Case Study

A 17-year-old male high school student is referred to the psychiatry clinic for evaluation of suspected schizophrenia. After a diagnosis is made, haloperidol is prescribed at a gradually increasing dose on an outpatient basis. The drug improves the patient's positive symptoms but ultimately causes intolerable side effects. Although more costly, risperidone is then prescribed, which, over the course of several weeks of treatment, improves his symptoms and is tolerated by the patient. What signs and symptoms would support an initial diagnosis of schizophrenia? In the treatment of schizophrenia, what benefits do the atypical antipsychotic drugs offer over the traditional agents such as haloperidol? In addition to the management of schizophrenia, what other clinical indications warrant consideration of the use of drugs nominally classified as antipsychotics?

*The author acknowledges the contributions of the previous author of this chapter, William Z. Potter, MD, PhD.

Antipsychotic Agents

Antipsychotic drugs are able to reduce psychotic symptoms in a wide variety of conditions, including schizophrenia, bipolar disorder, psychotic depression, senile psychoses, various organic psychoses, and drug-induced psychoses. They are also able to improve mood and reduce anxiety and sleep disturbances, but they are not the treatment of choice when these symptoms are the primary disturbance in nonpsychotic patients. A neuroleptic is a subtype of antipsychotic drug that produces a high incidence of extrapyramidal side effects (EPS) at clinically effective doses or catalepsy in laboratory animals. The "atypical" antipsychotic drugs, now the most widely used type of antipsychotic drug, dissociate antipsychotic action and EPS.

History

Reserpine and chlorpromazine were the first drugs found to be useful to reduce psychotic symptoms in schizophrenia. Reserpine was used only briefly for this purpose and is no longer of interest as an antipsychotic agent. Chlorpromazine is a neuroleptic agent; that is, it produces catalepsy in rodents and EPS in man. The discovery that its antipsychotic action was related to dopamine (D or DA)-receptor blockade led to the identification of other compounds as antipsychotics between the 1950 and 1970. The discovery of clozapine in 1959 led to the realization that antipsychotic drugs need not cause EPS in humans. Clozapine was called an atypical antipsychotic drug because of this dissociation; since its discovery, interest in antipsychotic drugs has shifted to the atypical group. The use of typical and atypical antipsychotic drugs led to massive changes in disease management, including brief instead of life-long hospitalizations. These drugs have also proved to be of great value in studying the pathophysiology of schizophrenia and other psychoses. Thus, schizophrenia and bipolar disorder are no longer believed by many to be separate disorders but rather to be part of a continuum of brain disorders with psychotic features.

Nature of Psychosis & Schizophrenia

The term "psychosis" denotes a variety of mental disorders: the presence of delusions (false beliefs), various types of hallucinations, usually auditory or visual, but sometimes tactile or olfactory, and grossly disorganized thinking in a clear sensorium. Schizophrenia is a particular kind of psychosis characterized mainly by a clear sensorium but a marked thinking disturbance. Psychosis is not unique to schizophrenia and is not present in all patients with schizophrenia at all times.

Schizophrenia is considered to be a neurodevelopmental disorder. This implies that structural and functional changes in the brain are present even in utero in some patients, or that they develop during childhood and adolescence, or both. Twin, adoption, and family studies have established that schizophrenia is a genetic disorder with high heritability. No single gene is involved. Current theories involve multiple genes with common and rare mutations combining to produce a very variegated clinical presentation and course.

The Serotonin Hypothesis of Schizophrenia

The discovery that indole hallucinogens such as LSD (lysergic acid diethylamide) and mescaline are serotonin (5-HT) agonists led to the search for endogenous hallucinogens in the urine, blood, and brains of patients with schizophrenia. This proved fruitless, but the identification of many 5-HT-receptor subtypes led to the pivotal discovery that 5-HT_2A-receptor stimulation was the basis for the hallucinatory effects of these agents.

It has been found that 5-HT_2A-receptor blockade is a key factor in the mechanism of action of the main class of atypical antipsychotic drugs such as clozapine and quetiapine. These drugs are inverse agonists of the 5-HT_2A receptor; that is, they block the constitutive activity of these receptors. These receptors modulate the release of dopamine in the cortex, limbic region, and striatum. Stimulation of 5-HT_2A receptors leads to depolarization of glutamate neurons, but also stabilizes NMDA receptors on postsynaptic NMDA receptors. Recently, it has been found that hallucinogens can modulate the stability of a complex consisting of 5-HT_2A and NMDA receptors.

5-HT_2C-receptor stimulation provides a further means of modulating cortical and limbic dopaminergic activity. 5-HT_2C agonists are currently being studied as antipsychotic agents.

The Dopamine Hypothesis of Schizophrenia

The dopamine hypothesis for schizophrenia was the first neurotransmitter-based concept to be developed but is no longer considered adequate to explain all aspects of schizophrenia. Nevertheless, it is still highly relevant to understanding the major dimensions of schizophrenia, such as positive and negative (emotional blunting, social withdrawal, lack of motivation) symptoms, cognitive impairment, and possibly depression. It is also essential to understanding the mechanism of the action of most and probably all antipsychotic drugs.

Several lines of evidence suggest that excessive limbic dopaminergic activity plays a role in psychosis: (1) many antipsychotic drugs strongly block postsynaptic D₂ receptors in the central nervous system, especially in the mesolimbic and striatal-frontal system; this includes partial dopamine agonists, such as aripiprazole and bifeprunox. (2) Drugs that increase dopaminergic activity, such as levodopa, amphetamines, and bromocriptine and apomorphine, either aggravate schizophrenia psychosis or produce psychosis de novo in some patients. (3) Dopamine-receptor density has been found postmortem to be increased in the brains of schizophrenics who have not been treated with antipsychotic drugs. (4) Some but not all postmortem studies of schizophrenic subjects have reported increased dopamine levels and D₂-receptor density in the nucleus accumbens, caudate, and putamen. (5) Imaging studies have shown increased amphetamine-induced striatal dopamine release, increased baseline occupancy of striatal D₂ receptors by extracellular dopamine, and other measures consistent with increased striatal dopamine synthesis and release.

However, the dopamine hypothesis is far from a complete explanation of all aspects of schizophrenia. Diminished cortical or hippocampal dopaminergic activity has been suggested to underlie the cognitive impairment and negative symptoms of schizophrenia. Postmortem and in vivo imaging studies of cortical, limbic, nigral and striatal dopaminergic neurotransmission in schizophrenic subjects have reported findings consistent with diminished dopaminergic activity in these regions. Decreased dopaminergic innervation in medial temporal cortex, dorsolateral prefrontal cortex, and hippocampus, and decreased levels of DOPAC, another metabolite of dopamine, in the anterior cingulate have been reported in postmortem studies. Imaging studies have found increased prefrontal dopamine D₁-receptor levels that correlated with working memory impairments.

The fact that several of the atypical antipsychotic drugs have much less effect on D₂ receptors and yet are effective in schizophrenia has redirected attention to the role of other dopamine receptors and to nondopamine receptors. Serotonin receptors—particularly the 5-HT_2A-receptor subtype—may mediate synergistic effects or protect against the extrapyramidal consequences of D₂ antagonism. As a result of these considerations, the direction of research has changed to a greater focus on compounds that may act on several transmitter-receptor systems, eg, serotonin and glutamate. The atypical antipsychotic drugs share the property of weak D₂-receptor antagonism and more potent 5-HT_2A-receptor blockade.

The Glutamate Hypothesis of Schizophrenia

Glutamate is the major excitatory neurotransmitter in the brain (see Chapter 21). Phencyclidine and ketamine are noncompetitive inhibitors of the NMDA receptor that exacerbate both cognitive impairment and psychosis in patients with schizophrenia. This was the starting point for the hypothesis that hypofunction of NMDA receptors, located on GABAergic interneurons, leading to diminished inhibitory influences on neuronal function, contributed to schizophrenia. The diminished GABAergic activity can induce disinhibition of downstream glutamatergic activity, which can lead to hyperstimulation of cortical neurons through non-NMDA receptors. Preliminary evidence suggests that LY2140023, a drug that acts as an agonist of the metabotropic 2/3 glutamate receptor (mGLuR2/3), may be effective in schizophrenia.

The NMDA receptor, an ion channel, requires glycine for full activation. It has been suggested that in patients with schizophrenia, the glycine site of the NMDA receptor is not fully saturated. There have been several trials of high doses of glycine to promote glutamatergic activity, but the results are far from convincing. Currently, glycine transport inhibitors are in development as possible antipsychotic agents.

Ampakines are drugs that potentiate currents mediated by AMPA-type glutamate receptors. In behavioral tests, ampakines are effective in correcting behaviors in various animal models of schizophrenia and depression. They protect neurons against neurotoxic insults, in part by mobilizing growth factors such as brain-derived neurotrophic factor (BDNF).

Basic Pharmacology of Antipsychotic Agents

Chemical Types

A number of chemical structures have been associated with antipsychotic properties. The drugs can be classified into several groups as shown in Figures 29–1 and 29–2.

Phenothiazine Derivatives

Three subfamilies of phenothiazines, based primarily on the side chain of the molecule, were once the most widely used of the antipsychotic agents. Aliphatic derivatives (eg, chlorpromazine ) and piperidine derivatives (eg, thioridazine ) are the least potent. These drugs produce more sedation and weight gain. Piperazine derivatives are more potent (effective in lower doses) but not necessarily more efficacious. Perphenazine, a piperazine derivative, was the typical antipsychotic drug used in the CATIE study described in the following text. The piperazine derivatives are also more selective in their pharmacologic effects (Table 29–1).

Recently, a large study in the USA (CATIE) reported that perphenazine was as effective as atypical antipsychotic drugs, with the modest exception of olanzapine, and concluded that typical antipsychotic drugs are the treatment of choice for schizophrenia based on their lower cost. However, this study did not adequately consider the risk of tardivedyskinesia or the treatment history of patients in the design of this study.

Thioxanthene Derivatives

This group of drugs is exemplified primarily by thiothixene.

Butyrophenone Derivatives

This group, of which haloperidol is the most widely used, has a very different structure from those of the two preceding groups. Haloperidol, a butyrophenone, is the most widely used typical antipsychotic drug, despite its high level of EPS relative to typical antipsychotic drugs. Diphenylbutylpiperidines are closely related compounds. The butyrophenones and congeners tend to be more potent and to have fewer autonomic effects but greater extrapyramidal effects than phenothiazines (Table 29–1).

Miscellaneous Structures

Pimozide and molindone are typical antipsychotic drugs. There is no significant difference in efficacy between these newer typical and the older typical antipsychotic drugs.

Atypical Antipsychotic Drugs

Loxapine, clozapine, asenapine, olanzapine, quetiapine, paliperidone, risperidone, sertindole, ziprasidone, zotepine, and aripiprazole are atypical antipsychotic drugs (Figure 29–2). Clozapine is the prototype. Paliperidone is 9-hydroxyrisperidone, the active metabolite of risperidone. Risperidone is rapidly converted to 9-hydroxyrisperidone in vivo in most patients, except for about 10% of patients who are poor metabolizers. Asenapine and sertindole are likely to be approved for use in the USA in 2009. Sertindole is approved in some European countries.

These drugs have complex pharmacology but they share a greater ability to alter 5-HT_2A-receptor activity than to interfere with D₂-receptor action. In most cases, this is accomplished through a partial agonist mechanism.

Sulpride and sulpiride constitute another class of atypical agents. They have equivalent potency for D₂ and D3 receptors, but they are also 5-HT₇ antagonists. They dissociate EPS and antipsychoticefficacy. However, they also produce marked increases in serum prolactin levels and are not as free of the risk of tardive dyskinesia as are drugs such as clozapine and quetiapine.

Pharmacokinetics

Absorption and Distribution

Most antipsychotic drugs are readily but incompletely absorbed. Furthermore, many undergo significant first-pass metabolism. Thus, oral doses of chlorpromazine and thioridazine have systemic availability of 25–35%, whereas haloperidol, which has less first-pass metabolism, has an average systemic availability of about 65%.

Most antipsychotic drugs are highly lipid-soluble and protein-bound (92–99%). They tend to have large volumes of distribution (usually more than 7 L/kg). They generally have a much longer clinical duration of action than would be estimated from their plasma half-lives. This is paralleled by prolonged occupancy of D₂ dopamine receptors in the brain by the typical antipsychotic drugs.

Metabolites of chlorpromazine may be excreted in the urine weeks after the last dose of chronically administered drug. Long-acting injectable formulations may still cause some blockade of D₂ receptors 3–6 months after the last injection. Time to recurrence of psychotic symptoms is highly variable after discontinuation of antipsychotic drugs. The average time for relapse in stable patients with schizophrenia who discontinue their medication is 6 months. Clozapine is an exception in that relapse after discontinuation is usually rapid and severe. Thus, clozapine should never be discontinued abruptly unless clinically needed because of adverse effects such as myocarditis or agranulocytosis, which are true medical emergencies.

Metabolism

Most antipsychotic drugs are almost completely metabolized by oxidation or demethylation, catalyzed by liver microsomal cytochrome P450 enzymes. CYP2D6, CYP1A2 and CYP3A4 are the major isoforms involved (see Chapter 4). Drug-drug interactions should be considered when combining antipsychotic drugs with various other psychotropic drugs or drugs—such as ketoconazole—that inhibit various cytochrome P450 enzymes. At the typical clinical doses, antipsychotic drugs do not usually interfere with the metabolism of other drugs.

Pharmacodynamics

The first phenothiazine antipsychotic drugs, with chlorpromazine as the prototype, proved to have a wide variety of central nervous system, autonomic, and endocrine effects. Although efficacy of these drugs is primarily driven by D₂-receptor blockade, their adverse actions were traced to blocking effects at a wide range of receptors including adrenoceptors and muscarinic, H₁ histaminic, and 5-HT₂ receptors.

Dopaminergic Systems

Five important dopaminergic systems or pathways are important for understanding schizophrenia and the mechanism of action of antipsychotic drugs. The first pathway—the one most closely related to behavior and psychosis—is the mesolimbic-mesocortical pathway, which projects from cell bodies near the substantia nigra to the limbic system and neocortex. The second system—the nigrostriatal pathway—consists of neurons that project from the substantia nigra to the dorsal striatum, which includes the caudate and putamen; it is involved in the coordination of voluntary movement. Blockade of the D₂ receptors in the nigrostriatal pathway is responsible for EPS. The third pathway—the tuberoinfundibular system—arises in the arcuate nuclei and periventricular neurons and releases dopamine into the pituitary portal circulation. Dopamine released by these neurons physiologically inhibits prolactin secretion from the anterior pituitary. The fourth dopaminergic system—the medullary-periventricular pathway—consists of neurons in the motor nucleus of the vagus whose projections are not well defined. This system may be involved in eating behavior. The fifth pathway—the incertohypothalamic pathway—forms connections from the medial zona incerta to the hypothalamus and the amygdala. It appears to regulate the anticipatory motivational phase of copulatory behavior in rats.

After dopamine was identified as a neurotransmitter in 1959, it was shown that its effects on electrical activity in central synapses and on production of the second messenger cAMP by adenylyl cyclase could be blocked by antipsychotic drugs such as chlorpromazine, haloperidol, and thiothixene. This evidence led to the conclusion in the early 1960s that these drugs should be considered dopamine-receptor antagonists and was responsible for the dopamine hypothesis of schizophrenia described earlier in this chapter. The antipsychotic action is now thought to be produced (at least in part) by their ability to block dopamine in the mesolimbic and mesocortical systems.

Dopamine Receptors and Their Effects

At present, five dopamine receptors have been described, consisting of two separate families, the D₁-like and D₂-like receptor groups. The D₁ receptor is coded by a gene on chromosome 5, increases cAMP by G_s-coupled activation of adenylyl cyclase, and is located mainly in the putamen, nucleus accumbens, and olfactory tubercle and cortex. The other member of this family, D₅, is coded by a gene on chromosome 4, also increases cAMP, and is found in the hippocampus and hypothalamus. The therapeutic potency of antipsychotic drugs does not correlate with their affinity for binding to the D₁ receptor (Figure 29–3, top) nor did a selective D₁ antagonist prove to be an effective antipsychotic in patients with schizophrenia. The clinical dose of the typical agents, a crude measure of efficacy, correlates strongly with D₂ affinity. The D₂ receptor is coded on chromosome 11, decreases cAMP (by G_i-coupled inhibition of adenylyl cyclase), and inhibits calcium channels but opens potassium channels. It is found both pre- and postsynaptically on neurons in the caudate-putamen, nucleus accumbens, and olfactory tubercle. A second member of this family, the D3 receptor, also coded by a gene on chromosome 11, is thought to also decrease cAMP and is located in the frontal cortex, medulla, and midbrain. D₄ receptors also decrease cAMP and are concentrated in the cortex.

The typical antipsychotic agents block D₂ receptors stereoselectively for the most part, and their binding affinity is very strongly correlated with clinical antipsychotic and extrapyramidal potency (Figure 29–3, bottom). In vivo imaging studies of D₂-receptor occupancy indicate that for antipsychotic efficacy, the typical antipsychotic drugs must be given in sufficient doses to achieve 60% occupancy of striatal D₂ receptors. This is not required for the atypical antipsychotic drugs such as clozapine and olanzapine, which are effective at lower occupancy levels of 30–50%, most likely because of their concurrent high occupancy of 5-HT_2A receptors. The typical antipsychotic drugs produce EPS when the occupancy of striatal D₂ receptors reaches 80% or higher.

Positron emission tomography (PET) studies with aripiprazole show very high occupancy of D₂ receptors, but this drug does not cause EPS because it is a partial D₂-receptor agonist. Aripiprazole also gains therapeutic efficacy through its 5-HT_2A antagonism and possibly 5-HT_1A partial agonism.

These findings have been incorporated into the dopamine hypothesis of schizophrenia. However, additional factors complicate interpretation of dopamine receptor data. For example, dopamine receptors exist in both high- and low-affinity forms, and it is not known whether schizophrenia or the antipsychotic drugs alter the proportions of receptors in these two forms. The fact that aripiprazole shows partial agonism at D₂ and 5-HT_1A receptors in preclinical studies suggests that the proportions of several receptors in their various affinity states may prove clinically important.

Of most importance, newer drugs—clozapine, olanzapine, quetiapine, and aripiprazole—do not have very high affinity for the D₂ receptor, which suggests that additional actions are critical to their antipsychotic effects. Nevertheless, it has not been convincingly demonstrated that antagonism of any dopamine receptor other than the D₂ receptor plays a role in the action of antipsychotic drugs. Selective and relatively specific D3 - and D₄-receptor antagonists have been tested repeatedly with no evidence of antipsychotic action. Most of the newer atypical antipsychotic agents and some of the traditional ones have a higher affinity for the 5-HT_2A-receptor than for the D₂ receptor (Table 29–1), suggesting an important role for the serotonin 5-HT system in the etiology of schizophrenia and the action of these drugs.

Differences among Antipsychotic Drugs

Although all effective antipsychotic drugs block D₂ receptors, the degree of this blockade in relation to other actions on receptors varies considerably among drugs. Vast numbers of ligand-receptor binding experiments have been performed in an effort to discover a single receptor action that would best predict antipsychotic efficacy. A summary of the relative receptor-binding affinities of several key agents in such comparisons illustrates the difficulty in drawing simple conclusions from such experiments:

Chlorpromazine: ₁ = 5-HT_2A > D₂ > D₁

Haloperidol: D₂ > ₁ > D₄ > 5-HT_2A > D₁ > H₁

Clozapine: D₄ = ₁ > 5-HT_2A > D₂ = D₁

Olanzapine: 5-HT_2A > H₁ > D₄ > D₂ > ₁ > D₁

Aripiprazole: D₂ = 5-HT_2A > D₄ > ₁ = H₁ >> D₁

Quetiapine: H₁ > ₁ > M_1,3 > D₂ > 5-HT_2A

Thus, most of the atypical and some typical antipsychotic agents are at least as potent in inhibiting 5-HT₂ receptors as they are in inhibiting D₂ receptors. The newest, aripiprazole, appears to be a partial agonist of D₂ receptors. Varying degrees of antagonism of ₂ adrenoceptors are also seen with risperidone, clozapine, olanzapine, quetiapine, and aripiprazole. The clinical relevance of these actions remains to be ascertained.

Current research is directed toward discovering atypical antipsychotic compounds that are either more selective for the mesolimbic system (to reduce their effects on the extrapyramidal system) or have effects on central neurotransmitter receptors—such as those for acetylcholine and excitatory amino acids—that have been proposed as new targets for antipsychotic action.

In contrast to the difficult search for receptors responsible for antipsychotic  efficacy, the differences in receptor effects of various antipsychotics do explain many of their toxicities (Tables 29–1 and 29–2). In particular, extrapyramidal toxicity appears to be consistently associated with high D₂ potency.

Psychological Effects

Most antipsychotic drugs cause unpleasant subjective effects in nonpsychotic individuals. The mild to severe EPS, including akathisia, sleepiness, restlessness, and autonomic effects are unlike any associated with more familiar sedatives or hypnotics. Nevertheless, low doses of some of these drugs, particularly quetiapine, are used to promote sleep onset and maintenance, although there is no approved indication for such usage.

Nonpsychotic persons also experience impaired performance as judged by a number of psychomotor and psychometric tests. Psychotic individuals, however, may actually show improvement in their performance as the psychosis is alleviated. The ability of the atypical antipsychotic drugs to improve some domains of cognition in patients with schizophrenia and bipolar disorder is controversial. Some individuals experience marked improvement and for that reason, cognition should be assessed in all patients with schizophrenia and a trial of an atypical agent considered, even if positive symptoms are well controlled by typical agents.

Electroencephalographic Effects

Antipsychotic drugs produce shifts in the pattern of electroencephalographic (EEG) frequencies, usually slowing them and increasing their synchronization. The slowing (hypersynchrony) is sometimes focal or unilateral, which may lead to erroneous diagnostic interpretations. Both the frequency and the amplitude changes induced by psychotropic drugs are readily apparent and can be quantitated by sophisticated electrophysiologic techniques. Some of the neuroleptic agents lower the seizure threshold and induce EEG patterns typical of seizure disorders; however, with careful dosage titration, most can be used safely in epileptic patients.

Endocrine Effects

Older typical antipsychotic drugs, as well as risperidone and paliperidone, produce adverse effects marked by elevations of prolactin, see Adverse Effects, below. Newer antipsychotics such as olanzapine, quetiapine, and aripiprazole cause no or minimal increases of prolactin and reduced risks of extrapyramidal system dysfunction and tardive dyskinesia, reflecting their diminished D₂ antagonism.

Cardiovascular Effects

The low-potency phenothiazines frequently cause orthostatic hypotension and tachycardia. Mean arterial pressure, peripheral resistance, and stroke volume are decreased. These effects are predictable from the autonomic actions of these agents (Table 29–2). Abnormal ECGs have been recorded, especially with thioridazine. Changes include prolongation of QT interval and abnormal configurations of the ST segment and T waves. These changes are readily reversed by withdrawing the drug. Thioridazine, however, is not associated with increased risk of torsade more than other typical antipsychotics, whereas haloperidol, which does not increase QT_c, is.

Among the newest atypical antipsychotics, prolongation of the QT or QT_c interval has received much attention. Because this was believed to indicate an increased risk of dangerous arrhythmias, sertindole has been delayed and ziprasidone and quetiapine are accompanied by warnings. There is, however, no evidence that this has actually translated into increased incidence of arrhythmias.

Animal Screening Tests

Inhibition of conditioned (but not unconditioned) avoidance behavior is one of the most predictive tests of antipsychotic action. Another is the inhibition of amphetamine- or apomorphine-induced stereotyped behavior. Other tests that may predict antipsychotic action are reduction of exploratory behavior without undue sedation, induction of a cataleptic state, inhibition of intracranial self-stimulation of reward areas, and prevention of apomorphine-induced vomiting. Most of these tests are difficult to relate to any model of clinical psychosis.

The psychosis produced by phencyclidine (PCP) has been used as a model for schizophrenia. Because this drug is an antagonist of the NMDA glutamate receptor, attempts have been made to develop antipsychotic drugs that work as NMDA agonists. Sigma receptor and cholecystokinin type b (CCK_b) antagonism have also been suggested as potential targets. Thus far, NMDA receptor-based models have pointed to agents that modulate glutamate release as potential antipsychotics. 5-HT_2A inverse agonists such as pimavanserin, ritanserin, and M100907 are potent inhibitors of PCP-induced locomotor activity, whereas D₂ antagonists are relatively weak in comparison. Thus, atypical antipsychotic drugs that act as 5-HT_2A antagonists appear much more potent than typical antipsychotic drugs in PCP models.

Clinical Pharmacology of Antipsychotic Agents

Indications

Psychiatric Indications

Schizophrenia is the primary indication for antipsychotic agents. Antipsychotic drugs are also used very extensively in patients with psychotic bipolar disorder (BP1), psychotic depression, and treatment resistant depression.

Catatonic forms of schizophrenia are best managed by intravenous benzodiazepines. After catatonia has ended, antipsychotic drugs may be needed to treat psychotic components of that form of the illness, and remain the mainstay of treatment for this condition. Unfortunately, many patients show little response, and virtually none show a complete response.

Antipsychotic drugs are also indicated for schizoaffective disorders, which share characteristics of both schizophrenia and affective disorders. No fundamental difference between these two diagnoses has been reliably demonstrated. They are part of a continuum with bipolar psychotic disorder. The psychotic aspects of the illness require treatment with antipsychotic drugs, which may be used with other drugs such as antidepressants, lithium, or valproic acid. The manic phase in bipolar affective disorder often requires treatment with antipsychotic agents, although lithium or valproic acid supplemented with high-potency benzodiazepines (eg, lorazepam or clonazepam) may suffice in milder cases. Recent controlled trials support the efficacy of monotherapy with atypical antipsychotics in the acute phase (up to 4 weeks) of mania, and olanzapine and quetiapine has been approved for this indication.

As mania subsides, the antipsychotic drug may be withdrawn, although maintenance treatment with atypical antipsychotic agents has become more common. Nonmanic excited states may also be managed by antipsychotics, often in combination with benzodiazepines.

Other indications for the use of antipsychotics include Tourette's syndrome, disturbed behavior in patients with Alzheimer's disease, and, with antidepressants, psychotic depression. Antipsychotics are not indicated for the treatment of various withdrawal syndromes, eg, opioid withdrawal. In small doses, antipsychotic drugs have been promoted (wrongly) for the relief of anxiety associated with minor emotional disorders. The antianxiety sedatives (see Chapter 22) are preferred in terms of both safety and acceptability to patients.

Nonpsychiatric Indications

Most older typical 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 H ₁ -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 an opioid, fentanyl, in neuroleptanesthesia. The use of these drugs in anesthesia practice is described in Chapter 25.

Drug Choice

Choice among antipsychotic drugs is based mainly on differences in adverse effects and possible differences in efficacy. Since 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, and aripiprazole. Each may have special benefits for selected patients. A representative group of antipsychotic drugs is presented in Table 29–3.

For approximately 70% of patients with schizophrenia, and probably for a similar proportion of patients with bipolar disorder with psychotic features, typical and atypical antipsychotic drugs are of equal efficacy for treating positive symptoms. However, the evidence favors atypical drugs for benefit for negative symptoms and cognition, for diminished risk of tardivedyskinesia and other forms of EPS, and for lesser increases in prolactin levels.

Some of the atypical antipsychotic drugs produce more weight gain and increases in lipids than some typical antipsychotic drugs. A small percentage of patients develop diabetes mellitus, most often seen with clozapine and olanzapine. Ziprasidone is the atypical drug causing the least weight gain. Risperidone, 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 efficacious in refractory schizophrenia when given over a 6-month period. Clozapine is the only atypical antipsychotic drug indicated to reduce the risk of suicide. All patients with schizophrenia who have made life-threatening suicide attempts should be seriously evaluated for switching to clozapine.

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 tardivedyskinesia suggest that these should provide the first line of treatment.

The best guide for selecting a drug for an individual patient is the patient's past responses to drugs. Within the older group, the trend has been away from low-potency agents such as chlorpromazine and thioridazine and toward the high-potency drugs such as haloperidol. 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 superior side-effect profile (compared with that of haloperidol) at dosages of 6 mg/d or less and the lower risk of tardivedyskinesia have contributed to its widespread use. Olanzapine and quetiapine may have even lower risk and have also achieved widespread use. Whether any of the other recently introduced antipsychotic drugs can substitute for clozapine remains to be established.

Dosage

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. These drugs salvage 30–50% of patients previously refractory to standard doses of other antipsychotic drugs. In such cases, the increased risk of clozapine can well be justified. Risperidone does not appear to substitute for clozapine, although reports are mixed. Whether other antipsychotics will show efficacy similar to that of clozapine remains to be determined.

Some dosage relationships between various antipsychotic drugs, as well as possible therapeutic ranges, are shown in Table 29–4.

Parenteral Preparations

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 noncompliant 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 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.

Dosage Schedules

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.

Maintenance Treatment

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 symptoms of early relapse and ready access to care.

Drug Combinations

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 antipsychotic 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 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.

Adverse Reactions

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.

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 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.

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 prefer to use a sedative antihistamine with anticholinergic properties, eg, diphenhydramine, which can be given either parenterally or orally.

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 atypicals 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. 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.

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.

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.

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 potential 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 3–6 month intervals. Measurement of hemoglobin A_1C 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.

Hyperprolactinemia in women results in the amenorrhea-galactorrhea 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 atypicals that do not raise prolactin levels, eg, aripiprazole, may be indicated.

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.

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.

Cardiac Toxicity

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, torsade 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 quinidine-like 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 IA or III 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 drug-related and there are no studies that definitively show increased risk with particular drugs. Monitoring of QT_c 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 torsade de pointes or sudden death in patients who were randomized to ziprasidone.

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.

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.

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.

Drug Interactions

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, -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.

Overdoses

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).

Psychosocial Treatment and Cognitive Remediation

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

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.

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, and 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. It is ironic that the weight of the evidence today is that there is profound overlap in these disorders. This is not to say that there are no pathophysiologically important differences or that 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 biological markers.

Lithium was the first agent shown to be useful in the treatment of the manic phase of bipolar disorder that was not also an antipsychotic drug. Lithium has no known use in schizophrenia. Lithium continues to be used for acute-phase illness as well as for prevention of recurrent manic and depressive episodes.

Another group of mood-stabilizing drugs that are also anticonvulsant agents have become more widely used than lithium. These include 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 FDA for this indication. Aripiprazole, chlorpromazine, olanzapine, quetiapine, risperidone, and ziprasidone are approved by FDA for the treatment of manic phase of bipolar disorder. Olanzapine plus fluoxetine in combination and quetiapine are approved for the treatment of bipolar depression.

Nature of Bipolar Affective Disorder

Bipolar affective (manic-depressive) 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 excitement, hyperactivity, impulsivity, disinhibition, aggression, diminished need for sleep, 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.

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.

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.

Basic Pharmacology of Lithium

The first use of lithium for therapeutic purposes began in the mid-19th century to treat gout. Lithium had a relatively brief period of use as a substitute for sodium chloride in hypertensive patients in the 1940s, but it proved too toxic when available without monitoring and was banned. In 1949, Cade discovered that lithium was an effective treatment for bipolar disorder, engendering a series of controlled trials which confirmed its efficacy as monotherapy for the manic phase of bipolar disorder.

Pharmacokinetics

Lithium is a small monovalent cation. Its pharmacokinetics are summarized in Table 29–5.

Pharmacodynamics

Despite considerable investigation, the biochemical basis for mood stabilizer therapies including lithium and anticonvulsant 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 insulin/insulin-like growth factor signaling, brain-derived neurotrophic factor (BDNF) signaling, and the Wnt signaling pathway. All of these lead to inhibition of GSK-3. GSK-3 phosphorylates -catenin, resulting in interaction with transcription factors. The pathways that are facilitated in this manner modulate energy metabolism, provide neuroprotection, and increase neuroplasticity.

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.

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. It inhibits the latter process; that is, Li⁺-Na⁺ exchange is gradually slowed after lithium is introduced into the body. At therapeutic concentrations (around 1 mmol/L), it does not significantly affect the Na⁺-Ca²⁺ exchanger or the Na⁺,K⁺ ATPase pump.

Effects on Second Messengers

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 -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 monophosphate) 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 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 the activity in these circuits.

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 antimanic 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 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.

Clinical Pharmacology of Lithium

Bipolar Affective Disorder

Until recently, 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 maintenance therapy.

The depressive phase of manic-depressive disorder often requires concurrent use of an antidepressant drug (see Chapter 30). 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. 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 many patients with bipolar depression. For some patients, however, one of the older monoamine oxidase inhibitors may be the antidepressant of choice. Quetiapine and the combination of olanzapine and fluoxetine has been approved for use in bipolar depression.

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.

Other Applications

Recurrent endogenous depression with a cyclic pattern is controlled by either lithium or imipramine, both of which are superior to placebo.

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.

An interesting application of lithium that is relatively well supported by controlled studies is as an adjunct to tricyclic antidepressants and selective serotonin reuptake inhibitors in patients with unipolar depression who do not respond fully to monotherapy with the antidepressant. For this application, concentrations of lithium at the lower end of the recommended range for manic-depressive illness appear to be adequate.

Monitoring Treatment

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.

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.

Maintenance Treatment

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. If the present attack was the patient's first or if the patient is unreliable, one might prefer to terminate treatment after the episode has subsided. Patients who have one or more episodes of illness per year are candidates for maintenance treatment. 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.

Drug Interactions

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.

Adverse Effects & Complications

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.

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.

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.

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.

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.

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.

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 ECG but is of questionable significance.

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.

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.

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.

Overdoses

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.

Valproic Acid

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 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. 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.

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.

Carbamazepine

Carbamazepine has been considered to be a reasonable alternative to lithium when the latter is less than optimally efficacious. 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.

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 no therapeutic range has 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).

Other Drugs

Lamotrigine has been reported to be useful in preventing the depression that often follows the manic phase of bipolar disorder. 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

Preparations Available

Antipsychotic Agents

Mood Stabilizers

References

Antipsychotic Drugs

Mood Stabilizers