Antipsychotic Medications

Antipsychotic Medications

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Psychosis is a catch-all term that describes an inability to perceive and react to reality. Modern therapy goals directly deal with quality of life issues along with symptom control. With several agents available, one might find the best fit for any particular patient.


Psychosis is a catch-all term that describes an inability to perceive and react to reality. Hallucinations, delusions and other thought disorders are present. This is not a physiological definition because the exact etiology and causes of psychosis are not precisely understood. Diagnosis is made by observation and interview (sometimes with family and friends).

A naïve public, inexperienced with psychotic patients, sometimes assumes a philosophical waffling – after all, don’t we all perceive reality differently? But for anyone who has interacted with a psychotic person, the condition is strikingly apparent. These patients are not faking, not joking, and are seriously impaired. Their altered mentation may be dangerous for themselves or others around them.

Historically, the goal of treatment was control of the patient. The degree of confinement was related to the severity of symptoms and very little was offered to ameliorate suffering other than time and hope. Physical and chemical restraint was common. The stories of what amounted to abuse by the medical profession remain an unfortunate black mark on Psychiatry.

Even today, psychosis remains a condition that society at large chooses to shun. The sight of a mumbling ‘bum’ or a wild-eyed prophet of doom causes consternation and fear in the general public. Depending on the extent of the handicap and the availability of modern psychiatric care, such people are pushed to the edges of society with the most functional becoming holy men and the least functional simply imprisoned.

This situation is the context needed to understand the boon that antipsychotic medications present. While all drugs used have serious side effects and other problems, they represent a solid advance in the treatment of what can be a crippling condition.


Antipsychotics, also called neuroleptics, are generally classified as typical (first generation) or atypical (second generation). The categories are historical and unnecessarily biased. The distinction is that the typical antipsychotics are classified by their chemical structure (three main types) and the atypical by their mode of action – which receptor subtype they function at. The newest agents are sometimes called third generation. The bias comes about because we are often conditioned to think that newer = better.

The bias remains in spite of a 2005 study by the National Institutes for Mental Health that compared second generation antipsychotics to a the typical agent, perphenazine. Only olanzapine had less discontinuation due to side effects (the primary metric). For updates and info, see the CATIE project.

Prevailing practice suggests the use of newer agents as a first trial upon diagnosis, with the expectation of a better side effects profile. Patients who have been stabilized on older medications, however, should not be switched without good reason and even then with caution.

The typical antipsychotics include the butyrophenones (i.e. Haloperidol); the phenothiazines (i.e. Chlorpromazine); and the thiozanthines (i.e. Flupenthixol).

Atypical or second generation drugs include those which act in various ways on the dopamine neurotransmitter system. They vary in their modes of action and what other neurotransmitter receptor sites they will bind to. This gives rise to a suite of side effect profiles and a ‘menu’ of agents to try. The only commonality among these agents is that they all find use in treating psychosis. Whether they are used primarily for schizophrenia, bipolar disorder or other labeled condition depends largely on a doctor’s preference, patient history, and the availability of studies showing a positive effect for a particular diagnosis. Off label uses are common as doctors attempt to titrate treatment to a particular patient’s condition and responses.

Atypicals include: Clozapine, Olanzapine (structurally related); Quetiapine, Risperidone and others.


The first antipsychotic was originally marketed as a surgical adjunct/anesthetic. Chorpromazine was found to have a calming activity with psychotic patients and this opened the door for exploration of similar compounds. The popularity of Thorazine (trade name for chlorpromazine) as an agent to control combative patients is well known and gave us the euphemism, “chemical straightjacket”.

Alleviating hyper-emotional and combative behavior in psychiatric emergencies is still a use for injectable haloperidol (in combination with a benzodiazepine) but long-term management of patients with high-dose antipsychotics is discouraged. This is because side effects are sure to arise. The goal when treating with antipsychotics is to balance symptom relief with the emergence of adverse reactions. It is common, in drug studies for these agents, to lose as much as two-thirds of the cohort because of unwanted reactions.

Some of the more serious adverse reactions include:

  • Onset of diabetes (especially those of African ethnicity) which may, in some cases be fatal (ketoacidosis) and pancreatitis.
  • Dramatic weight gain (metabolic, not just behaviorally induced).
  • Among the typical antipsychotics (and the main side effect reduced in atypical) is tardive dyskinesia, a movement disorder typified by the purposeless, robotic gait referred to cynically as the “Thorazine shuffle”.
  • Other side effects vary by agent and are often used to differentiate one product over another.

Of special note is a side effect that mirrors the goals of the treatment. Patients will complain of dysphoria, and in the treatment of mania and some types of schizophrenia, this is a nuance of some importance. Because one goal of treatment is to reduce excitability and feelings of grandiosity, a blunting of mood is desired. However, for some patients the treatment is worse than the disease. When emotional response is dulled to the degree that patients no longer care to live their ‘corrected’ life, they often stop taking medications which allow them to function in society. This sort of hard choice, between a less than adequate ‘cure’ and the condition itself is central to the management of psychosis. Another common side effect seen with these agents is sexual dysfunction, also perhaps a consequence of blunted affect and avolition.

Modern therapy goals directly deal with quality of life issues along with symptom control. With the multiple agents now available, several may be tried in an attempt to find the best fit for any particular patient. The practice of prescribing multiple antipsychotics simultaneously is currently discouraged, mostly because this becomes a ‘one-off’ experiment. Peer reviewed studies usually do not use more than one drug at a time. However, as in other areas of medicine that are not clearly, biologically elucidated, it becomes a matter of judgment, and psychiatrists must still rely on best guesses followed by modification.


The advent of medications that helped in psychosis was a large leap forward. Chemical agents have simultaneously helped ameliorate symptoms and shed light on the underlying mechanisms of the disease state. Much remains to be learned and exploration of the brain with fMRI and techniques in molecular biology offer continued improvements in care.

Newer drugs that target glutamate receptors show promise and non-drug therapies (Animal Assisted Therapy as an example) continue to be tried. The field is ripe for advances from several fronts. As always, caution coupled with scientific evaluation is the key.


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