Psychosis refers to symptoms such as delusions, hallucinations, disorganized thinking and speech, and bizarre and inappropriate motor behavior that indicate loss of contact with reality. A number of mental disorders cause symptoms of psychosis—see Introduction to Schizophrenia and Related Disorders.
Antipsychotic drugs can be effective in reducing or eliminating symptoms of psychosis. They appear to be most effective in treating hallucinations, delusions, disorganized thinking, and aggression. Although antipsychotic drugs are most commonly prescribed for schizophrenia, they appear to be effective in treating these symptoms whether they result from schizophrenia, mania, dementia, or use of a substance such as amphetamines.
After the immediate symptoms have cleared, depending on the cause of their psychosis, people may need to continue taking antipsychotic drugs to reduce the probability of future episodes.
Antipsychotic drugs work by influencing how information is transmitted between individual brain cells.
The adult brain is made up of more than 10 billion nerve cells called neurons. Each neuron in the brain has a single long fiber called an axon, which transmits information to other neurons (see Figure: Typical Structure of a Nerve Cell). Like wires connected in a vast telephone switchboard, each neuron makes contact with several thousand other neurons.
Information travels down a cell’s axon as an electrical impulse. When the impulse reaches the end of the axon, a tiny amount of a chemical called a neurotransmitter is released to pass information on to the next cell down the line. A receptor on the receiving cell detects the neurotransmitter, which causes the receiving cell to generate a new impulse.
Symptoms of psychosis appear to be caused by excessive activity of cells sensitive to the neurotransmitter dopamine. Therefore, antipsychotic drugs work by blocking receptors so that communication between groups of cells is reduced.
How well different antipsychotic drugs block different types of neurotransmitters varies. Every effective antipsychotic drug known blocks dopamine receptors. The newer antipsychotic drugs (asenapine, clozapine, iloperidone, lurasidone, olanzapine, quetiapine, risperidone, and ziprasidone) also block receptors for serotonin, another neurotransmitter. Experts thought that this property might make these drugs more effective. However, recent studies have not supported this view.
Clozapine, which also blocks many other receptors, is clearly the most effective drug for psychotic symptoms. But it is not commonly used because of its serious side effects and the need for monitoring with blood tests.
Antipsychotic drugs are divided into two groups:
Currently, about 95% of antipsychotics prescribed in the United States are second-generation antipsychotics. Doctors have thought that second-generation antipsychotics were somewhat more effective, but recent evidence casts doubt on this. They may have lower likelihood of some of the more serious adverse effects of first-generation drugs.
Second-generation antipsychotic drugs may relieve positive symptoms (such as hallucinations), negative symptoms (such as lack of emotion), and cognitive impairment (such as reduced mental functioning and attention span). However, doctors are not sure whether they relieve symptoms to a greater extent than the older antipsychotic drugs or whether people are just more likely to take them because they have fewer side effects.
Clozapine, the first of the second-generation antipsychotic drugs, is effective in up to half of people who do not respond to other antipsychotic drugs. However, clozapine can have serious side effects, such as seizures or potentially fatal suppression of bone marrow activity (which includes making blood cells). Thus, it is usually used only for people who have not responded to other antipsychotic drugs. People who take clozapine must have their white blood cell count measured weekly, at least for the first 6 months, so that clozapine can be stopped at the first indication that the number of white blood cells is decreasing.
Some conventional and second-generation antipsychotics are available as long-acting injectable preparations that need to be given only once every month or two. These preparations are useful for many people, including those who cannot reliably take oral drugs every day.
Antipsychotics with novel actions are currently being studied and may become available.
Some Side Effects
First-generation antipsychotic drugs
Increased heart rate and decreased blood pressure
Sudden but often reversible tremor and muscle stiffness that may progress to rigidity
Involuntary movements of the face and arms (tardive dyskinesia)
Muscle rigidity, fever, high blood pressure, and changes in mental function (neuroleptic malignant syndrome)
Side effects are much more likely in older people and in people with impaired balance or serious medical disorders.
Long-acting injectable forms of haloperidol and fluphenazine are available.
Eye examination and electrocardiography (ECG) are recommended while people are taking thioridazine.
Second-generation antipsychotic drugs
Drowsiness and weight gain (most common), which can be substantial
Some of these drugs increase risk of accumulation of fat in the abdomen, abnormal cholesterol levels in the blood, high blood pressure, and resistance to the effects of insulin (metabolic syndrome)
Newer antipsychotic drugs are less likely to cause tremor, muscle stiffness, involuntary movements (including tardive dyskinesia), and neuroleptic malignant syndrome, but these effects may occur.
A long-acting injectable form is available for aripiprazole, olanzapine, and risperidone.
Clozapine is used much less often because it can cause bone marrow suppression, a reduced white blood cell count, and seizures. However, it is often effective in people who are not responsive to other drugs.
Clozapine and olanzapine are most likely to cause weight gain, and aripiprazole is the least likely.
Ziprasidone does not cause weight gain but may lead to abnormalities on an electrocardiogram.
Aripiprazole, brexpiprazole, cariprazine, and ziprasidone are less likely to cause metabolic syndrome.
Lumateperone has a lower risk of motor and metabolic side effects, but it is contraindicated in older people with dementia-related psychosis.
* Available as a long-acting intramuscular (IM) injection for people who have difficulty taking oral drugs.
Antipsychotic drugs have significant side effects, which can include
Some newer second-generation antipsychotic drugs have fewer side effects. The risk of tardive dyskinesia, muscle stiffness, and tremors is significantly lower with these drugs than with the conventional antipsychotics. However, some of these drugs seem to cause significant weight gain. Some also increase the risk of metabolic syndrome. In this syndrome, fat accumulates in the abdomen, blood levels of triglycerides (a fat) are elevated, levels of high-density cholesterol (HDL, the “good” cholesterol) are low, and blood pressure is high. Also, insulin is less effective (called insulin resistance), increasing the risk of type 2 diabetes.
Tardive dyskinesia is a hyperactive involuntary movement disorder that can be caused by antipsychotic drugs. It is more likely with first-generation than second-generation drugs. Tardive dyskinesia is characterized by puckering of the lips and tongue or writhing of the arms or legs. Tardive dyskinesia may not go away even after the drug is stopped. For tardive dyskinesia that persists, there is no effective treatment, although the drugs clozapine or quetiapine may relieve symptoms a little. However, the new drug valbenazine has been found to be effective in improving symptoms of tardive dyskinesia. People who must take antipsychotic drugs for a long time are checked every 6 months for symptoms of tardive dyskinesia.
Neuroleptic malignant syndrome is a rare but potentially fatal side effect of antipsychotic drugs. It is characterized by muscle rigidity, fever, high blood pressure, and changes in mental function (such as confusion and lethargy).
Long-QT syndrome is a potentially fatal heart rhythm disorder that can be caused by several antipsychotics in both classes. These drugs include thioridazine, haloperidol, olanzapine, risperidone, and ziprasidone.