Chapter 29 Treatment of Psychotic Disorders

Abbreviations
ACh	Acetylcholine
DA	Dopamine
5-HT	Serotonin

Therapeutic Overview

Psychotic behaviors are characterized by disturbances of reality and perception, impaired cognitive functioning, and disturbances of affect (mood). Psychotic disorders may have an organic basis (disease-induced) or may be idiopathic (schizophrenia). Schizophrenia is the most common psychotic disorder, affects 2.2 million Americans (1% of the population), and typically develops between 16 and 30 years of age. Schizophrenia interferes with a person’s ability to think clearly, manage emotions, make decisions, and relate to others. The symptoms of schizophrenia fall into two clusters, positive and negative. Positive symptoms are characterized by delusions and hallucinations and reality distortions, which include thought disorders and bizarre and agitated behaviors. Negative symptoms include a flattened affect and emotional and social withdrawal. In addition, many schizophrenics exhibit cognitive impairments manifest by attentional and short-term memory deficits.

Although schizophrenia is of unknown etiology, evidence supports a role for genetic and environmental factors, including neurodevelopmental abnormalities that may involve defects in the normal pattern of neuronal proliferation and migration, alterations in neurotransmitter receptor expression, and aberrant neuronal myelination. Evidence supporting a role for genetic factors includes findings that relatives of schizophrenics have a higher risk of illness as compared with the general population and that there is a higher concordance of schizophrenia in monozygotic (50%) as compared with dizygotic (15%) twins. In fact, a child born to two schizophrenic parents has a 40 times greater risk of developing the illness than the general population.

Structural studies have demonstrated that brains of schizophrenics have enlarged cerebral ventricles; atrophy of cerebral cortical layers; a decreased number of synaptic connections in the prefrontal cortex; and alterations in neocortical, limbic, and subcortical structures. Functional abnormalities include reduced cerebral blood flow and reduced glucose use in the prefrontal cortex.

Although consistent neurochemical alterations have not been found in schizophrenia, studies have implicated changes in the expression or function of several neurotransmitter receptors including those for dopamine (DA), serotonin (5-HT), acetylcholine (ACh), and glutamate. Other studies have suggested that schizophrenia may involve alterations in signaling pathways, particularly those involving FOS and neuregulin, as well as a decreased expression of oligodendrocyte-associated genes, including proteolipid protein, the most abundant myelin-related protein.

Psychotic behaviors are treated pharmacologically with antipsychotic drugs, which have been classified into two categories, the typical and atypical compounds. The typical antipsychotics, often called first-generation or traditional compounds, include the prototypes chlorpromazine and haloperidol, which were introduced in the 1950s. The atypical antipsychotics, referred to as second-generation or novel antipsychotics, were developed recently and represent a more heterogeneous group that includes compounds such as clozapine and risperidone. The typical and atypical antipsychotics differ significantly with respect to their mechanisms of action, ability to relieve positive versus negative symptoms, and side effect profiles. Most importantly, many schizophrenic patients who fail to respond to the typical

Therapeutic Overview
Typical Antipsychotics
Alleviate positive symptoms
Bind to and block 70% to 80% of D₂ receptors at clinically effective doses
Atypical Antipsychotics
Alleviate positive and may improve negative symptoms
May improve cognitive impairments
Bind to and block 40% to 60% of D₂ receptors at clinically effective doses
Bind to and block 70% to 90% of 5-HT_2A receptors at clinically effective doses

compounds show significant improvement after administration of atypical antipsychotics. It is also critical to understand that within the schizophrenic population, few patients achieve full recovery with or without medication. Approximately 30% exhibit good responses, 30% demonstrate partial improvement, and 20% to 25% are resistant to all drugs. Thus schizophrenia likely represents a heterogeneous disorder.

Therapeutic issues related to the treatment of psychotic disorders are summarized in the Therapeutic Overview Box.

Mechanisms of Action

Typical Antipsychotics

The typical antipsychotics comprised the first group of compounds developed for the treatment of schizophrenia. Based on chemical structure, these compounds fall into three groups (Fig. 29-1):

• Phenothiazines

• Thioxanthines

• Butyrophenones

FIGURE 29–1 Structures of various antipsychotic agents.

Chlorpromazine was the first antipsychotic approved for use and is the prototypical phenothiazine, characterized by a three-ring structure. Thiothixene is representative of the thioxanthines, and haloperidol is representative of the butyrophenones.

The effects of the typical antipsychotics are due to blockade of postsynaptic DA receptors, specifically D₂ receptors. Indeed, a positive linear correlation exists between the therapeutic potency of typical antipsychotics and their ability to bind to and block D₂ receptors (Fig. 29-2). Inhibition of these receptors in mesolimbic and mesocortical regions (see Fig. 27-8) is believed to mediate the ability of these compounds to relieve some behavioral manifestations of schizophrenia. On the other hand, blockade of these receptors in the basal ganglia underlies the motor side effects of these compounds, and inhibition of these receptors in the tuberoinfundibular pathway in the hypothalamus leads to increases in prolactin secretion from the pituitary gland.

FIGURE 29–2 Correlation between the therapeutic dose of antipsychotics and the concentration to block D₂ receptors.

Acute administration of the typical antipsychotics increases the firing rate of both mesolimbic and nigrostriatal DA neurons as a compensatory response to DA receptor blockade. However, long-term administration inactivates these pathways via depolarization blockade. Because the therapeutic effects of the typical antipsychotics require several weeks to become apparent, it is believed that this inactivation of mesolimbic DA neurons mediates the time-dependent amelioration of psychotic symptoms. Long-term administration of antipsychotics also leads to an up regulation of DA receptors as a consequence of the depression of DA activity.

In addition to blocking DA receptors, the typical antipsychotics may also block muscarinic cholinergic receptors, α₁ adrenergic receptors, histamine receptors, and serotonin (5-HT₂) receptors. These actions underlie many of the side effects associated with these compounds.

The typical antipsychotics are of benefit primarily in alleviating the positive symptoms of schizophrenia.

Atypical Antipsychotics

The atypical antipsychotics represent a somewhat heterogeneous group of compounds with large differences in chemical structure (see Fig. 29-1), receptor antagonist activity, and therapeutic and side effect profiles. These compounds vary more in potency and range in treating specific symptoms as compared with the typical compounds. As heterogeneous as the group is, however, these compounds share several commonalities. They all occupy and block fewer D₂ receptors than the typical antipsychotics (40% to 60% as compared with >70% to 80%), and they all block a high number (70% to 90%) of 5-HT_2A receptors. Because of their lower occupancy of D₂ receptors, the atypical antipsychotics have a lower propensity than the typical compounds to induce motor side effects. In addition, they may have an increased ability to alleviate the negative symptoms of schizophrenia, and the rate of relapse is lower than that after administration of typical antipsychotics.

Clozapine was the first atypical antipsychotic drug to be characterized and is effective in a significant population of schizophrenics who fail to respond to typical antipsychotic drugs. In addition to having a low affinity for D₂ receptors, clozapine was the first antipsychotic demonstrated to have selective effects on specific DA pathways—that is, it produces a depolarization blockade of mesolimbic and mesocortical, but not nigrostriatal, DA neurons. Thus, in contrast to typical antipsychotics, clozapine does not disrupt DA function in the nigrostriatal pathway. Two of the newer compounds, olanzapine and quetiapine, both demonstrate similar anatomical specificity for DA pathways.

Clozapine also exhibits a high affinity for D₄ receptors and for 5-HT_2C receptors. The contribution of these effects to the actions of clozapine remains unknown. However, several other atypical antipsychotics, including olanzapine, risperidone, and ziprasidone, also have a very high affinity for 5-HT_2A, 5-HT_2C, and D₄ receptors.

In addition to actions at these receptors, clozapine and olanzapine increase regional blood flow in cerebral cortex through an undefined mechanism, an action that may contribute to the beneficial effects of these compounds on cognitive functions such as working memory and attention.

Only gold members can continue reading. Log In or Register to continue