As shown in Box 22-1, the symptoms of schizophrenia can be divided into two groups. The positive symptoms, which include delusions and hallucinations, probably result from excessive neuronal activity in mesolimbic neuronal pathways. These symptoms are usually the primary manifestations of acute psychotic episodes. The negative symptoms, which include apathy, withdrawal, and lack of motivation and pleasure, probably result from insufficient activity in mesocortical neuronal pathways. The negative symptoms generally are more difficult to treat, often persist after positive symptoms resolve, and are associated with a poor prognosis.

Box 22-1 Classification of Symptoms of Schizophrenia

POSITIVE SYMPTOMS	NEGATIVE SYMPTOMS
Agitation	Apathy (avolition)
Delusions	Affective flattening
Disorganized speech	Lack of motivation
Disorganized thinking	Lack of pleasure (anhedonia)
Hallucinations	Poverty of speech (alogia)
Insomnia	Social isolation

Dopamine Hypothesis

Many hypotheses exist regarding the biologic basis of schizophrenia. According to the dopamine hypothesis, schizophrenia results from abnormalities in dopamine neurotransmission in mesolimbic and mesocortical neuronal pathways (Box 22-2). Much of the evidence supporting this hypothesis is based on the clinical effects of agents that alter dopaminergic transmission.

Box 22-2 Neurobiology of Schizophrenia and Sites of Drug Action

Postulated Neuronal Dysfunction in Schizophrenia

As shown in the accompanying figure, numerous dopamine pathways are found in the brain.

1. Mesolimbic pathway. Dopamine travels from the midbrain tegmental area to the nucleus accumbens. Increased activity in this pathway may cause delusions, hallucinations, and other so-called positive symptoms of schizophrenia.

2. Mesocortical pathways. There are several mesocortical pathways. Decreased activity in the pathway that goes from the midbrain to the prefrontal lobe cortex can cause apathy, withdrawal, lack of motivation and pleasure, and other so-called negative symptoms of schizophrenia. Mesocortical dysfunction also disinhibits the mesolimbic pathway.

3. Nigrostriatal pathway. The pathway from the substantia nigra to the striatum is involved in the coordination of body movements. Inhibition of this pathway causes the extrapyramidal side effects of antipsychotic drugs.

4. Tuberoinfundibular pathway. The pathway from the hypothalamus to the pituitary inhibits the release of prolactin. Inhibition of this pathway leads to elevated serum prolactin levels.

Sites of Drug Action

Some antipsychotic drugs (e.g., clozapine, olanzapine, and risperidone) block serotonin 5-HT₂ receptors in the mesocortical pathway to the prefrontal lobe cortex. This increases the release of dopamine (DA) and thereby alleviates the negative symptoms of schizophrenia. Most antipsychotic drugs (including those listed previously) block dopamine D₂ receptors in the mesolimbic pathway to the nucleus accumbens, and this alleviates the positive symptoms of schizophrenia.

Several observations support the dopamine hypothesis. First, most antipsychotic drugs block dopamine D₂ receptors, and an excellent correlation exists between the clinical potency of these drugs and their in vitro binding affinity for these receptors. Second, drugs that act by increasing the neuronal release of dopamine (amantadine) or by blocking the reuptake of dopamine (drugs such as amphetamines and cocaine) can induce psychotic behavior that resembles the behavior of schizophrenic patients.

Dopamine turnover in the brain, which reflects the neuronal release of dopamine, can be studied by measuring the concentration of the principal metabolite of dopamine, homovanillic acid, in the cerebrospinal fluid. Although elevated levels of homovanillic acid are not found in patients with chronic schizophrenia, they are found in some schizophrenic patients having acute psychotic episodes. Evidence also exists for a dopamine receptor defect in schizophrenic patients. Positive emission tomography scanning using D₂ receptor ligands has revealed that schizophrenic patients have decreased D₂ receptor densities in the prefrontal lobe cortex (but increased D₂ receptor densities in the caudate nucleus). These findings lend overall support to the dopamine hypothesis, although it is clear from the clinical effectiveness of atypical antipsychotics that 5-hydroxytryptamine (5-HT₂) and other types of dopamine receptors may be involved (Box 22-3).

Box 22-3 The Case of the Paranoid Policeman

Case Presentation

A 24-year-old man employed as a policeman locks himself in an interrogation room, waving his handgun, and yelling incoherent statements such as “They aren’t going to take me alive!” and “Get out of my head!” His partner tells the police chief that the man has been acting strangely, talking about a conspiracy against him by the other policemen, and arriving for work in dirty clothes and unshaven. He was overheard talking and arguing with himself in the locker room that morning, and the partner says they almost got into a fight just minutes ago because the partner wouldn’t agree to shoot him when he insisted that he “wouldn’t be hurt and was immortal.” A medical emergency team arrives on the scene and at a moment when he is sitting in the corner cowering in fear, they forcibly enter the room, disarm him, and inject haloperidol into his thigh. He is transported to the locked ward of a psychiatric hospital and diagnosed with paranoid schizophrenia.

Case Discussion

Schizophrenia affects about 1 in 100 males and can be one of the most dangerous of all mental disorders, as it causes those it affects to lose touch with reality. They often show signs of confusion, inability to make decisions, auditory hallucinations, delusions, neglect of personal hygiene, strange statements or behavior, and changes in eating or sleeping habits, energy level, or weight. In the paranoid form of this disorder, schizophrenics develop delusions of persecution or personal grandeur. The first sign of paranoid schizophrenia usually surfaces at ages 15 to 30, and schizophrenia is much more common in males than females. There is no cure, but the disorder can be controlled with antipsychotic medications such as haloperidol. Haloperidol is a good choice for acute psychotic episodes as it is rapidly absorbed and has a high bioavailability after intramuscular injection, with plasma levels reaching their maximum within 20 minutes after injection.

Antipsychotic Drugs

Antipsychotic drugs are agents that reduce psychotic symptoms and improve the behavior of schizophrenic patients. Antipsychotic drugs were also called neuroleptic drugs because they suppress motor activity and emotional expression. The accidental discovery of the antipsychotic properties of chlorpromazine in the early 1950s began a new era in the treatment of schizophrenia and stimulated research concerning the neurobiology of mental illness and psychopharmacology. Nearly 40 years later, the introduction of clozapine had an equally important impact. Clozapine was the first agent to show greater activity against the negative symptoms of schizophrenia and to produce significantly fewer extrapyramidal side effects (EPSs) than the previous antipsychotic drugs. For this reason, the discovery of clozapine has stimulated the development of new antipsychotic drugs with improved pharmacologic properties.

Drug Properties

Mechanism of Action

The antipsychotic drugs interact with multiple neurotransmitter systems. Whereas the therapeutic effects of these drugs are believed to result from competitive blockade of dopamine receptors and serotonin (5-HT) receptors, the adverse effects are attributed to the blockade of a variety of receptors (Table 22-1).

TABLE 22-1

Mechanisms Responsible for the Therapeutic and Adverse Effects of Antipsychotic Drugs

MECHANISM	THERAPEUTIC EFFECTS	ADVERSE EFFECTS
Blockade of α₁-adrenoceptors	—	Dizziness, orthostatic hypotension, and reflex tachycardia
Blockade of dopamine D₂ receptors	Alleviation of positive symptoms of schizophrenia	Extrapyramidal effects (akathisia, dystonia, and pseudoparkinsonism) and elevated serum prolactin levels
Blockade of dopamine D₄ receptors	Alleviation of negative symptoms of schizophrenia and decrease in the incidence of extrapyramidal side effects	—
Blockade of histamine H₁ receptors	— (Sedation)*	Drowsiness and increase in appetite and weight
Blockade of muscarinic receptors	—	Blurred vision, constipation, dry mouth, and urinary retention
Blockade of serotonin 5-HT₂ receptors	Alleviation of negative symptoms of schizophrenia and decrease in the incidence of extrapyramidal side effects	Anxiety and insomnia

^*Sedation may be considered a therapeutic effect with a typical antipsychotic administered for acute psychosis.

Typical antipsychotic drugs have an equal or greater affinity for D₂ receptors than for 5-HT₂ receptors. As shown in Figure 22-1, an excellent correlation exists between the clinical potency of these drugs and their in vitro affinity for D₂ receptors. Whereas antagonism of D₂ receptors in mesolimbic pathways is thought to repress the positive symptoms of schizophrenia, blockade of D₂ receptors in the basal ganglia is believed to be responsible for the parkinsonian and other EPSs that sometimes occur in patients taking antipsychotic drugs.

FIGURE 22-1 Correlation of antipsychotic drug potency and dopamine D₂ receptor binding. The clinical potency of the typical antipsychotic drugs is highly correlated with their in vitro affinity for D₂ (but not D₁) receptors.

Atypical antipsychotic drugs (e.g., clozapine) have a greater affinity for 5-HT receptors than for D₂ receptors, and some atypical drugs have increased the affinity for D₃ or D₄ receptors.

Pharmacologic Effects

The mechanisms by which the blockade of dopamine and serotonin receptors alleviates the symptoms of schizophrenia are not completely understood. Whereas these receptors are blocked immediately when antipsychotic drugs are first administered, the therapeutic effects of the drugs usually require several weeks to fully develop. This is because antipsychotic drugs produce three time-dependent changes in dopamine neurotransmission. When first administered, the drugs cause an increase in dopamine synthesis, release, and metabolism. This probably represents a compensatory response to the acute blockade of postsynaptic dopamine receptors produced by antipsychotic drugs. Over time, continued dopamine receptor blockade leads to inactivation of dopaminergic neurons and produces what has been called depolarization blockade. Depolarization blockade results in reduced dopamine release from mesolimbic and nigrostriatal neurons. This action is believed to alleviate the positive symptoms of schizophrenia while causing EPSs. Eventually the reduction in dopamine release caused by depolarization blockade leads to dopamine receptor up-regulation and supersensitivity to dopamine agonists. This supersensitivity may contribute to the development of a delayed type of EPS called tardive dyskinesia (see later).

In mesocortical and nigrostriatal pathways, 5-HT₂ receptors mediate presynaptic inhibition of dopamine release. Blockade of these receptors by atypical antipsychotic drugs may increase dopamine release in these pathways. In the mesocortical pathway, this action may alleviate the negative symptoms of schizophrenia. In the nigrostriatal pathway, increased dopamine release counteracts the EPSs caused by D₂ receptor blockade.

Adverse Effects

In the peripheral autonomic nervous system, antipsychotic drugs also block muscarinic receptors and α₁-adrenoceptors, thereby causing the adverse effects described in Tables 22-1 and 22-2. Antagonism at α₁-adrenoceptors produces dizziness, orthostatic hypotension, and reflex tachycardia. Muscarinic receptor antagonism produces blurred vision, dry mouth, constipation, and urinary retention. Antagonism of brain H₁ receptors produces drowsiness and weight gain.

TABLE 22-2

Adverse Effects of Selected Antipsychotic Drugs *

DRUG	EXTRAPYRAMIDAL EFFECTS	SEDATION	ANTICHOLINERGIC EFFECTS	ORTHOSTATIC HYPOTENSION	OTHER ADVERSE EFFECTS
Typical Antipsychotics
Chlorpromazine	+++	++++	+++	++++	Elevated serum prolactin levels and poikilothermy
Fluphenazine	+++++	++	++	++	Same as chlorpromazine
Thioridazine	++	++++	++++	++++	Cardiac arrhythmia, elevated serum prolactin levels, poikilothermy, and retinopathy
Trifluoperazine	++++	++	++	++	Same as chlorpromazine
Thiothixene	++++	++	++	++	Same as chlorpromazine
Haloperidol	+++++	+	+	+	Same as chlorpromazine
Loxapine	++++	+++	++	+++	Same as chlorpromazine
Atypical Antipsychotics
Clozapine	+	+++++	+++++	++++	Agranulocytosis and cardiac arrhythmia
Olanzapine	+	++	+	+	Weight gain
Risperidone	++	+	+	++	Cardiac arrhythmia and elevated serum prolactin levels

^*Ratings range from extremely low (+) to extremely high (+++++).

The most disturbing adverse effect is the development of motor abnormalities after the administration of high-potency, typical antipsychotics. These and other adverse effects specific to particular agents are discussed later.

Neuroleptic malignant syndrome is a severe form of drug toxicity that occurs in 0.5% to 1% of patients treated with antipsychotic drugs. It is a life-threatening condition characterized by muscle rigidity, elevated temperature (>38° C), altered consciousness, and autonomic dysfunction (tachycardia, diaphoresis, tachypnea, and urinary and fecal incontinence). The syndrome resembles malignant hyperthermia triggered by halogenated anesthetics in its rapid onset and mortality rate. Neuroleptic malignant syndrome is managed by immediately discontinuing treatment with the offending antipsychotic drug, administering dantrolene to prevent further muscle abnormality (see Chapter 21), and providing supportive care. If future antipsychotic therapy is required in patients who have experienced this syndrome, an atypical drug should be used because the atypical drugs are associated with a lower incidence of neuroleptic malignant syndrome.

Recently the U.S. Food and Drug Administration (FDA) strengthened warnings against using any type of antipsychotic to treat dementia-related psychosis in the elderly after an increased number of deaths attributed to antipsychotic use in this population. In addition, stronger warnings were issued concerning the potential risk for abnormal motor movements or withdrawal effects in neonates of mothers who took an antipsychotic during their third trimester.

TABLE 22-3

Pharmacologic Properties of Selected Antipsychotic Drugs *

DRUG	RELATIVE POTENCY^†	RECEPTOR SELECTIVITY	ROUTE OF ADMINISTRATION	ELIMINATION HALF-LIFE AND ROUTE	MAJOR DRUG INTERACTIONS
Typical Antipsychotics
Chlorpromazine	Low	D₂ > 5-HT₂	Oral, IM, and IV	30 hr (M)	Additive effects with antiadrenergic, anticholinergic, and CNS depressants. Decreases serum levels of lithium. Concurrent use of a β-adrenoceptor antagonist or an antidepressant may increase serum levels of both drugs.
Fluphenazine	High	D₂ > 5-HT₂	Oral and depot IM	20 hr (M)	Additive effects with anticholinergic and CNS depressants. Concurrent use of a β-adrenoceptor antagonist or an antidepressant may increase serum levels of both drugs.
Thioridazine	Low	D₂ > 5-HT₂	Oral	30 hr (M)	Same as chlorpromazine.
Trifluoperazine	High	D₂ > 5-HT₂	Oral and IM	24 hr (M)	Same as chlorpromazine.
Thiothixene	High	D₂ > 5-HT₂	Oral and IM	35 hr (M)	Additive effects with anticholinergic and CNS depressants. Concurrent use of a β-adrenoceptor antagonist may increase serum levels of both drugs.
Haloperidol	High	D₂ > 5-HT₂	Oral and depot IM	24 hr (M)	Barbiturates and carbamazepine decrease serum levels. Quinidine increases serum levels.
Loxapine	Medium	D₂ > 5-HT₂	Oral and IM	20 hr (M)	Concurrent use of an antidepressant may increase serum levels of both drugs.
Atypical Antipsychotics
Clozapine	Low	5-HT₂ = D₄ and > D₂	Oral	24 hr (M)	Not established; possible interaction with drugs that induce or inhibit cytochrome P450 isozyme CYP1A2.
Olanzapine	High	5-HT₂ > D₂	Oral	30 hr (M)	Same as clozapine.
Molindone	Medium	D₂ > 5-HT₂	Oral	2 hr (M)	Additive effects with anticholinergic and CNS depressants. Concurrent use of a β-adrenoceptor antagonist or an antidepressant may increase serum levels of both drugs.
Risperidone	High	5-HT₂ > D₂	Oral	24 hr (M)	Not established; possible interaction with drugs that induce or inhibit cytochrome P450 isozyme CYP2D6.