Introduction to Antipsychotics

Antipsychotics (also known as neuroleptics or major tranquilizers) are a class of medication mainly used in the treatment of psychosis in schizophrenia and psychosis/mania in bipolar disorder. Its use has expanded to neurodevelopmental, neurodegenerative, and neuropsychiatric disorders in recent years.

The first antipsychotic chlorpromazine was introduced in 1955 by French psychiatrists Pierre Deniker and Jean Delay. Since then, antipsychotics have been the cornerstone treatment for psychotic disorders. Its role and scope has expanded in the treatment of other medical and psychiatric illnesses since then.

One theory in the pathophysiology of schizophrenia is that increased dopamine activity causes the positive symptoms of schizophrenia. Similar to how methamphetamine and cocaine also increases dopamine activity, and can cause schizophrenia-like symptoms. Therefore, antipsychotics target the mesolimbic pathway to decrease the incidence of positive symptoms. Antipsychotics work by binding to dopaminergic neuroreceptors. It is important to keep in mind that this is a theoretical model, and that the pathophysiology of schizophrenia remains poorly understood.

There are 4 key dopaminergic pathways that antipsychotics affect (See also: The Four Dopamine Pathways Relevant to Antipsychotics Pharmacology).

Fig. 1

The therapeutic action of an antipsychotic occurs when 65% to 85% of brain dopamine (D2) receptors are occupied.^[1] When more than 80% of the dopamine (D2) receptors are occupied, hyperprolactinemia and parkinsonism can result. In addition to percentage occupancy, the duration of time that the antipsychotic drug stays attached to the D2 receptor impacts the degree of extrapyramidal symptoms (EPS). For example, haloperidol remains attached to the D2 receptor in vitro for over 38 minutes. Atypicals like clozapine and quetiapine dissociate from the D2 receptor quickly, in about 15 seconds (this has been referred to as “kiss and run”).^[2][3] As a result, these rapidly dissociating atypical antipsychotics have a lower incidence of EPS. Of note, the serum level of antipsychotics do not correlate with brain occupancy due to the blood brain barrier.

Typical (first generation) antipsychotics are typically metabolized by CYP2D6. There is increased metabolism in Mediterranean populations. Clozapine and olanzapine (second generation antipsychotics) are metabolized by CYP1A2.

Antipsychotics have a relatively quick onset of action and patients begin responding within 1 week.^[9] Patients first have experience better sleep due to the sedating effects of antipsychotics, then decreased anxiety occurs from resolution of the psychotic symptoms. Insight may take months to develop, if at all.

How long should patients remain on antipsychotics for schizophrenia? The general consensus is that patients with chronic schizophrenia should remain on therapy long-term. However, there is some new evidence for first-episode psychosis patients that “less is more.”^{[10][11][12][13]} This study observed that compared with a standard maintenance treatment regimen, dose reduction or supervised discontinuation of antipsychotic medication during the early phases of FEP led to a higher relapse rate initially, but improved long-term outcomes. This study has been criticized for its unequal distribution across diagnostic groups, high attrition rate, failure to separate the dose reduction and discontinuation groups, and the fact that most patients in each arm of the study did receive medication. These findings have not been replicated. More importantly, clinicians and researchers are still unable to discern which populations will do well with an antipsychotic taper, and those who would worsen symptomatically. Studies are ongoing to investigate these questions.^[14] Other more recent studies have shown that the risk of relapse after antipsychotic discontinuation does not decrease over time, and that antipsychotic use is associated with increased survival.^[15] This indicates that long-term antipsychotic use for treating first-episode schizophrenia for the majority of patients remains a the most evidence-based practice, as the relapse rates are greater than 80% with medication-discontinuation after several years. Relapse involves hospitalization, psychosis, and significant psychosocial impact, and this needs to be weighed carefully against discontinuation of medication.

All patients who are on long-term antipsychotics must be medically monitored routinely. The following recommendations are from the 2005 Canadian Psychiatric Association Clinical Practice Guidelines.^[16]

The literature shows that clozapine and long-acting injectable antipsychotic medications have the highest rates of prevention of relapse in schizophrenia.^[17] The risk of rehospitalization is about 20% to 30% for patients treated with long-acting injectable treatments compared with the oral equivalents.^[18] If a patient is doing well on an existing first-generation long-acting injectable, switching them to a second-generation LAI puts them at a higher risk of treatment discontinuation and weight gain.^[19]

Antipsychotic polypharmacy (i.e. - taking more than 1 antipsychotic) is commonly seen, but should not occur! Patients with antipsychotic polypharmacy should be transitioned to monotherapy treatment. Furthermore, changing to monotherapy does not compromise the clinical response.^[20] Some patients may be on multiple antipsychotics due to treatment resistance, however, this should be a treatment of last resort.

When switching from one antipsychotic to another, there is no difference in clinical outcomes (psychopathology, extrapyramidal symptoms, and adverse effects) between maintaining the patient on the old antipsychotic for a period of time and starting the new antipsychotic, versus stopping the old antipsychotic immediately and introducing the new antipsychotic.^[21]

Discontinuation of antipsychotics is often a patient request due to intolerable side effects from the medication. This can present as a challenging clinical decision.^[22] Rapid or abrupt antipsychotic discontinuation is one of the major reasons for symptom recurrence and readmission to hospital. Therefore, any discontinuation should be carefully monitored and tapered slowly. The abrupt withdrawal of clozapine has been associated with cholinergic rebound and rapid onset of psychosis. Discontinuation-induced supersensitivity of dopamine receptors can lead to worsening and the appearance of new and more complex symptoms.^[23] Therefore, clozapine should always be gradually and slowly tapered over time.

Antipsychotics are not benign, and must be used judiciously. The main side effects include extrapyramidal symptoms and sexual side effects,^[24] (due to potent dopamine receptor blockade), anticholingeric side effects like sedation (from blockade of histaminergic and muscarinic receptors), and cardiovascular (from adrenergic blockade).^[25] Adverse reactions include neuroleptic malignant syndrome, seizures, and cardiovascular problems.

What is the effect of antipsychotics on brain volume? A controversial paper came out in 2011^[36] that suggested antipsychotics were linked to smaller gray matter volumes. What the paper did not address is what the actual clinical significance of this means for patients (i.e. - is this a good thing or a bad thing?). Since that paper, multiple recent studies have shown the opposite findings: that brain volume and cortical changes are not explained by exposure to antipsychotic drugs, but likely due to the pathophysiology behind psychosis.^[37][38] Other brain research studies have shown that unaffected first-degree relatives of schizophrenics also have thinner cortical volume.^[39] Clearly, there are implications from this research, and there should continue to be more research on the effects of antipsychotics on the brain. What is clear is that at this time, there are no clear indications what brain volume changes clinically means for patients. The current and overall research evidence suggests that global neuronal dysfunction from psychosis and schizophrenia better explains cortical thinning and brain volume loss, rather than from antipsychotic use.

There is no significant difference in the incidence of all-cause death and death due to suicide between oral psychotics, injection antipsychotics, and placebo.^[40]