to one of the newer atypical agents. A logical second step would be to eliminate all drugs with central anticholinergic action, particularly antiparkinsonism drugs and tricyclic antidepressants. These two steps are often enough to bring about improvement. If they fail, the addition of diazepam in doses as high as 30–40 mg/d may add to the improvement by enhancing GABAergic activity.


Pharmacology_Katzung

Pharmacology_Katzung. Seizures, though recognized as a complication of chlorpromazine treatment, were so rare with the high-potency older drugs as to merit little consideration. However, de novo seizures may occur in 2–5% of patients treated with clozapine. Use of an anticonvulsant is able to control seizures in most cases. C. Autonomic Nervous System Effects Most patients are able to tolerate the antimuscarinic adverse effects of antipsychotic drugs. Those who are made too uncomfortable or who develop urinary retention or other severe symptoms can be switched to an agent without significant antimuscarinic action. Orthostatic hypotension or impaired ejaculation—common complications of therapy with chlorpromazine or mesoridazine— should be managed by switching to drugs with less marked adrenoceptor-blocking actions. D. Metabolic and Endocrine Effects


Pharmacology_Katzung

Pharmacology_Katzung. D. Metabolic and Endocrine Effects Weight gain is very common, especially with clozapine and olanzapine, and requires monitoring of food intake, especially carbohydrates. Hyperglycemia may develop, but whether secondary to weight gain-associated insulin resistance or to other mechanisms remains to be clarified. Hyperlipidemia may occur. The management of weight gain, insulin resistance, and increased lipids should include monitoring of weight at each visit and measurement of fasting blood sugar and lipids at 3to 6-month intervals. Measurement of hemoglobin A1C may be useful when it is impossible to be sure of obtaining a fasting blood sugar. Diabetic ketoacidosis has been reported in a few cases. The triglyceride:HDL ratio should be less than 3.5 in fasting samples. Levels higher than that indicate increased risk of atherosclerotic cardiovascular disease.


Pharmacology_Katzung

Pharmacology_Katzung. Hyperprolactinemia in women results in the amenorrheagalactorrhea syndrome and infertility; in men, loss of libido, impotence, and infertility may result. Hyperprolactinemia may cause osteoporosis, particularly in women. If dose reduction is not indicated, or ineffective in controlling this pattern, switching to one of the atypical agents that do not raise prolactin levels, eg, aripiprazole, may be indicated. E. Toxic or Allergic Reactions Agranulocytosis, cholestatic jaundice, and skin eruptions occur rarely with the high-potency antipsychotic drugs currently used.


Pharmacology_Katzung

Pharmacology_Katzung. E. Toxic or Allergic Reactions Agranulocytosis, cholestatic jaundice, and skin eruptions occur rarely with the high-potency antipsychotic drugs currently used. In contrast to other antipsychotic agents, clozapine causes agranulocytosis in a small but significant number of patients— approximately 1–2% of those treated. This serious, potentially fatal effect can develop rapidly, usually between the 6th and 18th weeks of therapy. It is not known whether it represents an immune reaction, but it appears to be reversible upon discontinuance of the drug. Because of the risk of agranulocytosis, patients receiving clozapine must have weekly blood counts for the first 6 months of treatment and every 3 weeks thereafter. F. Ocular Complications


Pharmacology_Katzung

Pharmacology_Katzung. F. Ocular Complications Deposits in the anterior portions of the eye (cornea and lens) are a common complication of chlorpromazine therapy. They may accentuate the normal processes of aging of the lens. Thioridazine is the only antipsychotic drug that causes retinal deposits, which in advanced cases may resemble retinitis pigmentosa. The deposits are usually associated with “browning” of vision. The maximum daily dose of thioridazine has been limited to 800 mg/d to reduce the possibility of this complication. G. Cardiac Toxicity


Pharmacology_Katzung

Pharmacology_Katzung. Thioridazine in doses exceeding 300 mg daily is almost always associated with minor abnormalities of T waves that are easily reversible. Overdoses of thioridazine are associated with major ventricular arrhythmias, eg, torsades de pointes, cardiac conduction block, and sudden death; it is not certain whether thioridazine can cause these same disorders when used in therapeutic doses. In view of possible additive antimuscarinic and quinidinelike actions with various tricyclic antidepressants, thioridazine should be combined with the latter drugs only with great care. Among the atypical agents, ziprasidone carries the greatest risk of QT prolongation and therefore should not be combined with other drugs that prolong the QT interval, including thioridazine, pimozide, and group 1A or 3 antiarrhythmic drugs. Clozapine is sometimes associated with myocarditis and must be discontinued if myocarditis manifests. Sudden death due to arrhythmias is common in schizophrenia. It is not always


Pharmacology_Katzung

Pharmacology_Katzung. drugs. Clozapine is sometimes associated with myocarditis and must be discontinued if myocarditis manifests. Sudden death due to arrhythmias is common in schizophrenia. It is not always drug-related, and there are no studies that definitively show increased risk with particular drugs. Monitoring of QTc prolongation has proved to be of little use unless the values increase to more than 500 ms and this is manifested in multiple rhythm strips or a Holter monitor study. A 20,000-patient study of ziprasidone versus olanzapine showed minimal or no increased risk of torsades de pointes or sudden death in patients who were randomized to ziprasidone.


Pharmacology_Katzung

Pharmacology_Katzung. H. Use in Pregnancy; Dysmorphogenesis Although antipsychotic drugs appear to be relatively safe in pregnancy, a small increase in teratogenic risk could be missed. Questions about whether to use these drugs during pregnancy and whether to abort a pregnancy in which the fetus has already been exposed must be decided individually. If a pregnant woman could manage to be free of antipsychotic drugs during pregnancy, this would be desirable because of their effects on the neurotransmitters involved in neurodevelopment. I. Neuroleptic Malignant Syndrome


Pharmacology_Katzung

Pharmacology_Katzung. I. Neuroleptic Malignant Syndrome This life-threatening disorder occurs in patients who are extremely sensitive to the extrapyramidal effects of antipsychotic agents (see also Chapter 16). The initial symptom is marked muscle rigidity. If sweating is impaired, as it often is during treatment with anticholinergic drugs, fever may ensue, often reaching dangerous levels. The stress leukocytosis and high fever associated with this syndrome may erroneously suggest an infectious process. Autonomic instability, with altered blood pressure and pulse rate, is often present.


Pharmacology_Katzung

Pharmacology_Katzung. Muscle-type creatine kinase levels are usually elevated, reflecting muscle damage. This syndrome is believed to result from an excessively rapid blockade of postsynaptic dopamine receptors. A severe form of extrapyramidal syndrome follows. Early in the course, vigorous treatment of the extrapyramidal syndrome with antiparkinsonism drugs is worthwhile. Muscle relaxants, particularly diazepam, are often useful. Other muscle relaxants, such as dantrolene, or dopamine agonists, such as bromocriptine, have been reported to be helpful. If fever is present, cooling by physical measures should be tried. Various minor forms of this syndrome are now recognized. Switching to an atypical drug after recovery is indicated.


Pharmacology_Katzung

Pharmacology_Katzung. Antipsychotics produce more important pharmacodynamic than pharmacokinetic interactions because of their multiple effects. Additive effects may occur when these drugs are combined with others that have sedative effects, α-adrenoceptor-blocking action, anticholinergic effects, and—for thioridazine and ziprasidone— quinidine-like action. A variety of pharmacokinetic interactions have been reported, but none are of major clinical significance.


Pharmacology_Katzung

Pharmacology_Katzung. A variety of pharmacokinetic interactions have been reported, but none are of major clinical significance. Poisonings with antipsychotic agents (unlike tricyclic antidepressants) are rarely fatal, with the exception of those due to mesoridazine and thioridazine. In general, drowsiness proceeds to coma, with an intervening period of agitation. Neuromuscular excitability may be increased and proceed to convulsions. Pupils are miotic, and deep tendon reflexes are decreased. Hypotension and hypothermia are the rule, although fever may be present later in the course. The lethal effects of mesoridazine and thioridazine are related to induction of ventricular tachyarrhythmias. Patients should be given the usual “ABCD” treatment for poisonings (see Chapter 58) and treated supportively. Management of overdoses of thioridazine and mesoridazine, which are complicated by cardiac arrhythmias, is similar to that for tricyclic antidepressants (see Chapter 30).


Pharmacology_Katzung

Pharmacology_Katzung. Patients with schizophrenia need psychosocial support based around activities of daily living, including housing, social activities, returning to school, obtaining the optimal level of work they may be capable of, and restoring social interactions. Unfortunately, funding for this crucial component of treatment has been minimized in recent years. Case management and therapy services are a vital part of the treatment program that should be provided to patients with schizophrenia. First-episode patients are particularly needful of this support because they often deny their illness and are noncompliant with medication. Benefits & Limitations of Drug Treatment


Pharmacology_Katzung

Pharmacology_Katzung. Benefits & Limitations of Drug Treatment As noted at the beginning of this chapter, antipsychotic drugs have had a major impact on psychiatric treatment. First, they have shifted the vast majority of patients from long-term hospitalization to the community. For many patients, this shift has provided a better life under more humane circumstances and in many cases has made possible life without frequent use of physical restraints. For others, the tragedy of an aimless existence is now being played out in the streets of our communities rather than in mental institutions.


Pharmacology_Katzung

Pharmacology_Katzung. Second, these antipsychotic drugs have markedly shifted psychiatric thinking to a more biologic orientation. Partly because of research stimulated by the effects of these drugs on schizophrenia, we now know much more about central nervous system physiology and pharmacology than was known before the introduction of these agents. However, despite much research, schizophrenia remains a scientific mystery and a personal disaster for the patient. Although most schizophrenic patients obtain some degree of benefit from these drugs—in some cases substantial benefit—none are made well by them. ■ LITHIUM, MOOD-STABILIZING DRUGS, & OTHER TREATMENT FOR BIPOLAR DISORDER


Pharmacology_Katzung

Pharmacology_Katzung. ■ LITHIUM, MOOD-STABILIZING DRUGS, & OTHER TREATMENT FOR BIPOLAR DISORDER Bipolar disorder, once known as manic-depressive illness, was conceived of as a psychotic disorder distinct from schizophrenia at the end of the 19th century. Before that, both of these disorders were considered part of a continuum. The weight of the evidence today indicates that there is profound overlap in these disorders. However, there are pathophysiologically important differences, and some drug treatments are differentially effective in these disorders. According to DSM-IV, they are separate disease entities while research continues to define the dimensions of these illnesses and their genetic and other biologic markers.


Pharmacology_Katzung

Pharmacology_Katzung. Lithium was the first agent shown to be useful in the treatment of the manic phase of bipolar disorder that was not also an anti-psychotic drug. Lithium is sometimes used adjunctively in schizophrenia. Lithium continues to be used for acute-phase illness as well as for prevention of recurrent manic and depressive episodes.


Pharmacology_Katzung

Pharmacology_Katzung. A group of mood-stabilizing drugs that are also anticonvulsant agents has become more widely used than lithium. It includes carbamazepine and valproic acid for the treatment of acute mania and for prevention of its recurrence. Lamotrigine is approved for prevention of recurrence. Gabapentin, oxcarbazepine, and topiramate are sometimes used to treat bipolar disorder but are not approved by the FDA for this indication. Aripiprazole, chlorpromazine, olanzapine, quetiapine, risperidone, and ziprasidone are approved by the FDA for treatment of the manic phase of bipolar disorder. Olanzapine plus fluoxetine in combination and quetiapine are approved for treatment of bipolar depression. Nature of Bipolar Affective Disorder


Pharmacology_Katzung

Pharmacology_Katzung. Nature of Bipolar Affective Disorder Bipolar affective disorder occurs in 1–3% of the adult population. It may begin in childhood, but most cases are first diagnosed in the third and fourth decades of life. The key symptoms of bipolar disorder in the manic phase are expansive or irritable mood, hyperactivity, impulsivity, disinhibition, diminished need for sleep, racing thoughts, psychotic symptoms in some (but not all) patients, and cognitive impairment. Depression in bipolar patients is phenomenologically similar to that of major depression, with the key features being depressed mood, diurnal variation, sleep disturbance, anxiety, and sometimes, psychotic symptoms. Mixed manic and depressive symptoms are also seen. Patients with bipolar disorder are at high risk for suicide.


Pharmacology_Katzung

Pharmacology_Katzung. The sequence, number, and intensity of manic and depressive episodes are highly variable. The cause of the mood swings characteristic of bipolar affective disorder is unknown, although a preponderance of catecholamine-related activity may be present. Drugs that increase this activity tend to exacerbate mania, whereas those that reduce activity of dopamine or norepinephrine relieve mania. Acetylcholine or glutamate may also be involved. The nature of the abrupt switch from mania to depression experienced by some patients is uncertain. Bipolar disorder has a strong familial component, and there is abundant evidence that bipolar disorder is genetically determined.


Pharmacology_Katzung

Pharmacology_Katzung. Many of the genes that increase vulnerability to bipolar disorder are common to schizophrenia but some genes appear to be unique to each disorder. Genome-wide association studies of psychotic bipolar disorder have shown replicated linkage to chromosomes 8p and 13q. Several candidate genes have shown association with bipolar disorder with psychotic features and with schizophrenia. These include genes for dysbindin, DAOA/G30, disrupted-in-schizophrenia-1 (DISC-1), and neuregulin 1. Lithium was first used therapeutically in the mid-19th century in patients with gout. It was briefly used as a substitute for sodium chloride in hypertensive patients in the 1940s but was banned after it proved too toxic for use without monitoring. In 1949, Cade discovered that lithium was an effective treatment for bipolar disorder, engendering a series of controlled trials that confirmed its efficacy as monotherapy for the manic phase of bipolar disorder.


Pharmacology_Katzung

Pharmacology_Katzung. Lithium is a small monovalent cation. Its pharmacokinetics are summarized in Table 29–5. Despite considerable investigation, the biochemical basis for mood stabilizer therapies including lithium and anticonvulsant TABLE 29–5 Pharmacokinetics of lithium.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 29–5 Pharmacokinetics of lithium. mood stabilizers is not clearly understood. Lithium directly inhibits two signal transduction pathways. It both suppresses inositol signaling through depletion of intracellular inositol and inhibits glycogen synthase kinase-3 (GSK-3), a multifunctional protein kinase. GSK-3 is a component of diverse intracellular signaling pathways. These include signaling via insulin/insulin-like growth factor, brain-derived neurotrophic factor (BDNF), and the Wnt pathway. Lithium-induced inhibition of GSK-3 results in reduction of phosphorylation of β-catenin, which allows β-catenin to accumulate and translocate to the nucleus. There, β-catenin facilitates transcription of a variety of proteins. The pathways that are facilitated by the accumulation of β-catenin via GSK-3 inhibition modulate energy metabolism, provide neuroprotection, and increase neuroplasticity.


Pharmacology_Katzung

Pharmacology_Katzung. Studies on the enzyme prolyl oligopeptidase and the sodium myoinositol transporter support an inositol depletion mechanism for mood-stabilizer action. Valproic acid may indirectly reduce GSK-3 activity and can up-regulate gene expression through inhibition of histone deacetylase. Valproic acid also inhibits inositol signaling through an inositol depletion mechanism. There is no evidence of GSK-3 inhibition by carbamazepine, a second antiepileptic mood stabilizer. In contrast, this drug alters neuronal morphology through an inositol depletion mechanism, as seen with lithium and valproic acid. The mood stabilizers may also have indirect effects on neurotransmitters and their release. A. Effects on Electrolytes and Ion Transport


Pharmacology_Katzung

Pharmacology_Katzung. A. Effects on Electrolytes and Ion Transport Lithium is closely related to sodium in its properties. It can substitute for sodium in generating action potentials and in Na+-Na+ exchange across the membrane. At therapeutic concentrations (~1 mEq/L), it does not significantly affect the Na+-Ca2+ exchanger or the Na+/K+-ATPase pump. B. Effects on Second Messengers


Pharmacology_Katzung

Pharmacology_Katzung. Some of the enzymes affected by lithium are listed in Table 29–6. One of the best-defined effects of lithium is its action on inositol phosphates. Early studies of lithium demonstrated changes in brain inositol phosphate levels, but the significance of these changes was not appreciated until the second-messenger roles of inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) were discovered. As described in Chapter 2, inositol trisphosphate and diacylglycerol are important second messengers for both α-adrenergic and muscarinic transmission. Lithium inhibits inositol monophosphatase (IMPase) and other important enzymes in the normal recycling of membrane phosphoinositides, including conversion of IP2 (inositol diphosphate) to IP1 (inositol mono-phosphate) and the conversion of IP1 to inositol (Figure 29–4). This block leads to a depletion of free inositol and ultimately of phosphatidylinositol-4,5-bisphosphate (PIP2), the membrane precursor of IP3 and DAG. Over time, the effects


Pharmacology_Katzung

Pharmacology_Katzung. inositol (Figure 29–4). This block leads to a depletion of free inositol and ultimately of phosphatidylinositol-4,5-bisphosphate (PIP2), the membrane precursor of IP3 and DAG. Over time, the effects of transmitters on the cell diminish in proportion to the amount of activity in the PIP2-dependent pathways. The activity of these pathways is postulated to be markedly increased during a manic episode. Treatment with lithium would be expected to diminish activity in these circuits.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 29–6 Enzymes affected by lithium at therapeutic concentrations. AMP, adenosine monophosphate; IP3, inositol 1,4,5-trisphosphate. Studies of noradrenergic effects in isolated brain tissue indicate that lithium can inhibit norepinephrine-sensitive adenylyl cyclase. Such an effect could relate to both its antidepressant and its anti-manic effects. The relationship of these effects to lithium’s actions on IP3 mechanisms is currently unknown. Because lithium affects second-messenger systems involving both activation of adenylyl cyclase and phosphoinositol turnover, it is not surprising that G proteins are also found to be affected. Several studies suggest that lithium may uncouple receptors from their G proteins; indeed, two of lithium’s most common side effects, polyuria and subclinical hypothyroidism, may be due to


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 29–4 Effect of lithium on the IP3 (inositol trisphosphate) and DAG (diacylglycerol) second-messenger system. The schematic diagram shows the synaptic membrane of a neuron. (PI, inorganic phosphate; PIP2, phosphatidylinositol-4,5-bisphosphate; PLC, phospholipase C; G, coupling protein; Effects, activation of protein kinase C, mobilization of intracellular Ca2+, etc.) Lithium, by inhibiting the recycling of inositol substrates, may cause the depletion of the second-messenger source PIP2 and therefore reduce the release of IP3 and DAG. Lithium may also act by other mechanisms (see text). uncoupling of the vasopressin and thyroid-stimulating hormone (TSH) receptors from their G proteins.


Pharmacology_Katzung

Pharmacology_Katzung. uncoupling of the vasopressin and thyroid-stimulating hormone (TSH) receptors from their G proteins. The major current working hypothesis for lithium’s therapeutic mechanism of action supposes that its effects on phosphoinositol turnover, leading to an early relative reduction of myoinositol in human brain, are part of an initiating cascade of intracellular changes. Effects on specific isoforms of protein kinase C may be most relevant. Alterations of protein kinase C-mediated signaling alter gene expression and the production of proteins implicated in long-term neuroplastic events that could underlie long-term mood stabilization.


Pharmacology_Katzung

Pharmacology_Katzung. Until the late 1990s, lithium carbonate was the universally preferred treatment for bipolar disorder, especially in the manic phase. With the approval of valproate, aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone for this indication, a smaller percentage of bipolar patients now receive lithium. This trend is reinforced by the slow onset of action of lithium, which has often been supplemented with concurrent use of antipsychotic drugs or potent benzodiazepines in severely manic patients. The overall success rate for achieving remission from the manic phase of bipolar disorder can be as high as 80% but lower among patients who require hospitalization. A similar situation applies to maintenance treatment, which is about 60% effective overall but less in severely ill patients. These considerations have led to increased use of combined treatment in severe cases. After mania is controlled, the antipsychotic drug may be stopped and benzodiazepines and lithium continued as


Pharmacology_Katzung

Pharmacology_Katzung. These considerations have led to increased use of combined treatment in severe cases. After mania is controlled, the antipsychotic drug may be stopped and benzodiazepines and lithium continued as maintenance therapy.


Pharmacology_Katzung

Pharmacology_Katzung. The depressive phase of manic-depressive disorder often requires concurrent use of other agents including antipsychotics such as quetiapine or lurasidone. Antidepressants have not shown consistent utility and may be destabilizing. Tricyclic antidepressant agents have been linked to precipitation of mania, with more rapid cycling of mood swings, although most patients do not show this effect. Similarly, selective norepinephrine-serotonin reuptake inhibitor (SNRI) agents (see Chapter 30) have been associated with higher rates of switching to mania than some other antidepressants. Selective serotonin reuptake inhibitors are less likely to induce mania but may have limited efficacy. Bupropion has shown some promise but—like tricyclic antidepressants—may induce mania at higher doses. As shown in recent controlled trials, the anticonvulsant lamotrigine is effective for some patients with bipolar depression, but results have been inconsistent. For some patients, however, one of the older


Pharmacology_Katzung

Pharmacology_Katzung. in recent controlled trials, the anticonvulsant lamotrigine is effective for some patients with bipolar depression, but results have been inconsistent. For some patients, however, one of the older monoamine oxidase inhibitors may be the antidepressant of choice. Quetiapine and the combination of olanzapine plus fluoxetine have been approved for use in bipolar depression.


Pharmacology_Katzung

Pharmacology_Katzung. Unlike antipsychotic or antidepressant drugs, which exert several actions on the central or autonomic nervous system, lithium ion at therapeutic concentrations is devoid of autonomic blocking effects and of activating or sedating effects, although it can produce nausea and tremor. Most important is that the prophylactic use of lithium can prevent both mania and depression. Many experts believe that the aggressive marketing of newer drugs has inappropriately produced a shift to drugs that are less effective than lithium for substantial numbers of patients.


Pharmacology_Katzung

Pharmacology_Katzung. Recurrent depression with a cyclic pattern is controlled by either lithium or imipramine, both of which are superior to placebo. Lithium is also among the better-studied agents used to augment standard antidepressant response in acute major depression in those patients who have had inadequate response to monotherapy. For this application, concentrations of lithium at the lower end of the recommended range for bipolar disorder appear to be adequate. Schizoaffective disorder, another condition with an affective component characterized by a mixture of schizophrenic symptoms and depression or excitement, is treated with antipsychotic drugs alone or combined with lithium. Various antidepressants are added if depression is present. Lithium alone is rarely successful in treating schizophrenia, but adding it to an antipsychotic may salvage an otherwise treatment-resistant patient. Carbamazepine may work equally well when added to an antipsychotic drug.


Pharmacology_Katzung

Pharmacology_Katzung. Clinicians rely on measurements of serum lithium concentrations for assessing both the dosage required for treatment of acute mania and for prophylactic maintenance. These measurements are customarily taken 10–12 hours after the last dose, so all data in the literature pertaining to these concentrations reflect this interval.


Pharmacology_Katzung

Pharmacology_Katzung. An initial determination of serum lithium concentration should be obtained about 5 days after the start of treatment, at which time steady-state conditions should have been attained. If the clinical response suggests a change in dosage, simple arithmetic (new dose equals present dose times desired blood level divided by present blood level) should produce the desired level. The serum concentration attained with the adjusted dosage can be checked after another 5 days. Once the desired concentration has been achieved, levels can be measured at increasing intervals unless the schedule is influenced by intercurrent illness or the introduction of a new drug into the treatment program.


Pharmacology_Katzung

Pharmacology_Katzung. The decision to use lithium as prophylactic treatment depends on many factors: the frequency and severity of previous episodes, a crescendo pattern of appearance, and the degree to which the patient is willing to follow a program of indefinite maintenance therapy. Patients with a history of two or more mood cycles or any clearly defined bipolar I diagnosis are probable candidates for maintenance treatment. It has become increasingly evident that each recurrent cycle of bipolar illness may leave residual damage and worsen the long-term prognosis of the patient. Thus, there is greater consensus among experts that maintenance treatment be started as early as possible to reduce the frequency of recurrence. Although some patients can be maintained with serum levels as low as 0.6 mEq/L, the best results have been obtained with higher levels, such as 0.9 mEq/L.


Pharmacology_Katzung

Pharmacology_Katzung. Renal clearance of lithium is reduced about 25% by diuretics (eg, thiazides), and doses may need to be reduced by a similar amount. A similar reduction in lithium clearance has been noted with several of the newer nonsteroidal anti-inflammatory drugs that block synthesis of prostaglandins. This interaction has not been reported for either aspirin or acetaminophen. All neuroleptics tested to date, with the possible exception of clozapine and the newer atypical antipsychotics, may produce more severe extrapyramidal syndromes when combined with lithium. Many adverse effects associated with lithium treatment occur at varying times after treatment is started. Some are harmless, but it is important to be alert to adverse effects that may signify impending serious toxic reactions. A. Neurologic and Psychiatric Adverse Effects


Pharmacology_Katzung

Pharmacology_Katzung. A. Neurologic and Psychiatric Adverse Effects Tremor is one of the most common adverse effects of lithium treatment, and it occurs with therapeutic doses. Propranolol and atenolol, which have been reported to be effective in essential tremor, also alleviate lithium-induced tremor. Other reported neurologic abnormalities include choreoathetosis, motor hyperactivity, ataxia, dysarthria, and aphasia. Psychiatric disturbances at toxic concentrations are generally marked by mental confusion and withdrawal. Appearance of any new neurologic or psychiatric symptoms or signs is a clear indication for temporarily stopping treatment with lithium and for close monitoring of serum levels. B. Decreased Thyroid Function


Pharmacology_Katzung

Pharmacology_Katzung. B. Decreased Thyroid Function Lithium probably decreases thyroid function in most patients exposed to the drug, but the effect is reversible or nonprogressive. Few patients develop frank thyroid enlargement, and fewer still show symptoms of hypothyroidism. Although initial thyroid testing followed by regular monitoring of thyroid function has been proposed, such procedures are not cost-effective. Obtaining a serum TSH concentration every 6–12 months, however, is prudent. C. Nephrogenic Diabetes Insipidus and Other Renal Adverse Effects Polydipsia and polyuria are common but reversible concomitants of lithium treatment, occurring at therapeutic serum concentrations. The principal physiologic lesion involved is loss of responsiveness to antidiuretic hormone (nephrogenic diabetes insipidus). Lithium-induced diabetes insipidus is resistant to vasopressin but responds to amiloride (see Chapter 15).


Pharmacology_Katzung

Pharmacology_Katzung. Extensive literature has accumulated concerning other forms of renal dysfunction during long-term lithium therapy, including chronic interstitial nephritis and minimal-change glomerulopathy with nephrotic syndrome. Some instances of decreased glomerular filtration rate have been encountered but no instances of marked azotemia or renal failure. Patients receiving lithium should avoid dehydration and the associated increased concentration of lithium in urine. Periodic tests of renal concentrating ability should be performed to detect changes. D. Edema Edema is a common adverse effect of lithium treatment and may be related to some effect of lithium on sodium retention. Although weight gain may be expected in patients who become edematous, water retention does not account for the weight gain observed in up to 30% of patients taking lithium. E. Cardiac Adverse Effects


Pharmacology_Katzung

Pharmacology_Katzung. E. Cardiac Adverse Effects The bradycardia-tachycardia (“sick sinus”) syndrome is a definite contraindication to the use of lithium because the ion further depresses the sinus node. T-wave flattening is often observed on the electrocardiogram but is of questionable significance. F. Use During Pregnancy Renal clearance of lithium increases during pregnancy and reverts to lower levels immediately after delivery. A patient whose serum lithium concentration is in a good therapeutic range during pregnancy may develop toxic levels after delivery. Special care in monitoring lithium levels is needed at these times. Lithium is transferred to nursing infants through breast milk, in which it has a concentration about one third to one half that of serum. Lithium toxicity in newborns is manifested by lethargy, cyanosis, poor suck and Moro reflexes, and perhaps hepatomegaly.


Pharmacology_Katzung

Pharmacology_Katzung. The issue of lithium-induced dysmorphogenesis is not settled. An earlier report suggested an increase in cardiac anomalies— especially Ebstein’s anomaly—in lithium babies, and it is listed as such in Table 59–1 in this book. However, more recent data suggest that lithium carries a relatively low risk of teratogenic effects. Further research is needed in this important area. G. Miscellaneous Adverse Effects Transient acneiform eruptions have been noted early in lithium treatment. Some of them subside with temporary discontinuance of treatment and do not recur with its resumption. Folliculitis is less dramatic and probably occurs more frequently. Leukocytosis is always present during lithium treatment, probably reflecting a direct effect on leukopoiesis rather than mobilization from the marginal pool. This adverse effect has now become a therapeutic effect in patients with low leukocyte counts.


Pharmacology_Katzung

Pharmacology_Katzung. Therapeutic overdoses of lithium are more common than those due to deliberate or accidental ingestion of the drug. Therapeutic overdoses are usually due to accumulation of lithium resulting from some change in the patient’s status, such as diminished serum sodium, use of diuretics, or fluctuating renal function. Since the tissues will have already equilibrated with the blood, the plasma concentrations of lithium may not be excessively high in proportion to the degree of toxicity; any value over 2 mEq/L must be considered as indicating likely toxicity. Because lithium is a small ion, it is dialyzed readily. Both peritoneal dialysis and hemodialysis are effective, although the latter is preferred.


Pharmacology_Katzung

Pharmacology_Katzung. Valproic acid (valproate), discussed in detail in Chapter 24 as an antiepileptic, has been demonstrated to have antimanic effects and is now being widely used for this indication in the USA. (Gabapentin is not effective, leaving the mechanism of antimanic action of valproate unclear.) Overall, valproic acid shows efficacy equivalent to that of lithium during the early weeks of treatment. It is significant that valproic acid has been effective in some patients who have failed to respond to lithium. For example, mixed states and rapid cycling forms of bipolar disorder may be more responsive to valproate than to lithium. Moreover, its side-effect profile is such that one can rapidly increase the dosage over a few days to produce blood levels in the apparent therapeutic range, with nausea being the only limiting factor in some patients. The starting dosage is 750 mg/d, increasing rapidly to the 1500–2000 mg range with a recommended maximum dosage of 60 mg/kg/d.


Pharmacology_Katzung

Pharmacology_Katzung. Combinations of valproic acid with other psychotropic medications likely to be used in the management of either phase of bipolar illness are generally well tolerated. Valproic acid is an appropriate first-line treatment for mania, although it is not clear that it will be as effective as lithium as a maintenance treatment in all subsets of patients. Many clinicians advocate combining valproic acid and lithium in patients who do not fully respond to either agent alone.


Pharmacology_Katzung

Pharmacology_Katzung. Carbamazepine has been considered to be a reasonable alternative to lithium when the latter is less than optimally efficacious. However, the pharmacokinetic interactions of carbamazepine and its tendency to induce the metabolism of CYP3A4 substrates make it a more difficult drug to use with other standard treatments for bipolar disorder. The mode of action of carbamazepine is unclear, and oxcarbazepine is not effective. Carbamazepine may be used to treat acute mania and also for prophylactic therapy. Adverse effects (discussed in Chapter 24) are generally no greater and sometimes less than those associated with lithium. Carbamazepine may be used alone or, in refractory patients, in combination with lithium or, rarely, valproate.


Pharmacology_Katzung

Pharmacology_Katzung. The use of carbamazepine as a mood stabilizer is similar to its use as an anticonvulsant (see Chapter 24). Dosage usually begins with 200 mg twice daily, with increases as needed. Maintenance dosage is similar to that used for treating epilepsy, ie, 800–1200 mg/d. Plasma concentrations between 3 and 14 mg/L are considered desirable, although the optimal therapeutic range has not been established. Blood dyscrasias have figured prominently in the adverse effects of carbamazepine when it is used as an anticonvulsant, but they have not been a major problem with its use as a mood stabilizer. Overdoses of carbamazepine are a major emergency and should generally be managed like overdoses of tricyclic antidepressants (see Chapter 58).


Pharmacology_Katzung

Pharmacology_Katzung. Lamotrigine is approved as a maintenance treatment for bipolar disorder. Although not effective in treating acute mania, it appears effective in reducing the frequency of recurrent depressive cycles and may have some utility in the treatment of bipolar depression. A number of novel agents are under investigation for bipolar depression, including riluzole, a neuroprotective agent that is approved for use in amyotrophic lateral sclerosis; ketamine, a noncompetitive NMDA antagonist previously discussed as a drug believed to model schizophrenia but thought to act by producing relative enhancement of AMPA receptor activity; and AMPA receptor potentiators. SUMMARY Antipsychotic Drugs & Lithium Subclass, Drug Mechanism of Action Effects Clinical Applications Pharmacokinetics, Toxicities, Interactions


Pharmacology_Katzung

Pharmacology_Katzung. GENERIC NAME AVAILABLE AS ANTIPSYCHOTIC AGENTS Aripiprazole Abilify Asenapine Saphris Brexpiprazole Rexulti Cariprazine Vraylar Chlorpromazine Generic, Thorazine Clozapine Generic, Clozaril, others Fluphenazine Generic Fluphenazine decanoate Generic, Prolixin Decanoate Haloperidol Generic, Haldol Haloperidol ester Haldol Decanoate Iloperidone Fanapt Loxapine Adasuve Lurasidone Latuda Molindone Moban Olanzapine Generic, Zyprexa Paliperidone Invega Ziprasidone Generic, Geodon MOOD STABILIZERS GENERIC NAME AVAILABLE AS Perphenazine Generic, Trilafon Pimavanserin Nuplazid Pimozide Orap Prochlorperazine Generic, Compazine Quetiapine Generic, Seroquel Risperidone Generic, Risperdal Thioridazine Generic, Mellaril Thiothixene Generic, Navane Trifluoperazine Generic, Stelazine Carbamazepine Generic, Tegretol Divalproex Generic, Depakote Lamotrigine Generic, Lamictal Lithium carbonate Generic, Eskalith Topiramate Generic, Topamax Valproic acid Generic, Depakene PREP AR A TIONS A V AIL ABLE


Pharmacology_Katzung

Pharmacology_Katzung. Bhattacharjee J, El-Sayeh HG: Aripiprazole versus typical antipsychotic drugs for schizophrenia. Cochrane Database Syst Rev 2008;16(3):CD006617. Caccia S et al: A new generation of antipsychotics: Pharmacology and clinical utility of cariprazine in schizophrenia. Ther Clin Risk Manag 2013;9:319. Chue P: Glycine reuptake inhibition as a new therapeutic approach in schizophrenia: Focus on the glycine transporter 1 (GlyT1). Curr Pharm Des 2013;19:1311. Citrome L: A review of the pharmacology, efficacy and tolerability of recently approved and upcoming oral antipsychotics: An evidence-based medicine approach. CNS Drugs 2013;27:879. Citrome L: Cariprazine: Chemistry, pharmacodynamics, pharmacokinetics, and metabolism, clinical efficacy, safety, and tolerability. Expert Opin Drug Metab Toxicol 2013;9:193. Citrome L: Cariprazine in bipolar disorder: Clinical efficacy, tolerability, and place in therapy. Adv Ther 2013;30:102.


Pharmacology_Katzung

Pharmacology_Katzung. Citrome L: Cariprazine in bipolar disorder: Clinical efficacy, tolerability, and place in therapy. Adv Ther 2013;30:102. Citrome L: Cariprazine in schizophrenia: Clinical efficacy, tolerability, and place in therapy. Adv Ther 2013;30:114. Correll CU et al: Efficacy of brexpiprazole in patients with acute schizophrenia: Review of three randomized, double-blind, placebo-controlled studies. Schizophr Res 2016;174:82. Coyle JT: Glutamate and schizophrenia: Beyond the dopamine hypothesis. Cell Mol Neurobiol 2006;26:365. Durgam S et al: An 8-week randomized, double-blind, placebo-controlled evaluation of the safety and efficacy of cariprazine in patients with bipolar I depression. Am J Psychiatry 2016;173:271. Durgam S et al: Cariprazine in acute exacerbation of schizophrenia: A fixed-dose, phase 3, randomized, double-blind, placeboand active-controlled trial. J Clin Psychiatry 2015;76:e1574. Escamilla MA, Zavala JM: Genetics of bipolar disorder. Dialogues Clin Neurosci 2008;10:141.


Pharmacology_Katzung

Pharmacology_Katzung. Escamilla MA, Zavala JM: Genetics of bipolar disorder. Dialogues Clin Neurosci 2008;10:141. Fava M et al: Adjunctive brexpiprazole in patients with major depressive disorder and irritability: an exploratory study. J Clin Psychiatry 2016;77:1695. Fountoulakis KN, Vieta E: Treatment of bipolar disorder: A systematic review of available data and clinical perspectives. Int J Neuropsychopharmacol 2008;11:999. Freudenreich O, Goff DC: Antipsychotic combination therapy in schizophrenia: A review of efficacy and risks of current combinations. Acta Psychiatr Scand 2002;106:323. Glassman AH: Schizophrenia, antipsychotic drugs, and cardiovascular disease. J Clin Psychiatry 2005;66(Suppl 6):5. Grunder G, Nippius H, Carlsson A: The “atypicality” of antipsychotics: A concept re-examined and re-defined. Nat Rev Drug Discov 2009;8:197. Haddad PM, Anderson IM: Antipsychotic-related QTc prolongation, torsade de pointes and sudden death. Drugs 2002;62:1649.


Pharmacology_Katzung

Pharmacology_Katzung. Haddad PM, Anderson IM: Antipsychotic-related QTc prolongation, torsade de pointes and sudden death. Drugs 2002;62:1649. Harrison PJ, Weinberger DR: Schizophrenia genes, gene expression, and neuropathology: On the matter of their convergence. Mol Psychiatry 2005;10:40. Hashimoto K et al: Glutamate modulators as potential therapeutic drugs in schizophrenia and affective disorders. Eur Arch Psychiatry Clin Neurosci 2013;263:367. Herman EJ et al: Metabotropic glutamate receptors for new treatments in schizophrenia. Handb Exp Pharmacol 2012;213:297. Hermanowicz S, Hermanowicz N: The safety, tolerability and efficacy of pimavanserin tartrate in the treatment of psychosis in Parkinson’s disease. Expert Rev Neurother 2016;16:625. Hovelsø N et al: Therapeutic potential of metabotropic glutamate receptor modulators. Curr Neuropharmacol 2012;10:12. Javitt DC: Glycine transport inhibitors in the treatment of schizophrenia. Handb Exp Pharmacol 2012;213:367.


Pharmacology_Katzung

Pharmacology_Katzung. Javitt DC: Glycine transport inhibitors in the treatment of schizophrenia. Handb Exp Pharmacol 2012;213:367. Kane JM et al: Overview of shortand long-term tolerability and safety of brexpiprazole in patients with schizophrenia. Schizophr Res 2016;174:93. Karam CS et al: Signaling pathways in schizophrenia: Emerging targets and therapeutic strategies. Trend Pharmacol Sci 2010;31:381. Lao KS et al: Tolerability and safety profile of cariprazine in treating psychotic disorders, bipolar disorder and major depressive disorder: a systematic review with meta-analysis of randomized controlled trials. CNS Drugs 2016;30:1043. Lieberman JA et al: Antipsychotic drugs: Comparison in animal models of efficacy, neurotransmitter regulation, and neuroprotection. Pharmacol Rev 2008;60:358. Lieberman JA et al: Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005;353:1209.


Pharmacology_Katzung

Pharmacology_Katzung. Lieberman JA et al: Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005;353:1209. McKeage K, Plosker GL: Amisulpride: A review of its use in the management of schizophrenia. CNS Drugs 2004;18:933. Meltzer HY: Treatment of schizophrenia and spectrum disorders: Pharmacotherapy, psychosocial treatments, and neurotransmitter interactions. Biol Psychiatry 1999;46:1321. Meltzer HY, Massey BW: The role of serotonin receptors in the action of atypical antipsychotic drugs. Curr Opin Pharmacol 2011;11:59. Meltzer HY et al: A randomized, double-blind comparison of clozapine and high-dose olanzapine in treatment-resistant patients with schizophrenia. J Clin Psychiatry 2008;69:274. Newcomer JW, Haupt DW: The metabolic effects of antipsychotic medications. Can J Psychiatry 2006;51:480. Pimavanserin (Nuplazid) for Parkinson’s disease psychosis. Med Lett Drugs Ther 2016;58:74.


Pharmacology_Katzung

Pharmacology_Katzung. Newcomer JW, Haupt DW: The metabolic effects of antipsychotic medications. Can J Psychiatry 2006;51:480. Pimavanserin (Nuplazid) for Parkinson’s disease psychosis. Med Lett Drugs Ther 2016;58:74. Schwarz C et al: Valproate for schizophrenia. Cochrane Database Syst Rev 2008;3:CD004028. Urichuk L et al: Metabolism of atypical antipsychotics: Involvement of cytochrome p450 enzymes and relevance for drug-drug interactions. Curr Drug Metab 2008;9:410. Walsh T et al: Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 2008;320:539. Zhang A, Neumeyer JL, Baldessarini RJ: Recent progress in development of dopamine receptor subtype-selective agents: Potential therapeutics for neurological and psychiatric disorders. Chem Rev 2007;107:274. Baraban JM, Worley PF, Snyder SH: Second messenger systems and psychoactive drug action: Focus on the phosphoinositide system and lithium. Am J Psychiatry 1989;146:1251.


Pharmacology_Katzung

Pharmacology_Katzung. Baraban JM, Worley PF, Snyder SH: Second messenger systems and psychoactive drug action: Focus on the phosphoinositide system and lithium. Am J Psychiatry 1989;146:1251. Bowden CL, Singh V: Valproate in bipolar disorder: 2000 onwards. Acta Psychiatr Scand Suppl 2005;426:13. Catapano LA, Manji HK: Kinases as drug targets in the treatment of bipolar disorder. Drug Discov Today 2008;13:295. Fountoulakis KN, Vieta E: Treatment of bipolar disorder: A systematic review of available data and clinical perspectives. Int J Neuropsychopharmacol 2008;11:999. Jope RS: Anti-bipolar therapy: Mechanism of action of lithium. Mol Psychiatry 1999;4:117. Mathew SJ, Manji HK, Charney DS: Novel drugs and therapeutic targets for severe mood disorders. Neuropsychopharmacology 2008;33:2080. Quiroz JA et al: Emerging experimental therapeutics for bipolar disorder: Clues from the molecular pathophysiology. Mol Psychiatry 2004;9:756.


Pharmacology_Katzung

Pharmacology_Katzung. Quiroz JA et al: Emerging experimental therapeutics for bipolar disorder: Clues from the molecular pathophysiology. Mol Psychiatry 2004;9:756. Vieta E, Sanchez-Moreno J: Acute and long-term treatment of mania. Dialogues Clin Neurosci 2008;10:165. Yatham LN et al: Third generation anticonvulsants in bipolar disorder: A review of efficacy and summary of clinical recommendations. J Clin Psychiatry 2002;63:275.


Pharmacology_Katzung

Pharmacology_Katzung. Schizophrenia is characterized by a disintegration of thought processes and emotional responsiveness. Symp-toms commonly include auditory hallucinations, paranoid or bizarre delusions, disorganized thinking and speech, and social and occupational dysfunction. For many patients, first-generation (eg, haloperidol) and second-generation agents (eg, risperidone) are of equal efficacy for treating positive symptoms. Second generation agents are often more effective for treating negative symptoms and cogni-tive dysfunction and have lower risk of tardive dyskinesia and hyperprolactinemia. Other indications for the use of selected antipsychotics include bipolar disorder, psychotic depression, Tourette syndrome, disturbed behavior in patients with Alzheimer’s disease and in the case of older drugs (eg, chlorpromazine), treatment of emesis, and pruritus.


Pharmacology_Katzung

Pharmacology_Katzung. Charles DeBattista, MD house and has no motivation, interest, or energy to pursue recreational activities that she once enjoyed such as hiking. She describes herself as “chronically miserable and worried all the time.” Her medical history is notable for chronic neck pain from a motor vehicle accident for which she is being treated with tramadol and meperidine. In addition, she is on hydrochlorothiazide and propranolol for hypertension. The patient has a history of one depressive episode after a divorce that was treated successfully with fluoxetine. Medical workup including complete blood cell count, thyroid func-tion tests, and a chemistry panel reveals no abnormalities. She is started on fluoxetine for a presumed major depressive episode and referred for cognitive behavioral psychotherapy. What CYP450 and pharmacodynamic interactions might be associated with fluoxetine use in this patient? Which class of antidepressants would be contraindicated in this patient? A 47-year-old woman


Pharmacology_Katzung

Pharmacology_Katzung. What CYP450 and pharmacodynamic interactions might be associated with fluoxetine use in this patient? Which class of antidepressants would be contraindicated in this patient? A 47-year-old woman presents to her primary care physician with a chief complaint of fatigue. She indicates that she was promoted to senior manager in her company approximately 11 months earlier. Although her promotion was welcome and came with a sizable raise in pay, it resulted in her having to move away from an office and group of colleagues she very much enjoyed. In addition, her level of responsibility increased dramatically. The patient reports that for the last 7 weeks, she has been waking up at 3 am every night and been unable to go back to sleep. She dreads the day and the stresses of the workplace. As a consequence, she is not eating as well as she might and has dropped 7% of her body weight in the last 3 months. She also reports being so stressed that she breaks down crying in the office occasionally


Pharmacology_Katzung

Pharmacology_Katzung. she is not eating as well as she might and has dropped 7% of her body weight in the last 3 months. She also reports being so stressed that she breaks down crying in the office occasionally and has been calling in sick frequently. When she comes home, she finds she is less motivated to attend to chores around the


Pharmacology_Katzung

Pharmacology_Katzung. The diagnosis of depression still rests primarily on the clinical interview. Major depressive disorder (MDD) is characterized by depressed mood most of the time for at least 2 weeks or loss of interest or pleasure in most activities, or both. In addition, depression is characterized by disturbances in sleep and appetite as well as deficits in cognition and energy. Thoughts of guilt, worthlessness, and suicide are common. Coronary artery disease, diabetes, and stroke appear to be more common in depressed patients, and depression may considerably worsen the prognosis for patients with a variety of comorbid medical conditions.


Pharmacology_Katzung

Pharmacology_Katzung. According to the Centers for Disease Control and Prevention, antidepressants are consistently among the three most commonly prescribed classes of medications in the USA. The wisdom of such widespread use of antidepressants is debated. However, it is clear that American physicians have been increasingly inclined to use antidepressants to treat a host of conditions and that patients have been increasingly receptive to their use.


Pharmacology_Katzung

Pharmacology_Katzung. The primary indication for antidepressant agents is the treatment of MDD. Major depression, with a lifetime prevalence of around 17% in the USA and a point prevalence of 5%, is associated with substantial morbidity and mortality. MDD represents one of the most common causes of disability in the developed world. In addition, major depression is commonly associated with a variety of medical conditions—from chronic pain to coronary artery disease. When depression coexists with other medical conditions, the patient’s disease burden increases, and the quality of life—and often the prognosis for effective treatment—decreases significantly.


Pharmacology_Katzung

Pharmacology_Katzung. Some of the growth in antidepressant use may be related to the broad application of these agents for conditions other than major depression. For example, antidepressants have received US Food and Drug Administration (FDA) approvals for the treatment of panic disorder, generalized anxiety disorder (GAD), post-traumatic stress disorder (PTSD), and obsessive-compulsive disorder (OCD). In addition, antidepressants are commonly used to treat pain disorders such as neuropathic pain and the pain associated with fibromyalgia. Some antidepressants are used for treating premenstrual dysphoric disorder (PMDD), mitigating the vasomotor symptoms of menopause, and treating stress urinary incontinence. Thus, antidepressants have a broad spectrum of use in medical practice. However, their primary use remains the treatment for MDD.


Pharmacology_Katzung

Pharmacology_Katzung. There has been a marked shift in the last decade in our understanding of the pathophysiology of major depression. In addition to the older idea that a deficit in function or amount of mono-amines (the monoamine hypothesis) is central to the biology of depression, there is evidence that neurotrophic and endocrine factors play a major role (the neurotrophic hypothesis). Histologic studies, structural and functional brain imaging research, genetic findings, and steroid research all suggest a complex pathophysiology for MDD with important implications for drug treatment.


Pharmacology_Katzung

Pharmacology_Katzung. There is substantial evidence that nerve growth factors such as brain-derived neurotrophic factor (BDNF) are critical in the regulation of neural plasticity, resilience, and neurogenesis. The evidence suggests that depression is associated with the loss of neurotrophic support and that effective antidepressant therapies increase neurogenesis and synaptic connectivity in cortical areas such as the hippocampus. BDNF is thought to exert its influence on neuronal survival and growth effects by activating the tyrosine kinase receptor B in both neurons and glia (Figure 30–1).


Pharmacology_Katzung

Pharmacology_Katzung. Several lines of evidence support the neurotrophic hypothesis. Animal and human studies indicate that stress and pain are associated with a drop in BDNF levels and that this loss of neurotrophic support contributes to atrophic structural changes in the hippocampus and perhaps other areas such as the medial frontal cortex and anterior cingulate. The hippocampus is known to be important both in contextual memory and regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Likewise, the anterior cingulate plays a role in the integration of emotional stimuli and


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 30–1 The neurotrophic hypothesis of major depression. Changes in trophic factors (especially brain-derived neurotrophic factor, BDNF) and hormones appear to play a major role in the development of major depression (A). Successful treatment results in changes in these factors (B). CREB, cAMP response element-binding (protein). BDNF, brain-derived neurotrophic factor. (Reproduced, with permission, from Nestler EJ: Neurobiology of depression. Neuron 2002;34[1]:13–25. Copyright Elsevier.) attention functions, whereas the medial orbital frontal cortex is also thought to play a role in memory, learning, and emotion.


Pharmacology_Katzung

Pharmacology_Katzung. Over 30 structural imaging studies suggest that major depression is associated with a 5–10% loss of volume in the hippocampus, although some studies have not replicated this finding. Depression and chronic stress states have also been associated with a substantial loss of volume in the anterior cingulate and medial orbital frontal cortex. Loss of volume in structures such as the hippocampus also appears to increase as a function of the duration of illness and the amount of time that the depression remains untreated.


Pharmacology_Katzung

Pharmacology_Katzung. Another source of evidence supporting the neurotrophic hypothesis of depression comes from studies of the direct effects of BDNF on emotional regulation. Direct infusion of BDNF into the midbrain, hippocampus, and lateral ventricles of rodents has an antidepressant-like effect in animal models. Moreover, all known classes of antidepressants are associated with an increase in BDNF levels in animal models with chronic (but not acute) administration. This increase in BDNF levels is consistently associated with increased neurogenesis in the hippocampus in these animal models. Other interventions thought to be effective in the treatment of major depression, including electroconvulsive therapy, also appear to robustly stimulate BDNF levels and hippocampus neurogenesis in animal models.


Pharmacology_Katzung

Pharmacology_Katzung. Human studies seem to support the animal data on the role of neurotrophic factors in stress states. Depression appears to be associated with a drop in BDNF levels in the cerebrospinal fluid and serum as well as with a decrease in tyrosine kinase receptor B activity. Conversely, administration of antidepressants increases BDNF levels in clinical trials and may be associated with an increase in hippocampus volume in some patients. Much evidence supports the neurotrophic hypothesis of depression, but not all evidence is consistent with this concept. Animal studies in BDNF knockout mice have not always suggested an increase in depressive or anxious behaviors that would be expected with a deficiency of BDNF. In addition, some animal studies have found an increase in BDNF levels after some types of social stress and an increase rather than a decrease in depressive behaviors with lateral ventricle injections of BDNF.


Pharmacology_Katzung

Pharmacology_Katzung. A proposed explanation for the discrepant findings on the role of neurotrophic factors in depression is that there are polymorphisms for BDNF that may yield very different effects. Mutations in the BDNF gene have been found to be associated with altered anxiety and depressive behavior in both animal and human studies. Thus, the neurotrophic hypothesis continues to be intensely investigated and has yielded new insights and potential targets in the treatment of MDD. The monoamine hypothesis of depression (Figure 30–2) suggests that depression is related to a deficiency in the amount or function of cortical and limbic serotonin (5-HT), norepinephrine (NE), and dopamine (DA).


Pharmacology_Katzung

Pharmacology_Katzung. Evidence to support the monoamine hypothesis comes from several sources. It has been known for many years that reserpine treatment, which is known to deplete monoamines, is associated with depression in a subset of patients. Similarly, depressed patients who respond to serotonergic antidepressants such as fluoxetine often rapidly suffer relapse when given diets free of tryptophan, a precursor of serotonin synthesis. Patients who respond to noradrenergic antidepressants such as desipramine are less likely to relapse on a tryptophan-free diet. Moreover, depleting catecholamines in depressed patients who have previously responded to noradrenergic agents likewise tends to be associated with relapse. Administration of an inhibitor of norepinephrine synthesis is also associated with a rapid return of depressive symptoms in patients who respond to noradrenergic but not necessarily in patients who had responded to serotonergic antidepressants.


Pharmacology_Katzung

Pharmacology_Katzung. Another line of evidence supporting the monoamine hypothesis comes from genetic studies. A functional polymorphism exists for the promoter region of the serotonin transporter gene, which regulates how much of the transporter protein is available. Subjects who are homozygous for the s (short) allele may be more vulnerable to developing major depression and suicidal behavior in response to stress. In addition, homozygotes for the s allele may also be less likely to respond to and tolerate serotonergic antidepressants. Conversely, subjects with the l (long) allele tend to be more resistant to stress and may be more likely to respond to serotonergic antidepressants.


Pharmacology_Katzung

Pharmacology_Katzung. Studies of depressed patients have sometimes shown an alteration in monoamine function. For example, some studies have found evidence of alteration in serotonin receptor numbers (5-HT1A and 5-HT2C) or norepinephrine (α2) receptors in depressed and suicidal patients, but these findings have not been consistent. A reduction in the primary serotonin metabolite 5-hydroxyindoleacetic acid in the cerebrospinal fluid is associated with violent and impulsive behavior, including violent suicide attempts. However, this finding is not specific to major depression and is associated more generally with violent and impulsive behavior.


Pharmacology_Katzung

Pharmacology_Katzung. Finally, perhaps the most convincing line of evidence supporting the monoamine hypothesis is the fact that (at the time of this writing) all available antidepressants appear to have significant effects on the monoamine system. All classes of antidepressants appear to enhance the synaptic availability of 5-HT, norepinephrine, or dopamine. Attempts to develop antidepressants that work on other neurotransmitter systems have not been effective to date. The monoamine hypothesis, like the neurotrophic hypothesis, is at best incomplete. Many studies have not found an alteration in function or levels of monoamines in depressed patients. In addition, some candidate antidepressant agents under study do not act directly on the monoamine system.


Pharmacology_Katzung

Pharmacology_Katzung. In addition to the monoamines, the excitatory neurotransmitter glutamate appears to be important in the pathophysiology of depression. A number of studies of depressed patients have found elevated glutamate content in the cerebrospinal fluid of depressed patients and decreased glutamine/glutamate ratios in their plasma. In addition, postmortem studies have revealed significant increases in the frontal and dorsolateral prefrontal cortex of depressed patients. Likewise, structural neuroimaging studies have consistently found volumetric changes in the brain areas of depressed patients in which glutamate neurons and their connections are most abundant, including the amygdala and hippocampus. Antidepressants are known to impact glutamate neurotransmission in a variety of ways. For example, chronic antidepressant ˜°˜°G Gi s cAMPIP , DAG PKCPKACREB PLCACATP 3 Nucleus Cytoplasm Postsynaptic neuron ˛˛


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 30–2 The amine hypothesis of major depression. Depression appears to be associated with changes in serotonin or norepinephrine signaling in the brain (or both) with significant downstream effects. Most antidepressants cause changes in amine signaling. AC, adenylyl cyclase; CREB, cAMP response element-binding (protein); DAG, diacyl glycerol; 5-HT, serotonin; IP3, inositol trisphosphate; MAO, monoamine oxidase; NET, norepinephrine transporter; PKC, protein kinase C; PLC, phospholipase C; SERT, serotonin transporter. (Adapted from Belmaker R, Agam


Pharmacology_Katzung

Pharmacology_Katzung. G: Major depressive disorder. N Engl J Med 2008;358:59.) use is associated with reducing glutamatergic transmission, including the presynaptic release of glutamate in the hippocampus and cortical areas. Similarly, the chronic administration of antidepressants significantly reduces depolarization-evoked release of glutamate in animal models. Stress is known to enhance the release of glutamate in rodents, and antidepressants inhibit stress-induced presynaptic release of glutamate in these models.


Pharmacology_Katzung

Pharmacology_Katzung. Given the effect of antidepressants on the glutamate system, there has been a growing interest in the development of pharmaceutical agents that might modulate the glutamate system. Ketamine is a potent, high-affinity, noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist that has long been used in anesthesia and is a common drug of abuse in some parts of the world. A number of preclinical and clinical studies have demonstrated rapid antidepressant effects of ketamine. Multiple studies have suggested that a single dose of intravenous ketamine at subanesthetic doses produces rapid relief of depression, even in treatment-resistant patients, that may persist for 1 week or longer. Unfortunately, ketamine is associated with cognitive, dissociative, and psychotomimetic properties that make it impractical as a long-term treatment for depression. Still, a number of other NMDA receptor antagonists, partial antagonists, and metabotropic glutamate receptor modulators (see Chapter 29) are


Pharmacology_Katzung

Pharmacology_Katzung. it impractical as a long-term treatment for depression. Still, a number of other NMDA receptor antagonists, partial antagonists, and metabotropic glutamate receptor modulators (see Chapter 29) are under investigation as potential antidepressants.


Pharmacology_Katzung

Pharmacology_Katzung. Neuroendocrine Factors in the Pathophysiology of Depression Depression is associated with a number of hormonal abnormalities. Among the most replicated of these findings are abnormalities in the HPA axis in patients with MDD. For example, MDD is associated with elevated cortisol levels (Figure 30–1), nonsuppression of adrenocorticotropic hormone (ACTH) release in the dexamethasone suppression test, and chronically elevated levels of corticotropin-releasing hormone. The significance of these HPA abnormalities is unclear, but they are thought to indicate a dysregulation of the stress hormone axis. More severe types of depression, such as psychotic depression, tend to be associated with HPA abnormalities more commonly than milder forms of major depression. It is well known that both exogenous glucocorticoids and endogenous elevation of cortisol are associated with mood symptoms and cognitive deficits similar to those seen in MDD.


Pharmacology_Katzung

Pharmacology_Katzung. Thyroid dysregulation has also been reported in depressed patients. Up to 25% of depressed patients are reported to have abnormal thyroid function. These abnormalities include a blunting of response of thyrotropin to thyrotropin-releasing hormone and elevations in circulating thyroxine during depressed states. Clinical hypothyroidism often presents with depressive symptoms, which resolve with thyroid hormone supplementation. Thyroid hormones are also commonly used in conjunction with standard antidepressants to augment therapeutic effects of the latter.


Pharmacology_Katzung

Pharmacology_Katzung. Finally, sex steroids are also implicated in the pathophysiology of depression. Estrogen deficiency states, which occur in the postpartum and postmenopausal periods, are thought to play a role in the etiology of depression in some women. Likewise, severe testosterone deficiency in men is sometimes associated with depressive symptoms. Hormone replacement therapy in hypogonadal men and women may be associated with an improvement in mood and depressive symptoms. Integration of Hypotheses Regarding the Pathophysiology of Depression


Pharmacology_Katzung

Pharmacology_Katzung. Integration of Hypotheses Regarding the Pathophysiology of Depression The several pathophysiologic hypotheses just described are not mutually exclusive. It is evident that the monoamine, neuroendocrine, and neurotrophic systems are interrelated in important ways. For example, HPA and steroid abnormalities may contribute to suppression of transcription of the BDNF gene. Glucocorticoid receptors are found in high density in the hippocampus. Binding of these hippocampal glucocorticoid receptors by cortisol during chronic stress states such as major depression may decrease BDNF synthesis and may result in volume loss in stress-sensitive regions such as the hippocampus. The chronic activation of monoamine receptors by antidepressants appears to have the opposite effect of stress and results in an increase in BDNF transcription. In addition, activation of monoamine receptors appears to down-regulate the HPA axis and may normalize HPA function.


Pharmacology_Katzung

Pharmacology_Katzung. One of the weaknesses of the monoamine hypothesis is the fact that amine levels increase immediately with antidepressant use, but maximum beneficial effects of most antidepressants are not seen for many weeks. The time required to synthesize neurotrophic factors has been proposed as an explanation for this delay of antidepressant effects. Appreciable protein synthesis of products such as BDNF typically takes 2 weeks or longer and coincides with the clinical course of antidepressant treatment. The currently available antidepressants make up a remarkable variety of chemical types. These differences and the differences in their molecular targets provide the basis for distinguishing several subgroups. A. Selective Serotonin Reuptake Inhibitors


Pharmacology_Katzung

Pharmacology_Katzung. The selective serotonin reuptake inhibitors (SSRIs) represent a chemically diverse class of agents that have as their primary action the inhibition of the serotonin transporter (SERT; Figure 30–3). Fluoxetine was introduced in the United States in 1988 and quickly became one of the most commonly prescribed medications in medical practice. The development of fluoxetine emerged out of the search for chemicals that had high affinity for monoamine receptors but lacked the affinity for histamine, acetylcholine, and α adrenoceptors that is seen with the tricyclic antidepressants (TCAs). There are currently six available SSRIs, and they are the most common antidepressants in clinical use. In addition to their use in major depression, SSRIs have indications in GAD, PTSD, OCD, panic disorder, PMDD, and bulimia. Fluoxetine, sertraline, and citalopram exist as isomers and are formulated in the racemic forms, whereas paroxetine and fluvoxamine are not optically active. Escitalopram is the (S)


Pharmacology_Katzung

Pharmacology_Katzung. and bulimia. Fluoxetine, sertraline, and citalopram exist as isomers and are formulated in the racemic forms, whereas paroxetine and fluvoxamine are not optically active. Escitalopram is the (S) enantiomer of citalopram. As with all antidepressants, SSRIs are highly lipophilic. The popularity of SSRIs stems largely from their ease of use, safety in overdose, relative tolerability, cost (all are available as generic products), and broad spectrum of uses.


Pharmacology_Katzung

Pharmacology_Katzung. B. Serotonin-Norepinephrine Reuptake Inhibitors Two classes of antidepressants act as combined serotonin and norepinephrine reuptake inhibitors: selective serotoninnorepinephrine reuptake inhibitors (SNRIs) and TCAs. Citalopram, escitalopram FIGURE 30–3 Structures of several selective serotonin reuptake inhibitors (SSRIs). 1. Selective serotonin-norepinephrine reuptake inhibitors—The SNRIs include venlafaxine, its metabolite desvenlafaxine, duloxetine, and levomilnacipran. Levomilnacipran is the active enantiomer of a racemic SNRI, milnacipran. Milnacipran has been approved for the treatment of fibromyalgia in the USA and has been used in the treatment of depression in Europe for many years. In addition to their use in major depression, SNRIs have applications in the treatment of pain disorders including neuropathies and fibromyalgia. SNRIs are also used in the treatment of generalized anxiety, stress urinary incontinence, and vasomotor symptoms of menopause.


Pharmacology_Katzung

Pharmacology_Katzung. R = CH3 : Venlafaxine R = H : Desvenlafaxine SNRIs are chemically unrelated to each other. Venlafaxine was discovered in the process of evaluating chemicals that inhibit binding of imipramine. Venlafaxine’s in vivo effects are similar to those of imipramine but with a more favorable adverse-effect profile. All SNRIs bind the serotonin (SERT) and norepinephrine (NET) transporters, as do the TCAs. However, unlike the TCAs, the SNRIs do not have much affinity for other receptors. Venlafaxine and desvenlafaxine are bicyclic compounds, whereas duloxetine is a three-ring structure unrelated to the TCAs. Milnacipran contains a cyclopropane ring and is provided as a racemic mixture.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Tricyclic antidepressants—The TCAs were the dominant class of antidepressants until the introduction of SSRIs in the 1980s and 1990s. Nine TCAs are available in the USA, and they all have an iminodibenzyl (tricyclic) core (Figure 30–4). The chemical differences between the TCAs are relatively subtle. For example, the prototype TCA imipramine and its metabolite, desipramine, differ by only a methyl group in the propylamine side chain. However, this minor difference results in a substantial change in their pharmacologic profiles. Imipramine is highly anticholinergic and is a relatively strong serotonin as well as norepinephrine reuptake inhibitor. In contrast, desipramine is much less anticholinergic and is a more potent and somewhat more selective norepinephrine reuptake inhibitor than is imipramine.


Pharmacology_Katzung

Pharmacology_Katzung. At present, the TCAs are used primarily in depression that is unresponsive to more commonly used antidepressants such as the SSRIs or SNRIs. Their loss of popularity stems in large part from relatively poorer tolerability compared with newer agents, difficulty of use, and lethality in overdose. Other uses for TCAs include the treatment of pain conditions, enuresis, and insomnia. R1 R1 R1 R1:–(CH2)3N(CH3)2 R1: = CH(CH2)2N(CH3)2 R1: = CH(CH2)2N(CH3)2 R2: H R1: = (CH2)3NHCH3 R1: = CH(CH2)2NHCH3 R2: H Nortriptyline R1: = (CH2)3N(CH3)2 R2: – Cl R1: = CH2CH(CH)3CH2N(CH3)2 R2: – H FIGURE 30–4 Structures of some tricyclic antidepressants (TCAs). C. 5-HT2 Receptor Modulators


Pharmacology_Katzung

Pharmacology_Katzung. R1: = (CH2)3N(CH3)2 R2: – Cl R1: = CH2CH(CH)3CH2N(CH3)2 R2: – H FIGURE 30–4 Structures of some tricyclic antidepressants (TCAs). C. 5-HT2 Receptor Modulators Two antidepressants are thought to act primarily as antagonists at the 5-HT2 receptor: trazodone and nefazodone. Trazodone’s structure includes a triazolo moiety that is thought to impart antidepressant effects. Its primary metabolite, m-chlorphenylpiperazine (m-cpp), is a potent 5-HT2 antagonist. Trazodone was among the most commonly prescribed antidepressants until it was supplanted by the SSRIs in the late 1980s. The most common use of trazodone in current practice is as an unlabeled hypnotic, since it is highly sedating and not associated with tolerance or dependence.


Pharmacology_Katzung

Pharmacology_Katzung. Nefazodone is chemically related to trazodone. Its primary metabolites, hydroxynefazodone and m-cpp are both inhibitors of the 5-HT2 receptor. Nefazodone received an FDA black box warning in 2001 implicating it in hepatotoxicity, including lethal cases of hepatic failure. Although still available generically, nefazodone is no longer commonly prescribed. The primary indications for both nefazodone and trazodone are major depression, although both have also been used in the treatment of anxiety disorders. R1 R1: = (CH2)3NCH3


Pharmacology_Katzung

Pharmacology_Katzung. R1 R1: = (CH2)3NCH3 Vortioxetine is a newer agent that acts as an antagonist of the 5-HT3, 5-HT7, and 5-HT1D receptors, a partial agonist of the 5-HT1B receptor, and an agonist of the 5HT1A receptor. It also inhibits the serotonin transporter, but its actions are not primarily related to SERT inhibition and it is therefore not classified as an SSRI. Vortioxetine has demonstrated efficacy in major depression in a number of controlled clinical studies. In addition, vortioxetine is approved in Europe and the USA to treat cognitive dysfunction associated with depression. D. Tetracyclic and Unicyclic Antidepressants


Pharmacology_Katzung

Pharmacology_Katzung. D. Tetracyclic and Unicyclic Antidepressants A number of antidepressants do not fit neatly into the other classes. Among these are bupropion, mirtazapine, amoxapine, vilazodone, and maprotiline (Figure 30–5). Bupropion has a unicyclic aminoketone structure. Its unique structure results in a different side-effect profile than most antidepressants (described below). Bupropion somewhat resembles amphetamine in chemical structure and, like the stimulant, has central nervous system (CNS) activating properties. Mirtazapine was introduced in 1994 and, like bupropion, is one of the few antidepressants not commonly associated with FIGURE 30–5 Structures of the tetracyclics, amoxapine, maprotiline, and mirtazapine and the unicyclic, bupropion. sexual effects. It has a tetracyclic chemical structure and belongs to the piperazino-azepine group of compounds.


Pharmacology_Katzung

Pharmacology_Katzung. sexual effects. It has a tetracyclic chemical structure and belongs to the piperazino-azepine group of compounds. Mirtazapine, amoxapine, and maprotiline have tetracyclic structures. Amoxapine is the N-demethylated metabolite of loxapine, an older antipsychotic drug. Amoxapine and maprotiline share structural similarities and side effects comparable to the TCAs. As a result, these tetracyclics are not commonly prescribed in current practice. Their primary use is in MDD that is unresponsive to other agents. Vilazodone has a multi-ring structure that allows it to bind potently to the serotonin transporter but minimally to the dopamine and norepinephrine transporter. E. Monoamine Oxidase Inhibitors


Pharmacology_Katzung

Pharmacology_Katzung. E. Monoamine Oxidase Inhibitors Arguably the first modern class of antidepressants, monoamine oxidase inhibitors (MAOIs) were introduced in the 1950s but are now rarely used in clinical practice because of toxicity and potentially lethal food and drug interactions. Their primary use now is in the treatment of depression unresponsive to other antidepressants. However, MAOIs have also been used historically to treat anxiety states, including social anxiety and panic disorder. In addition, selegiline is used in the treatment of Parkinson’s disease (see Chapter 28).


Pharmacology_Katzung

Pharmacology_Katzung. Current MAOIs include the hydrazine derivatives phenelzine and isocarboxazid and the nonhydrazines tranylcypromine, selegiline, and moclobemide (the latter is not available in the USA). The hydrazines and tranylcypromine bind irreversibly and nonselectively with MAO-A and -B, whereas other MAOIs may have more selective or reversible properties. Some of the MAOIs such as tranylcypromine resemble amphetamine in chemical structure, whereas other MAOIs such as selegiline have amphetamine-like metabolites. As a result, these MAOIs tend to have substantial CNS-stimulating effects. The antidepressants share several pharmacokinetic features (Table 30–1). Most have fairly rapid oral absorption, achieve peak plasma levels within 2–3 hours, are tightly bound to plasma proteins, undergo hepatic metabolism, and are renally cleared. However, even within classes, the pharmacokinetics of individual antidepressants varies considerably. A. Selective Serotonin Reuptake Inhibitors


Pharmacology_Katzung

Pharmacology_Katzung. A. Selective Serotonin Reuptake Inhibitors The prototype SSRI, fluoxetine, differs from other SSRIs in some important respects (Table 30–1). Fluoxetine is metabolized to an active product, norfluoxetine, which may have plasma concentrations greater than those of fluoxetine. The elimination half-life of norfluoxetine is about three times longer than fluoxetine and contributes to the longest half-life of all the SSRIs. As a result, fluoxetine has to be discontinued 4 weeks or longer before an MAOI can be administered to mitigate the risk of serotonin syndrome. TABLE 30–1 Pharmacokinetic profiles of selected antidepressants. 1Desvenlafaxine has similar properties but is less completely metabolized. MAOIs, monoamine oxidase inhibitors; ND, no data found; SNRIs, serotonin-norepinephrine reuptake inhibitors; SSRIs, selective serotonin reuptake inhibitors.


Pharmacology_Katzung

Pharmacology_Katzung. Fluoxetine and paroxetine are potent inhibitors of the CYP2D6 isoenzyme, and this contributes to potential drug interactions (see Drug Interactions). In contrast, fluvoxamine is an inhibitor of CYP3A4, whereas citalopram, escitalopram, and sertraline have more modest CYP interactions. B. Serotonin-Norepinephrine Reuptake Inhibitors 1. Selective serotonin-norepinephrine reuptake inhibitors—Venlafaxine is extensively metabolized in the liver via the CYP2D6 isoenzyme to O-desmethylvenlafaxine (desvenlafaxine). Both have similar half-lives of about 8–11 hours. Despite the relatively short half-lives, both drugs are available in formulations that allow once-daily dosing. Venlafaxine and desvenlafaxine have the lowest protein binding of all antidepressants (27–30%). Unlike most antidepressants, desvenlafaxine is conjugated and does not undergo extensive oxidative metabolism. At least 45% of desvenlafaxine is excreted unchanged in the urine compared with 4–8% of venlafaxine.


Pharmacology_Katzung

Pharmacology_Katzung. Duloxetine is well absorbed and has a half-life of 12–15 hours but is dosed once daily. It is tightly bound to protein (97%) and undergoes extensive oxidative metabolism via CYP2D6 and CYP1A2. Hepatic impairment significantly alters duloxetine levels unlike desvenlafaxine. Both milnacipran and levomilnacipran are well absorbed after oral dosing. Both have shorter half-lives and lower protein binding than venlafaxine (Table 30–1). Milnacipran and levomilnacipran are largely excreted unchanged in the urine. Levomilnacipran also undergoes desethylation via 3A3/4.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Tricyclic antidepressants—The TCAs tend to be well absorbed and have long half-lives (Table 30–1). As a result, most are dosed once daily at night because of their sedating effects. TCAs undergo extensive metabolism via demethylation, aromatic hydroxylation, and glucuronide conjugation. Only about 5% of TCAs are excreted unchanged in the urine. The TCAs are substrates of the CYP2D6 system, and the serum levels of these agents tend to be substantially influenced by concurrent administration of drugs such as fluoxetine. In addition, genetic polymorphism for CYP2D6 may result in low or extensive metabolism of the TCAs. The secondary amine TCAs, including desipramine and nortriptyline, lack active metabolites and have fairly linear kinetics. These TCAs have a wide therapeutic window, and serum levels are reliable in predicting response and toxicity. C. 5-HT Receptor Modulators