Addressing Side Effects From Antipsychotic Treatment in Schizophrenia

John M. Kane, MD

Department of Psychiatry, The Zucker Hillside Hospital, Glen Oaks, and the Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY


Antipsychotic treatment for schizophrenia can produce a variety of adverse events. As discussed in “Improving Treatment Adherence in Patients With Schizophrenia,” unpleasant and serious side effects can contribute to nonadherence to an antipsychotic regimen, which severely limits the effectiveness of treatment and promotes psychotic relapse. When choosing among the various antipsychotics, knowledge of the medications’ profiles of neurotransmitter receptor binding may help clinicians determine which adverse effects an agent is more likely to cause (AV 1AV 1), such as extrapyramidal symptoms (EPS), hyperprolactinemia, weight gain, sedation, cognitive deficits, or hypotension.


Antipsychotics with an increased affinity for dopamine D2 receptors are associated with greater risk for EPS, which can have a profoundly negative effect on adherence rates by interfering with functioning and stigmatizing patients. A meta-analysis1 found that the reviewed second-generation, or atypical, antipsychotics were each associated with significantly less need for antiparkinsonian medication than the high-potency first-generation, or typical, antipsychotic haloperidol (P < .05). Compared with low-potency typical antipsychotics, clozapine, olanzapine, and risperidone were the only atypical agents that were associated with significantly fewer EPS (P < .05). Another meta-analysis2 comparing first- and second-generation antipsychotics found a reduction in the annual incidence of tardive dyskinesia associated with the atypical drugs (0.8%) versus haloperidol (5.4%). When planning long-term treatment, clinicians need to consider the risk of nonadherence due to EPS as well as the potential impact of persistent EPS on psychosocial and vocational functioning, subjective well-being, and stigmatization.



All first-generation antipsychotics are associated with prolactin elevation, or hyperprolactinemia, via D2 antagonism.3 Symptoms of hyperprolactinemia over the short term include sexual dysfunction, galactorrhea, and irregular menstruation. Chronic hyperprolactinemia may play a role in the development of osteoporosis and some cancers, although more research is needed to better define the relationship between chronically elevated prolactin levels and these diseases. Atypical antipsychotics as a group have less of an association with hyperprolactinemia than first-generation antipsychotics, but, within the atypical class, the association with prolactin elevation varies by medication (AV 2AV 2). Asenapine, a newer atypical antipsychotic not included in AV 2AV 2, does not pose a significant risk for prolactin elevation.4 Risperidone is associated with a greater degree of prolactin elevation than other atypical antipsychotics, possibly due to poor penetration of the blood-brain barrier,3 and paliperidone, which is related to risperidone, has similar prolactin-elevating effects.5 A study of paliperidone showed a dose-related increase in mean prolactin levels, which suggests that reducing the dose may be a first step to try if a patient experiences adverse events related to hyperprolactinemia. Because patients often avoid mentioning sexual side effects, clinicians need to inquire specifically about these types of problems.3


Weight Gain

Weight gain is a major adverse effect associated with some antipsychotics that may not always be avoidable when treating patients with schizophrenia. Patients being treated with an antipsychotic should be monitored for weight gain and associated health problems, particularly metabolic syndrome, because these developments can contribute to premature mortality. If clinically significant weight gain occurs, consider switching to an antipsychotic not known to cause weight gain and encourage patients to eat a healthier diet and exercise regularly.


An antipsychotic’s potential for causing weight gain has been found to be significantly associated with histamine H1 receptor affinity (P < .01), as well as its affinity for 1 α-adrenergic and 2 serotonergic receptors (P < .05 for all).6 Among the atypical antipsychotics, clozapine and olanzapine have the greatest H1 receptor affinity and are associated with the greatest likelihood of weight gain (AV 3AV 3).6 With the exception of ziprasidone, the second-generation antipsychotics are associated with more weight gain than haloperidol.


Sedation, another major problem with some antipsychotics, may also be associated with increased H1 receptor affinity.7 Haloperidol causes significantly less sedation than clozapine and quetiapine (P = .043 and P = .047, respectively) but more sedation than aripiprazole (P = .024). Clozapine was the only atypical antipsychotic found to be more sedating than the low-potency first-generation antipsychotics.1 If a patient develops sedation that does not resolve, various steps can be tried, such as removing other medications that promote sleep, prescribing the antipsychotic for bedtime, lowering the dose, switching the antipsychotic, and checking the patient for other comorbid conditions that could be contributing to the problem.7 It is also helpful to review the patient’s sleep hygiene and provide appropriate guidance.

Cognitive Deficits

Antagonism at muscarinic M1 receptors is associated with deficits in cognition, and M1-receptor impairments may be caused by schizophrenia itself or by antipsychotic agents.8 Cognitive deficits can contribute to treatment nonadherence, thereby potentially compromising a medication’s benefits. While some antipsychotics may be antagonists and others agonists at muscarinic receptors, still others may have both antagonistic and agonistic actions or be nonreactive at muscarinic receptors. Reducing the dose of the antipsychotic or of concomitant medications with anticholinergic effects may be a useful first step in addressing cognitive deficits, and switching to another antipsychotic is also an option.9


The degree to which an antipsychotic interacts with α1-adrenergic receptors is associated with the agent’s potential for causing orthostatic, or postural, hypotension.10 Among atypical antipsychotics, clozapine and quetiapine are most likely to cause hypotension,10,11 followed by olanzapine and risperidone, which have approximately equal risks for hypotension; aripiprazole and ziprasidone have little to no risk for hypotension when administered at therapeutic doses. Low-potency typical antipsychotics have greater risk for orthostatic hypotension than high-potency typical agents such as haloperidol.11 Clinicians should monitor for orthostatic hypotension, especially when prescribing multiple medications, as the addition of selective serotonin reuptake inhibitors or mood stabilizers to antipsychotics may increase the risk of orthostatic hypotension.12 Hypotension should always be monitored in older patients because of the risk of falls.


Clinicians should work with patients to ensure that troubling side effects are prevented or minimized, but patients must be aware that any medication is going to have some negative side effects. Patients and clinicians should collaborate in weighing an antipsychotic’s potential benefits against its potential risks with a particular focus on the patient’s illness profile, vulnerability to certain adverse events, history of treatment response, and treatment preferences.

For Clinical Use


  • Educate patients about the benefits and risks of antipsychotics, include patients in the treatment selection process, and select treatments according to patient illness profiles and treatment preferences
  • Monitor patients for adverse events associated with antipsychotics such as EPS, hyperprolactinemia, weight gain, sedation, cognitive deficits, and hypotension
  • Minimize adverse events to reduce the occurrence of partial adherence or nonadherence to antipsychotic medication


Drug Names

aripiprazole (Abilify), asenapine (Saphris), clozapine (Clozaril, FazaClo, and others), haloperidol (Haldol and others), olanzapine (Zyprexa), paliperidone (Invega), quetiapine (Seroquel), risperidone (Risperdal and others), ziprasidone (Geodon)

Take the online posttest.


  1. Leucht S, Corves C, Arbter D, et al. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet. 2009;373(9657):31–41.
  2. Correll CU, Leucht S, Kane JM. Lower risk of tardive dyskinesia associated with second-generation antipsychotics: a systematic review of 1-year studies. Am J Psychiatry. 2004;161(3):414–425.
  3. Perkins DO. Antipsychotic-induced hyperprolactinemia: pathophysiology and clinical consequences. Adv Stud Med. 2004;4(10F):S982–S986.
  4. Bishara D, Taylor D. Asenapine monotherapy in the acute treatment of both schizophrenia and bipolar I disorder. Neuropsychiatr Dis Treat. 2009;5:483–490.
  5. Berwaerts J, Cleton A, Rossenu S, et al. A comparison of serum prolactin concentrations after administration of paliperidone extended-release and risperidone tablets in patients with schizophrenia. J Psychopharmacol. 2010;24(7):1011–1018.
  6. Kroeze WK, Hufeisen SJ, Popadak BA, et al. H1-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs. Neuropsychopharmacology. 2003;28(3):519–526.
  7. Miller DD. Atypical antipsychotics: sleep, sedation, and efficacy. Prim Care Companion J Clin Psychiatry. 2004;6(suppl 2):3–7.
  8. Sellin AK, Shad M, Tamminga C. Muscarinic agonists for the treatment of cognition in schizophrenia. CNS Spectr. 2008;13(11):985–995.
  9. Lieberman JA. Managing anticholinergic side effects. Prim Care Companion J Clin Psychiatry. 2004;6(suppl 2):20–23.
  10. Lehman AF, Lieberman JA, Dixon LB, et al, for the Work Group on Schizophrenia. Practice Guideline for the Treatment of Patients With Schizophrenia. 2nd ed. Washington, DC: American Psychiatric Association; 2004.
  11. Mackin P. Cardiac side effects of psychiatric drugs. Hum Psychopharmacol. 2008;23(suppl 1):3–14.
  12. McIntyre RS, Jerrell JM. Metabolic and cardiovascular adverse events associated with antipsychotic treatment in children and adolescents. Arch Pediatr Adolesc Med. 2008;162(10):929–935.