Schizophrenia: Antipsychotic Drugs

 

Characteristics of Schizophrenia

• Schizophrenia is a chronic psychosis that occurs in 1% to 1.5% of the population worldwide. Symptoms begin during late adolescence and early adulthood. Men have an earlier onset than women and a poorer prognosis.
• Schizophrenia is a thought disorder, characterized by illogical thinking, lack of reasoning, and failure to recognize reality. Specific symptoms show large variation among individuals, making diagnosis difficult.
• Positive symptoms are dramatic and lead to diagnosis. They include hallucinations, delusions, disorganized speech, unusual ways of thinking, and bizarre behavior. These symptoms respond to antipsychotic drug treatment.
• Negative symptoms are the absence of normal functions and include reduced speech, flat affect, loss of motivation, social withdrawal, apathy, and anhedonia.
• Cognitive deficits include impaired working memory, executive function, and attention. Negative symptoms and cognitive deficits are resistant to current treatments.

Etiology of Schizophrenia

Preclinical Models of Schizophrenia

• Imaging shows cerebral atrophy, enlargement of ventricles, and smaller basal ganglia, temporal lobe, and hippocampus in patients with schizophrenia. Hippocampal cells are disorganized. Lack of gliosis indicates developmental error rather than degeneration.
• Abnormal myelination and organization of white matter tracts is responsible for reduced connectivity between brain regions, which prevents integration of signals for cognitive processing.
• Brain function deficits include hypofrontality during tasks of working memory, executive function, response inhibition, and planning and strategy.
• Elevated cytokines and microglia activation are associated with higher risk for schizophrenia. The immune responses are localized to brain regions with gray and white matter abnormalities. Microglia activation is greatest during acute illness relapses.
• Family studies show that relatives of individuals with schizophrenia have increased risk for the disorder. The closer the genetic relationship, the greater is the risk.
• Concordance for schizophrenia is much higher in monozygotic than dizygotic twins, indicating significant genetic contribution.
• Linkage studies and genome-wide association studies have identified numerous gene variants that may each contribute a small amount to the increased risk for schizophrenia.
• Mutations of the DISC1 gene increase the probability of developing schizophrenia. This gene codes for proteins necessary for embryonic brain development.
• Gene variants are associated with EEG abnormalities, impaired cognitive function, and brain volume reductions.
• Perinatal events such as stress during pregnancy and delivery, exposure to viral infection, and malnutrition may alter the trajectory of brain development and predispose the individual to schizophrenia. Activation of the immune response by the perinatal events may be the common factor explaining altered brain development.
• Behavioral abnormalities, apparent in young children who later develop schizophrenia, suggest early developmental errors. Other developmental errors during adolescence cause twice the cell loss in cortical areas compared with that seen in healthy teens.
• Animal models of schizophrenia created by pharmacological or environmental manipulations generally focus on one aspect of the disorder and induce similar changes in animal behavior. Neurodevelopmental models and genetic mutations are also used.

Neurochemical Models of Schizophrenia

• To understand the neurobiology of any psychiatric disorder, researchers create animal models, evaluate mechanisms of effective drug treatment, and measure biological substances in patients or image their brains.
• The dopamine hypothesis suggests that positive symptoms are caused by excessive mesolimbic DA activity. Evidence includes the following: (1) amphetamine produces positive symptoms in healthy individuals and makes symptoms worse in patients with schizophrenia; (2) intracerebral DA into the forebrain of rodents produces stereotyped behavior reversed by antipsychotics; (3) a strong correlation exits between D₂ receptor blockade and antipsychotic efficacy; (4) schizophrenic individuals show exaggerated DA release after amphetamine challenge as well as in basal conditions; and (5) there is some evidence for increased D₂ receptors in schizophrenia.
• Evidence that the negative and cognitive symptoms are due to reduced frontal lobe function includes the following: (1) the negative/cognitive symptoms resemble characteristics after frontal lobotomy; (2) the severity of negative symptoms is negatively correlated with prefrontal brain activity and decreased DA function; and (3) prefrontal brain lesions or D₁ receptor antagonists injected into PFC impair cognitive performance.
• The neurodevelopmental model suggests that early mesocortical deficits due to genetics or environmental events that alter brain development are followed by loss of inhibitory control of mesolimbic cells and the onset of positive symptoms.
• Poor glutamate signaling due to hypofunction of NMDA receptors may be responsible for positive, negative, and cognitive symptoms and corresponding changes in DA activity.
• Descending glutamate neurons from PFC activate mesocortical neurons. Low glutamate signaling at NMDA receptors (or NMDA receptor antagonist administration) reduces mesocortical function, causing negative/cognitive symptoms.
• Descending glutamate neurons from PFC activate midbrain inhibitory GABA cells that reduce mesolimbic DA cell firing. Low glutamate signaling at NMDA receptors (or NMDA receptor antagonist administration) prevents the inhibition, leading to excessive mesolimbic firing and positive symptoms.
• Accumulating evidence from challenge studies, rodent studies, receptor subunit studies, and genetics suggests that NMDA hypofunction is central to schizophrenia.
• Low levels of glutamate are found in hippocampus and PFC of patients with schizophrenia postmortem, and low levels are correlated with greater brain atrophy. Glutamate release is lower in patients with schizophrenia than in controls, and glutamate receptor subunits are different.

Classic Neuroleptics and Atypical Antipsychotics

• All antipsychotics are significantly better than placebo in reducing positive symptoms and decreasing length of hospitalization.
• The law of thirds says one-third of patients treated with antipsychotics improve dramatically and return to normal lives. A second third show some improvement but experience relapses and need help with day-to-day living. The final third show little improvement and have significant periods of hospitalization.
• Prolonged maintenance therapy doubles the odds of avoiding relapse.
• There is a strong positive correlation between antipsychotic binding to D₂ receptors and clinical effectiveness.
• Antipsychotic blocking of D₂ autoreceptors causes an initial increase in DA neuron firing and increased turnover of DA, followed by a gradual decrease as the autoreceptors up-regulate. Depolarization block may contribute to the decrease in turnover. These adaptive changes may explain the gradual onset of effectiveness.
• Parkinsonian symptoms are the most troubling side effects with traditional antipsychotic treatment. Combining the drugs with anticholinergic agents reduces risk. Second-generation drugs have a lower incidence of motor side effects.
• Tardive dyskinesia involves involuntary movement of face, jaw, tongue, neck, or extremities, which may be irreversible in some patients.
• Neuroendocrine side effects are caused by DA receptor blockade of tuberohypophyseal neurons that project to the pituitary.
• Neuroleptic malignant syndrome is a potentially life-threatening effect of antipsychotics.
• Anticholinergic effects of antipsychotics produce widespread effects on autonomic nervous system function.
• Antipsychotics cause little tolerance or physical dependence and have no addiction potential.
• Atypical antipsychotics may be selective D₂ antagonists, DA partial agonists (DA system stabilizers), or broad-spectrum antipsychotics.
• The atypical antipsychotics are heterogeneous neurochemically and clinically but overall cause fewer motor side effects than the older drugs.
• Several of the atypical antipsychotics are especially problematic in causing weight gain, hyperglycemia, cardiotoxicity, elevated cholesterol, and increased risk for diabetes.
• Only clozapine improves negative and cognitive symptoms without motor side effects and is often effective for treatment-resistant patients. Serious side effects limit its use.
• The neurochemical property that makes clozapine unique is not known. It may be high affinity for D₄ receptors, antagonism of 5-HT₂ receptors, or low D₂ affinity.
• A practical clinical trial (CATIE) using 1500 patients under “real-world” conditions showed that the atypical antipsychotics were no more effective than the traditional agents in reducing positive, negative, or cognitive symptoms. Occurrence of EPS was the same for both. Only clozapine is superior.
• Nicotinic partial agonists, D₁ agonists, COMT inhibitors, glycine agonists, glycine transporter inhibitors, anti-inflammatories, and combined drug with behavioral intervention programs are being investigated as methods to improve cognitive processing and negative symptoms.