Schizophrenia is a chronic psychotic illness that typically begins early in adulthood. Some cases begin with a prodromal period of several years, characterized by nonspecific symptoms (depression, social withdrawal, and subtle perceptual changes), that is followed by the eventual development of acute, frank psychosis (i.e., hallucinations, delusions, or disorganized thinking or behavior). Other cases have a more abrupt onset of psychosis. Often, the illness course shows periods of less florid psychosis, punctuated by acute exacerbations. Unfortunately, the overall course of this illness generally leads to a diminished plateau of function and an inability to maintain an active and productive life. Symptoms of schizophrenia are often divided into positive symptoms (i.e., symptoms that are not present in normal human cognitions, perceptions, or affect, such as hallucinations, delusions, and thought disorder), negative or deficit symptoms (i.e., loss of qualities normally present in healthy individuals, such as impoverishment of thought, blunted affect, and lack of initiative and motivation), and cognitive symptoms (particularly impairment in executive function and verbal memory). The cognitive impairment and the negative symptoms are essential features of the illness in that they underlie the poor functioning that is typical for many patients.

Many patients also have co-occurring anxiety disorders (e.g., obsessive-compulsive disorder or panic disorder) and depression. Suicide is the leading cause of death. Substance abuse occurs in approximately half of the patients. These co-occurring disorders worsen the course of the illness and complicate treatment. Stimulant use and alcohol binges often lead to psychosis exacerbation. Nicotine dependence is highly prevalent, and while cigarette smoking may help improve attention (by partially correcting the so-called sensory gating deficit) and provide some pleasure, it clearly contributes to cardiovascular and pulmonary diseases frequently experienced by these patients.

Patients with schizophrenia often neglect their health and avoid getting medical and dental treatment. They frequently have untreated medical conditions, including hypertension, coronary artery disease, diabetes, chronic obstructive pulmonary disease, and dyslipidemia. Unfortunately, even when patients have laboratory evidence of medical conditions such as diabetes, they frequently go undertreated or untreated. Patients with schizophrenia die young—10 to 15 years younger than the general population, on average. Cardiovascular disease is the most common medical cause of death. Several of the second-generation antipsychotics, unfortunately, may contribute to cardiovascular morbidity because of their propensity to cause weight gain, dyslipidemia, and insulin resistance.

Even though antipsychotics are critical for illness treatment, these drugs do not treat the full syndrome of schizophrenia, and rarely does drug treatment alone lead to patients regaining their premorbid function. Antipsychotics are frequently helpful for the positive symptoms of schizophrenia, but they provide only limited to no benefit for primary negative and cognitive symptoms. Other psychosocial treatments including social skills and vocational training, case management, and cognitive behavioral therapy are necessary adjuncts to achieve the best possible satisfactory outcomes.

In addition to schizophrenia, several other closely related psychotic conditions such as schizophreniform disorder, schizoaffective disorder, or delusional disorder may be amenable to antipsychotic treatment. Schizoaffective disorder probably represents a heterogeneous group of diseases rather than a single disease entity. The diagnosis is applied to patients who have periods of major manic or depressive symptoms or both but who have prominent psychotic symptoms which meet criteria for schizophrenia, even at times when they are relatively free of affective symptoms. Clinically, affective symptoms sometimes respond to lithium, antidepressants, or an anticonvulsant. Psychotic symptoms, especially those that occur between episodes of mood disorder, generally require treatment with antipsychotic medication. The dosages of antipsychotic medication for both acute florid symptoms and chronic maintenance are the same as those for the analogous stages of schizophrenia. All second-generation compounds are likely to be effective for schizoaffective disorder, although more study is warranted.

Schizophreniform disorder involves overt psychotic symptoms of less than 6 months’ duration, with return to the premorbid level of functioning. The onset of symptoms tends to be rapid, rather than insidious, and patients may demonstrate confusion or perplexity at the height of their syndrome. Many, but not all, patients lack the flat affect of typical schizophrenia. Schizophreniform patients represent a heterogeneous group. Depending on the population studied, some investigators predominantly find mood disorders represented, whereas others find heterogeneity, with perhaps half of them going on to manifest schizophrenia over time. The early stages of treatment of schizophreniform disorder are the same as for any acute psychosis (see later section on therapeutic use). Given that the long-term prognosis for recovery of many of these patients is good, after the first episode an attempt can be made to taper and discontinue antipsychotic drugs entirely if symptoms fully remit and remain in remission for 6 months to a year. Many patients who meet criteria for schizophreniform disorder will also benefit from lithium or anticonvulsants (see Chapter 4) if symptoms of bipolar disorder emerge.

Delusional disorder entails the presence of delusions without hallucinations or language impairment. This condition is considerably less common than schizophrenia, and usually starts in middle age. The most common types include paranoid delusions, but some patients may experience delusional jealousy, erotomania, or somatic delusions. Patients with delusional disorder are often difficult to treat because of illness denial, and their pervasive suspiciousness often extends to physicians and medical treatment. As a result, they are often brought to treatment by others and are often nonadherent to treatment. If medication is introduced to the patient as a means of helping cope with anxiety, stress, or other complaints rather than explicitly confronting delusions, the initiation of treatment may be more acceptable. Nonetheless, over time, it is best if the patient can be helped to develop insight into the distortions and misperceptions.

Antipsychotic drugs are effective in some patients with delusional disorder, especially in those whose symptoms are of recent onset. As with other psychotic disorders, the agents of choice are the atypical antipsychotics. For patients with chronic, systematized delusions, the response rate may be lower than for those with a more recent onset. Pending systematic studies of this clinical population, dosing guidelines should follow those for treating schizophrenia, while considering the possibility that lower doses may be adequate for some patients. If first-generation drugs are tried, low doses should be used initially (e.g., haloperidol 2 to 5 mg per day or the equivalent) to minimize side effects and to enhance compliance. Consideration should be given to a trial of antidepressants or lithium if affective symptoms are apparent or if there is a family history of mood disorder.

The antipsychotic drugs are the cornerstone of treatment of schizophrenia and other psychotic disorders, such as schizoaffective disorder. Antipsychotic drugs have been in clinical use since the 1950s, when chlorpromazine, a phenothiazine derivative that was developed as an antihistamine, was found to have antipsychotic properties. The key observation was that chlorpromazine and later antipsychotic drugs were not acting as nonspecific sedatives but were ameliorating core psychotic symptoms such as hallucinations and delusions.

Chlorpromazine provided a model for the development of a wide variety of chemically distinct compounds effective for the psychoses, but all of these first-generation compounds (with the exception of clozapine) had a liability for causing extrapyramidal symptoms (EPS) by virtue of their major shared property, potent antagonism of the D₂ dopamine receptor. In addition to their antipsychotic properties, these drugs have had other uses on the basis of their ability to block D₂ dopamine receptors (e.g., as antiemetics and in palliation of some movement disorders characterized by excessive movement). The first-generation D₂ antagonist antipsychotic drugs have come to be described as typical to contrast them with clozapine and with newer second-generation or so-called atypical drugs that have a reduced liability for EPS. The EPS burden also led to use of the term neuroleptic for these older drugs because these drugs could produce neurologic disorders that looked similar to Parkinson’s disease or dystonias. In addition, long-term use of these drugs, as is typically required in schizophrenia, posed a high risk of a permanent movement disorder, tardive dyskinesia (TD). Even in the short term, in addition to producing parkinsonian symptoms, first generation antipsychotic drugs produce side effects (e.g., akathisia or akinesia) that could mimic or exacerbate the symptoms for which the drugs were originally prescribed. In short, these older antipsychotic drugs were effective and indeed critically important in the treatment of psychotic disorders for more than 40 years, but at the price of serious motor system problems that could limit therapy. Although the liability for extrapyramidal neurologic side effects is an intrinsic liability of first-generation drugs, as a result of their selective blockade of D₂ dopamine receptors, they were often also administered at excessive doses, which markedly exacerbated the problem.

The introduction of risperidone (Consta and Risperdal) in 1993 began a new era in the treatment of psychotic illnesses with the introduction and widespread adoption of a group of compounds that have a reduced liability for producing EPS. These have variously been referred to as “atypical” or second-generation antipsychotic drugs. However, this change began with the reintroduction of clozapine, an older drug with very low risk for EPS liability and the greatest efficacy in schizophrenia. Clozapine had not been marketed because it carried approximately a 1% risk of potentially lethal agranulocytosis. Studies that demonstrated the drug’s not only very low EPS liability but also greater efficacy for treating schizophrenia than any other antipsychotic drug led to its reintroduction. Because of the risk of agranulocytosis, however, cumbersome and expensive weekly monitoring of white blood cell (WBC) counts became part of any clozapine regimen. In addition, clozapine has its own troublesome side effects (including sedation, weight gain, and a reduction in seizure threshold). However, the benefits of clozapine have been demonstrated to outweigh its risks for many individuals with schizophrenia who respond poorly to other treatments. Although it is still unclear what gives clozapine its enhanced efficacy (it has relatively low affinity for D₂ receptors compared with the other older drugs, exhibits potent antagonism of serotonin 5-HT_2A receptors, and interacts with many other receptors), it became a new, if partly mysterious, model for drug development. Since the reintroduction of clozapine, several newer compounds—risperidone, olanzapine (Zyprexa), quetiapine (Seroquel), ziprasidone (Geodon), and aripiprazole (Abilify)—have been shown to be effective for schizophrenia
and other psychoses and useful for mania as well, though, unlike clozapine, they are not superior to the older drugs. Because these drugs have reduced EPS liability, have a generally milder side-effect profile than does clozapine, and do not pose a risk of agranulocytosis, they have rapidly become the first-line drugs for the treatment of psychotic disorders. As a group, these drugs have been shown in well-controlled trials of greater than 4 to 20 weeks to be at least as effective as the older typical antipsychotic drugs, although they do not exhibit the clear efficacy advantages of clozapine in the most resistant cases. Moreover, many of these drugs have their own problematic side effects. Recent prospective studies showing similar effectiveness between the old and new drugs have made us question the enthusiasm once accompanying the second-generation antipsychotics.

As noted, a high affinity for D₂ dopamine receptors among the older compounds is clearly associated with their liability for producing EPS. However, the decreased liability for EPS in the newer compounds appears to reflect diverse mechanisms and is still not fully understood. For example, although risperidone has high affinity for the D₂ receptor, like haloperidol (Table 2.1), its high affinity for the serotonin 5-HT_2A receptor may mitigate its EPS liability when it is given at lower doses (<6 mg per day). In contrast, quetiapine has a lower affinity for the 5-HT_2A receptor than haloperidol, but it also has a lower affinity for the D₂ dopamine receptor. As described, clozapine has a relatively low D₂ receptor affinity and a high affinity for the 5-HT_2A receptor, but it interacts with so many receptors (Table 2.1) that the basis of its efficacy and atypical side-effect profile remains unclear.

Multiple clinical trials have shown that antipsychotic drugs are effective both for acute exacerbations of schizophrenia and for long-term maintenance. Rigorous studies of clozapine have shown that it may be of particular benefit in chronic schizophrenia refractory to other antipsychotic drugs; case series and anecdotal reports suggest that it also may be effective in refractory atypical psychoses, such as schizoaffective disorder. Clinical trials have not convincingly shown superior efficacy of second-generation antipsychotics, other than clozapine, in schizophrenia when the comparator, most often haloperidol, is administered at appropriately low doses and combined with anticholinergic agents. Use of high doses of haloperidol in several comparison trials creates conditions for newer drugs looking better than they may be.

It has often been stated that traditional antipsychotic drugs are more effective in treating positive symptoms than negative symptoms. However, when examined
carefully, this generalization is not entirely accurate in that those negative symptoms that occur during an acute exacerbation of schizophrenia often respond well to antipsychotic drugs. Moreover, many patients continue to have some residual positive symptoms, such as hallucinations and delusions, despite the use of antipsychotic medication. The expectation that all positive symptoms should respond to antipsychotic therapy has led to the use of excessive doses in some patients. Negative symptoms that characterize the patient’s chronic course (i.e., negative symptoms that are present even at times when positive symptoms are minimal) tend to be relatively refractory to antipsychotic drug treatment and appear somewhat more responsive to clozapine. No existing drugs appear to ameliorate executive dysfunction and other core cognitive deficits like impaired verbal memory. These symptoms ultimately contribute substantially to disability even when other symptoms improve.

It is also important to recall that side effects of first generation antipsychotic drugs can mimic both positive and negative features of schizophrenia. Akathisia can be indistinguishable from agitation and anxiety (positive symptoms), and EPS effects of antipsychotics (e.g., bradykinesia, akinesia, and masked facies) can masquerade as negative symptoms of the disorder. Indeed, the D₂ dopamine receptor antagonism of antipsychotic drugs, by causing even subtle akinesia, may create a therapeutic ceiling effect vis-à-vis negative symptoms in some patients.

Phenothiazines, the first chemical class of antipsychotic drugs developed, are tricyclic molecules. Three subtypes of phenothiazines are available: aliphatics, piperidines, and piperazines. Those phenothiazines with aliphatic side chains (e.g., chlorpromazine) tend to be low-potency compounds (i.e., higher doses are needed to achieve therapeutic effectiveness). Piperidine substitutions impart anticholinergic properties and a lower incidence of EPS (e.g., thioridazine, mesoridazine). Piperazine phenothiazines (e.g., perphenazine, trifluoperazine, fluphenazine) are among the most potent antipsychotic molecules.

The thioxanthene class of antipsychotic drugs is chemically similar to the phenothiazines. The butyrophenones represent a class of extremely potent antipsychotic drugs. Of these, only haloperidol is currently approved for psychiatric use in the United States. Droperidol, a shorter-acting butyrophenone, is approved for use as a preanesthetic agent.

Several other compounds of varied chemical structures have been approved for the treatment of psychotic and other illnesses in the United States. Pimozide, a diphenylbutylpiperidine approved for Gilles de la Tourette syndrome (but not necessarily superior in efficacy to other antipsychotic drugs for this indication), is also a potent antipsychotic drug with a very long half-life (several days). In addition, there are compounds called dibenzodiazepines that closely resemble the tricyclic antidepressants with a seven-member central ring and a piperazine substitution; this class of antipsychotic drug is represented by the typical antipsychotic drug loxapine, as well as by the atypical drug clozapine. Risperidone is a benzisoxazole derivative that combines high affinity for D₂ dopamine receptors and 5-HT₂ serotonin receptors. Olanzapine is a thienobenzodiazepine agent with greater affinity for the serotonin 5-HT₂ receptors than for dopamine receptors and that, compared with other second-generation antipsychotics, is most like clozapine in its receptor affinities. Quetiapine is a dibenzothiazepine derivative with low affinity for serotonin receptors but weaker activity at dopamine receptors and multiple other receptors. Ziprasidone is a benzisothiazolyl piperazine derivative with greater affinity for serotonin 5-HT_2A receptors than for dopamine receptors but higher affinity for D₂ dopamine receptors than does clozapine or quetiapine. In this regard, it is similar to risperidone. Ziprasidone also has relatively low affinity for H₁
histamine receptors and α₁-norepinephrine receptors, which limits its liabilities for sedation and orthostatic hypotension. Aripiprazole is a quinolinone derivative, which like risperidone and ziprasidone, shows higher affinity for serotonin 5-HT_2A receptors than for dopamine receptors. In addition, aripiprazole appears to have partial agonist activity at D₂ dopamine receptors, although the clinical significance of this effect remains unknown.

The therapeutic mechanism of action of the antipsychotic drugs is only partly understood. The first-generation (e.g., haloperidol-like) antipsychotic drugs and the second-generation drugs risperidone, paliperidone, ziprasidone, and aripiprazole are all potent antagonists of D₂ dopamine receptors. On the other hand, clozapine and quetiapine are weak D₂ antagonists, and by positron emission tomography, they show significantly lower levels of D₂ receptor occupancy at effective doses, compared with the haloperidol-like drugs. A common property of second-generation antipsychotic drugs is the ability to block serotonin 5-HT_2A receptors. Olanzapine, risperidone, aripiprazole, and ziprasidone do so with high affinity; quetiapine has relatively lower affinity for all its receptor targets (Table 2.1). The second-generation drugs interact with a variety of other serotonin receptors but not with any obvious pattern. All but quetiapine have high affinity for 5-HT_2C receptors; all but risperidone have high affinity for 5-HT₆ receptors; risperidone has a particularly high affinity for the 5-HT₇ receptor. All of the second-generation antipsychotics antagonize α₁-adrenergic receptors and histamine H₁ receptors, which may contribute to side effects. Both clozapine and olanzapine are strongly anticholinergic.

This complex picture of binding properties makes it difficult to pinpoint the mechanism of action. D₂ receptor antagonism correlates well with both efficacy and EPS liability for the first-generation (haloperidol-like) antipsychotic drugs. In addition, blockade of 5-HT_2A receptors appears to correlate with diminished EPS liability. Drugs that antagonize only 5-HT_2A receptors, however, do not have antipsychotic properties. Given that clozapine exhibits a high ratio of D₄ antagonism to D₂ antagonism, there was much excitement about a possible role for D₄ antagonists as antipsychotic drugs. However, relatively selective D₄ antagonists, as well as a mixed D₄ and 5-HT_2A antagonist (fananserin), have not shown antipsychotic efficacy.

To date it appears that blockade of D₂ receptors in the targets of mesolimbic and mesocortical dopamine projections from the ventral tegmental area is responsible for initiating the therapeutic actions of first-generation antipsychotic drugs and likely for the clozapine-like drugs that exhibit lower D₂ affinity. D₂ blockade in the striatum is responsible for the extrapyramidal effects of the typical antipsychotic drugs (Fig. 2.1). In addition to these midbrain dopamine systems, there is a dopamine projection in the tuberoinfundibular system of the hypothalamus. In this system, dopamine acts as an inhibitor of the synthesis and release of prolactin by pituitary lactotrophs. By antagonizing dopamine in this system, antipsychotic
drugs with strong D₂ antagonist properties often produce hyperprolactinemia. The key to the increased efficacy of clozapine, despite low affinity for the dopamine D₂ receptors, remains unknown.

The full therapeutic effects of antipsychotic drugs take weeks to accrue (similar to the antidepressants) and are far slower than the time required to block central nervous system (CNS) receptors or, in most cases, to achieve steady-state plasma levels of the drug. Similarly, behavioral effects in patients can last long after serum levels are no longer detectable. Such observations suggest that the therapeutic response to antipsychotic drugs is a secondary or adaptive response to receptor blockade with a time course characterized by slower onset and offset than would be predicted by serum or even brain levels. (D₂ receptor occupancy in the human brain may now be measured experimentally from positron emission tomography.) In as much as some initially responsive patients relapse even with apparently adequate serum levels of drugs, other types of adaptations may occur in the brain, reflecting such factors as primary alterations in the disease process, changes in the psychosocial circumstances of the patient’s life, intercurrent psychiatric or physical illness, or drug tolerance. The therapeutically relevant delayed-onset neurobiologic effects of antipsychotic drugs remain unknown but are believed to reflect drug-activated changes in gene expression, protein synthesis, and subsequent synaptic reorganization. However, there is clearly an early response to antipsychotics as well, and acutely ill patient can show benefit after a few doses. This suggests another hypothesis for the apparent delayed response to antipsychotics. Perhaps once D₂ is sufficiently blocked, psychosis starts to recede. The full resolution of psychosis, however, occurs only if patients deconstruct their psychotic worldview. This psychological process of course takes time and might have led to the somewhat incorrect view that antipsychotics take weeks to show an effect.

In addition to their effects on dopamine receptors, antipsychotic drugs may cause side effects by binding to a variety of other neurotransmitter receptors. For example, low-potency conventional antipsychotic drugs are potent antagonists of muscarinic cholinergic receptors with highest relative affinity for thioridazine
followed by chlorpromazine. Among the second-generation drugs, clozapine and olanzapine also have substantial anticholinergic potency. As a result, these drugs can produce side effects such as dry mouth and constipation. Postural hypotension is produced by antagonism of α1-adrenergic receptors. Antipsychotic drugs with substantial affinity for this receptor include many first-generation compounds, especially chlorpromazine and thioridazine. Haloperidol, however, has very little propensity for antagonism of α1-adrenergic receptors. Several of the second-generation antipsychotics, especially risperidone and quetiapine, have substantial affinity for α1-adrenergic receptors and may cause orthostatic hypotension.

Sedation appears to result from antagonism of several neurotransmitter receptors, including α1-adrenergic, muscarinic, and histamine H₁ receptors. Because of substantial affinity for these receptor types, low-potency antipsychotics, such as chlorpromazine and thioridazine, and all the second-generation drugs can be sedating (particularly clozapine, olanzapine, and quetiapine). Weight gain is a significant consequence of certain second-generation antipsychotics, particularly for clozapine and olanzapine. Weight gain is less problematic with ziprasidone and aripiprazole. The mechanism of weight gain is unknown and may be multifactorial. Blockade of histamine H₁ receptors and increases in plasma leptin or insulin levels are currently being investigated as possible mechanisms. New-onset diabetes or worsening of existing diabetes may occur with clozapine or olanzapine and sometimes with other antipsychotic drugs. In addition, many antipsychotic drugs block certain calcium channels on neurons, cardiac muscle, and smooth muscle.

Glutamate receptors may also be involved in antipsychotics’ mechanism of action, though their involvement remains poorly understood. The hypothesized contribution of glutamate to the symptoms of psychosis is largely derived from pharmacologic studies that find that the N-methyl-D-aspartate glutamate antagonist phenylcyclidine induces a clinical syndrome similar to schizophrenia and may exacerbate psychosis in patients with schizophrenia. Because the N-methyl-D-aspartate receptor requires the presence of glutamate and the co-agonist glycine for effective gating, studies have been done with glycine agonists such as D-cycloserine, though these have been disappointing. On the other hand, a recent study of a drug under development finds that a drug (LY 404039) that is an agonist at metabotropic glutamate receptors, but does not antagonize dopamine receptors, was clinically superior to placebo for treating schizophrenia. This drug, however, was less effective than olanzapine in this trial. This promising study may open a new line of investigation into drugs that do not directly affect dopamine receptors.

Many studies have proven that long-term treatment with antipsychotic drugs increases the time between exacerbations among schizophrenic patients who respond to short-term treatment. The relapse rate for schizophrenic patients who are not on maintenance antipsychotic drugs may be as high as 50% at 6 months and 65% to 80% at 12 months, whereas for those maintained on antipsychotic drugs, the relapse rate may be 10% to 15% at 6 months and no higher than 25% at 12 months. Given the disorder’s morbidity, most patients with well-diagnosed schizophrenia will have net benefit from long-term maintenance treatment. Intermittent treatment is problematic in patients with chronic psychosis but might be a possibility in selected patients who can recognize the beginning of a new episode. Because long-term treatment with typical antipsychotic drugs brings with it the risk of TD, the clinician should carefully consider the risks and benefits of using the older drugs over time with each patient.

Some patients with refractory symptoms have been treated with high antipsychotic drug doses (more than the equivalent of 20 mg per day of haloperidol),
often more reflective of physician frustration than appropriate therapy. There is no evidence of extra benefit at very high doses of antipsychotic drugs, although side effects are clearly worsened. Currently, for patients who have failed to respond to adequate doses of several antipsychotic drugs, including atypical drugs, a trial of clozapine is indicated. As described previously, clozapine is the only antipsychotic drug that has been convincingly shown to be effective for substantial numbers of patients with schizophrenia who have proved refractory to other antipsychotic drugs.