This page is about antipsychotics as a drug treatment for schizophrenia and other psychotic disorders. It provides a review of the evidence for their short-term use, their adverse effects, and their effect on long-term outcomes. The primary purpose of this review is to detail the research on long-term outcomes.
In addition, there are these resources on Mad in America for researching antipsychotics:
Evidence for Short-term Use
Although it is widely assumed that there is abundant evidence from clinical trials that antipsychotics are effective in knocking down psychotic symptoms over the short term, there is a big hole in the evidence base. As researchers reported in 2017, “no placebo-controlled trials have [ever] been reported in first-episode psychosis patients.” This means that there is an absence of evidence for this class of drugs in medication-naïve patients (i.e., patients who have never been exposed to antipsychotics before).
The evidence for the short-term use of antipsychotics comes primarily from randomized controlled trials conducted in hospitalized patients. In these studies, patients on antipsychotics are abruptly withdrawn from their medication, and then after a few days those who have become actively psychotic are randomized to placebo or to treatment with an antipsychotic. Researchers then measure the decrease in psychotic symptoms over the next four to six weeks.
In 2009, Leucht published a meta-analysis of 38 trials of second-generation antipsychotics, and reported a response rate of 41% for the drug-treated patients versus 24% for the placebo group. Response was defined as a 50% decrease in symptoms. While this difference is statistically significant, the results nevertheless reveal that the majority of patients treated with an antipsychotic receive no additional benefit beyond placebo and yet are exposed to the adverse effects of the drugs.
To assess the impact of a drug treatment on all patients, researchers calculate the number of patients that must be treated (NNT) to produce one additional positive response beyond placebo. In this meta-analysis, the response rate was 41% for those treated with drug versus 24% for those with placebo, which means that for every 100 patients treated with an antipsychotic, there are 17 more responders than there would be with placebo alone. The NNT in the Leucht study was six.
This means that six out of every seven patients treated with an antipsychotic are exposed to the adverse effects of the drug without receiving any benefit from the treatment. This no-benefit group is composed of those who are non-responders to the drug (59%) and those who respond to placebo (24%). Thus, 83% of all patients could be said to be harmed by short-term treatment w with an antipsychotic, while 17% benefit.
In 2017, Leucht and colleagues published a meta-analysis of all double-blind, randomized clinical trials of antipsychotics that had been conducted since the first antipsychotic, chlorpromazine, was introduced in 1953. They concluded that only 51% of the patients in these 167 trials had even a “minimal response” to the antipsychotic, versus 30% of the placebo group. This difference in minimal response produces an NNT of five, which means that 80% of patients suffer the adverse effects of an antipsychotic without gaining any additional benefit in terms of the reduction of their psychotic symptoms.
Although the second-generation antipsychotics are often grouped together as “atypical” antipsychotics, which suggests they share a common mechanism of action, these drugs act on a number of different neurotransmitter pathways and do so with varying degrees of potency. For that reason, the drugs have “adverse event profiles” that vary widely.
A drug’s disruption of a neurotransmitter pathway causes many predictable adverse events. Since dopaminergic pathways are involved in the control of motor movements, drugs that block dopamine receptors can cause Parkinsonian symptoms, muscle dystonias, and akathisia. In addition, dopaminergic pathways are vital to the normal functioning of the limbic system and the frontal lobes, and thus dopamine-blocking drugs may inhibit emotional responses to the world (a limbic system function) and self-awareness (frontal lobes). Blocking serotonergic receptors can cause an increase in appetite, weight gain, and metabolic changes associated with an increased risk of diabetes. Blocking muscarinic M1 receptors can cause memory and cognition problems. And so on. Each neurotransmitter has its own side effect profile.
As can be seen in the above graphic, SGAs may cause a dizzying array of physical, emotional and cognitive problems. The easiest way to conceptualize the risks of an individual SGA may be to look at the neurotransmitter pathways it blocks, and at what potency, and then see which adverse effects are associated with those pathways.
In short, antipsychotics cause a broad range of side effects: metabolic dysfunction, endocrine dysfunction, motor dysfunction, sexual dysfunction, cardiac and respiratory problems, and brain atrophy. The drugs can induce akathisia, an intense inner agitation that is associated with an increase in homicidal and suicidal behavior. Over the longer term, they may cause tardive dyskinesia, which is characterized by rhythmic, involuntary motor movements. In adults, tardive dyskinesia usually persists even after the antipsychotic is withdrawn, evidence of permanent damage to the basal ganglia. Together, all of these adverse effects lead to poor global health.
The long-term outcomes literature for antipsychotics, which has been compiled over a period of nearly 60 years, consistently tells of drugs that increase the likelihood that a person diagnosed with schizophrenia will become chronically ill. Also see “The Case Against Antipsychotics,” for an in-depth review of this literature.
A. The Chronicity Problem Becomes Apparent (1960s-1970s)
1. NIMH’s first follow-up study
This NIMH study looked at one-year outcomes for 299 patients who had been treated either with neuroleptics or placebo upon their admission to a hospital. This was the first long-term study conducted by the NIMH, and the researchers found that patients who received placebo “were less likely to be rehospitalized than those who received any of the three active phenothiazines.”
2. NIMH’s first two relapse studies
a) Relapse in Chronic Schizophrenics Following Abrupt Withdrawal of Tranquilizing Medication. Prien, R. British Journal of Psychiatry 115 (1968):679-86.
The critical finding of this NIMH study was that relapse rates rose in direct relation to dosage–the higher the dosage that patients were on before the antipsychotic was withdrawn, the greater the relapse rate. At the start of the study, 18 patients were on placebo, and only one got worse over the next six months (6%). Sixty-five patients were on 300 mg of chlorpromazine at the start of the study, and 54% of those patients worsened after the drug was withdrawn. One hundred thirteen patients were on more than 300 mg of chlorpromazine at the start of the study, and 66% of those patients got worse after drug withdrawal (See table 3 on page 684 of the article).
b) Discontinuation of Chemotherapy for Chronic Schizophrenics. Prien, R. Hospital and Community Psychiatry 22 (1971):20-23.
In this NIMH study, the earlier finding that relapse rates rose in correlation with neuroleptic dosage was confirmed. Only two out of 30 patients who were on placebo at the start of the study relapsed during the next 24 weeks (7%). Twenty-three percent of the 99 patients who were on less than 300 mg of chlorpromazine at the start of the study relapsed following drug withdrawal. Fifty-two percent of the 91 patients who were on 300 to 500 mg of chlorpromazine at the start of the study relapsed following drug withdrawal, and 65% of the 81 patients who were on more than 500 mg of chlorpromazine at the start of the study relapsed following drug withdrawal. The researchers concluded: “Relapse was found to be significantly related to the dose of the tranquilizing medication the patient was receiving before he was put on placebo–the higher the dose, the greater the probability of relapse” (See pages 22-23 of the article).
3. A study comparing five-year outcomes in the pre-Thorazine and post-Thorazine eras
a) Comparison of Two Five-Year Follow-up Studies. Bockoven, J. American Journal of Psychiatry 132 (1975):796-801.
In this study, Boston psychiatrists Sanbourne Bockoven and Harry Solomon compared relapse rates in the pre-drug era to those in the drug era, and found that patients in the pre-drug era had done better. Forty-five percent of the patients treated at Boston Psychopathic Hospital in 1947 had not relapsed in the five years following discharge, and 76% were successfully living in the community at the end of that follow-up period. In contrast, only 31% of patients treated in 1967 with drugs at a Boston community health center remained relapse-free for the next five years, and as a group they were much more “socially dependent” (e.g., receiving government assistance) than those in the 1947 cohort.
Other researchers who reviewed relapse rates for New York psychiatric hospitals in the 1940s and early 1950s reported similar findings: roughly 50% of discharged schizophrenia patients had remained continuously well through lengthy follow-up periods, which was markedly superior to outcomes with neuroleptics (See Nathaniel Lehrman, “A state hospital population five years after admission: a yardstick for evaluative comparison of follow-up studies,” Psychiatric Quarterly 34 (1960):658-681; and H.L. Rachlin, “Follow-up study of 317 patients discharged from Hillside Hospital in 1950,” Journal of Hillside Hospital 5 (1956):17-40).
4. Two NIMH studies in the 1970s investigating longer-term outcomes in non-medicated patients
a) The Treatment of Acute Schizophrenia Without Drugs. Carpenter, W. American Journal of Psychiatry 134 (1977):14-20.
In this 1977 NIMH study, 49 schizophrenia patients, placed into an experimental hospital program that provided them with psychosocial support, were randomized into drug and non-drug cohorts. Only 35% of the non-medicated patients relapsed within a year after discharge, compared to 45% of those treated with medication. The medicated patients also suffered more from depression, blunted emotions, and retarded movements.
b. Are There Schizophrenics for Whom Drugs May be Unnecessary or Contraindicated? Rappaport, M. International Pharmacopsychiatry 13 (1978):100-111.
In this 1978 study, Maurice Rappaport and his colleagues at the University of California, San Francisco randomized 80 young male schizophrenics admitted to Agnews State Hospital to drug and non-drug groups. Only 27% of the drug-free patients relapsed in the three years following discharge, compared to 62% of the medicated group. Most notably, only two of 24 patients (8%) who weren’t medicated in the hospital and continued to forgo such treatment after discharge subsequently relapsed. At the end of the study, this group of 24 drug-free patients was functioning at a dramatically higher level than drug-treated patients.
5. The Soteria project
a) A Non-Neuroleptic Treatment for Schizophrenia. Mathews, S. Schizophrenia Bulletin 5 (1979):322-332.
b) Community Residential Treatment for Schizophrenia. Mosher, L. Hospital and Community Psychiatry 29 (1978):715-723
c) The Treatment of Acute Psychosis Without Neuroleptics. Mosher, L. International Journal of Social Psychiatry 41 (1995):157-173.
d) Treatment of Acute Psychosis Without Neuroleptics. Bola, J. The Journal of Nervous and Mental Disease 191 (2003):219-229.
During the 1970s, the head of schizophrenia studies at the NIMH, Loren Mosher, conducted an experiment that compared treatment in a homelike environment (called Soteria), where antipsychotics were minimally used, to conventional treatment in a hospital setting. At the end of two years, the Soteria patients had “lower psychopathology scores, fewer (hospital) readmissions, and better global adjustment” than those treated conventionally with antipsychotics. Only 31% of the patients treated without drugs in in the Soteria House who remained off neuroleptics after leaving the program relapsed over the next two years.
6. Is the cure worse than the disease?
a) Maintenance Antipsychotic Therapy. Cole, J. American Journal of Psychiatry 132 (1977):32-6.
In 1977, Jonathan Cole, the former head of the NIMH Psychopharmacology Service Center, concluded that given the myriad of problems caused by antipsychotics, “every chronic schizophrenic outpatient maintained on an antipsychotic medication should have the benefit of an adequate trial without drugs.” He titled his article, “Is the Cure Worse than the Disease?”
B. A Biological Explanation for Drug-Induced Chronicity
7. Drug-induced supersensitivity psychosis
a) Dopaminergic Supersensitivity After Neuroleptics. Muller, P. Psychopharmacology 60 (1978):1-11.
b) Neuroleptic-Induced Supersensitivity Psychosis:Chouinard, G. American Journal of Psychiatry 135 (1978):1409-1410.
c) Neuroleptic-Induced Supersensitivity Psychosis:Chouinard, G. American Journal of Psychiatry 137 (1980):16-20.
d) Neuroleptic-induced supersensitivity psychosis, the “hump course” and tardive dyskinesia. Chouinard, G. Journal of Clinical Psychopharmacology 2 (1982):143-4.
In the late 1970s, two physicians at McGill University, Guy Chouinard and Barry Jones, identified the biological changes induced in the brain by antipsychotics that led to the high relapse rates for drug-treated patients. Because the drugs dampen dopamine activity, the brain tries to compensate by becoming “supersensitive” to dopamine. In particular, the drugs trigger an increase in the density of dopamine receptors. This perturbation in dopamine function, over the long term, makes the patients more biologically prone to psychosis and to worse relapses upon drug withdrawal. Chouinard and Jones concluded: “Neuroleptics can produce a dopamine supersensitivity that leads to both dyskinetic and psychotic symptoms. An implication is that the tendency toward psychotic relapse in a patient who has developed such a supersensitivity is determined by more than just the normal course of the illness.”
C. Thirty-Five Years of Confirming Evidence
Psychiatry has mostly ignored the problem of “neuroleptic-induced supersensitivity psychosis” since the early 1980s. But since that time there have been a number of long-term outcome studies that have confirmed the fact that antipsychotics increase the likelihood a person will become chronically ill.
8. Philip Seeman’s animal model of psychosis
a) Dopamine Supersensitivity Correlates with D2 HIGH States, Implying Many Paths to Psychosis. Seeman, P. Proceedings of the Nat Acad of Science 102 (2005):3513-18.
b) Breakthrough Dopamine Supersensitivity During Ongoing Antipsychotic Treatment Leads to Treatment Failure Over Time. Samaha, A. J Neuroscience 27 (2007):2979-86.
In these two articles, Philip Seeman from the University of Toronto reported that agents that trigger psychotic-like behavior in animals (e.g., amphetamines, angel dust, lesions to the hippocampus, gene-knockout manipulations) all cause an increase in D2 receptors that have a high affinity for dopamine. However, he found that haloperidol and olanzapine both doubled the density of D2 HIGH receptors, and thus cause the very biological abnormality that in animal models had been identified as a final pathway. In a 2007 paper, he concluded that “these results are the first to demonstrate that ‘breakthrough’ supersensitivity during ongoing antipsychotic treatment undermines treatment efficacy.”
9. Cross-cultural studies
a) The International Pilot Study of Schizophrenia. Leff, J. Psychological Medicine 22 (1992):131-145.
The first World Health Organization study that compared schizophrenia outcomes in “developed” and “developing” countries was called The International Pilot Study of Schizophrenia. It began in 1968, and involved 1,202 patients in nine countries. At both two-year and five-year follow-ups, the patients in the poor countries were doing much better. The researchers concluded that schizophrenia patients in the poor countries “had a considerably better course and outcome than (patients) in developed countries. This remained true whether clinical outcomes, social outcomes, or a combination of the two was considered.” Two-thirds of the patients in India and Nigeria were asymptomatic at the end of five years. The WHO investigators, however, were unable to identify a variable that explained this notable difference in outcomes (See pages 132, 142, and 143 of the article).
b) Schizophrenia: Manifestations, Incidence and Course in Different Cultures. Jablensky, A. Psychological Medicine 20 (1992):1-95.
The second WHO study of this type was called the Determinants of Outcome of Severe Mental Disorders. It involved 1,379 patients from 10 countries, and was designed as a follow-up study to the International Pilot Study of Schizophrenia. The patients in this study were first-episode patients, and 86% had been ill fewer than 12 months. This study confirmed the findings of the first: two-year outcomes were much better for the patients in the poor countries. In broad terms, 37% of the patients in the poor countries (India, Nigeria and Colombia) had a single psychotic episode and then fully recovered; another 26.7% of the patients in the poor countries had two or more psychotic episodes but still were in “complete remission” at the end of the two years. In other words, 63.7% of the patients in the poor countries were doing fairly well at the end of two years. In contrast, only 36.9% of the patients in the U.S. and six other developed countries were doing fairly well at the end of two years. The researchers concluded that “being in a developed country was a strong predictor of not attaining a complete remission.” Although the WHO researchers didn’t identify a variable that would explain this difference in outcomes, they did note that in the developing countries, only 15.9% of patients were continuously maintained on neuroleptics, compared to 61% of patients in the U.S. and other developed countries.
WHO Data Summarized
c) Cross-national Clinical and Functional Remission Rates. Haro, J. Brit J of Psychiatry 199 (2011):194-201
In this study funded by Eli Lilly, 11,078 schizophrenia patients in 37 countries were all treated with antipsychotics. The patients in the developing countries (North Africa and the Middle East) had functional outcomes as poor as patients in Europe. Thus, in this study where all patients were medicated, the functional outcomes of patients in the poor countries were much worse than in the earlier WHO studies, and now were no better than functional outcomes in the richer countries.
10. The Vermont longitudinal study
a) The Vermont Longitudinal Study of Persons with Severe Mental Illness, II. Harding, C. American Journal of Psychiatry 144 (1987):727-734.
b) Empirical Correction of Seven Myths about Schizophrenia With Implications for Treatment. Harding, C. Acta Psychiatrica Scandinavica 90 (1990):140-146.
In a long-term study of schizophrenia patients released during the late 1950s and early 1960s from the back wards of Vermont State Hospital, Courtenay Harding reported that, 20 years later, 25% to 50% of the patients were completely off their medications, suffered no further signs and symptoms of schizophrenia, and were functioning well. She concluded that it was a “myth” that schizophrenia patients must be on the drugs all their lives, and the reality was that “it may be a small percentage who need medication indefinitely.”
11. A meta-analysis of the outcomes literature
a) One Hundred Years of Schizophrenia. Hegerty, J. American Journal of Psychiatry 151 (1994):1409-1416.
In 1994, Harvard Medical School researchers reported that outcomes for schizophrenia patients in the U.S. had declined since the 1970s, to the point that they were no better than they had been in 1900. Although the researchers did not blame antipsychotics for the poor outcomes, it is notable that this decline occurred during a period when American psychiatrists began telling the public that people diagnosed with schizophrenia had to stay on the drugs for life. In other words, the decline coincided with the adoption of a paradigm of care that emphasized lifelong drug therapy.
12. MRI studies (1990s)
a) Increase in Caudate Nuclei Volumes of First-Episode Schizophrenia Patients Taking Antipsychotic Drugs. Chakos, M. American Journal of Psychiatry 151 (1994):1430-1436.
b) Neuroleptics in Progressive Structural Brain Abnormalities in Psychiatric Illness. Madsen, A. The Lancet 32 (1998):784-785.
c) Subcortical Volumes in Neuroleptic Naive and Treated Patients with Schizophrenia. Gur, R. American Journal of Psychiatry 155 (1998):1711-1717.
During the 1990s, researchers using MRI technology discovered that antipsychotics shrink the frontal lobes and cause an enlargement of the basal ganglia. In the “Follow-up Magnetic Resonance Imaging” study, researchers reported that the enlargement of the basal ganglia was associated with a worsening of both the positive and negative symptoms of schizophrenia. This was powerful evidence of how the drugs cause chronic illness over time.
13. Nancy Andreasen’s research on brain volumes
a) Progressive Structural Brain Abnormalities and Their Relationship to Clinical Outcome. Ho, B. Arch Gen Psych 60 (2003):585-94.
b) Long-term Antipsychotic Treatment and Brain Volumes. Ho, B. Arch Gen Psych 68 (2011):128-37.
Starting in 2003, Nancy Andreasen, the former editor of the American Journal of Psychiatry, began reporting on her large MRI study of schizophrenia patients treated with antipsychotics. She found that the patients progressively lost “frontal white matter volume,” and that this brain shrinkage was associated with a worsening of negative symptoms, increased functional impairment, and, after five years, cognitive decline. In a 2011 article, she reported that this shrinkage was drug-related. Use of the old neuroleptics, the atypical antipsychotics, and clozapine were all “associated with smaller brain tissue volumes,” with decreases in both white and grey matter. The severity of illness and substance abuse had “minimal or no effect” on brain volumes.”
14. Tardive dyskinesia and global decline
a) Tardive Dyskinesia in Patients Treated with Major Neuroleptics. Crane, G. American Journal of Psychiatry 124 (1968):40-47.
b) Clinical Psychopharmacology in its 20th Year. Crane, G. Science 181 (1973):124-128.
c) Functional Impairment in Tardive Dyskinesia. Yassa, R. Acta Psychiatrica Scandinavica 80 (1989):64-67.
d) Central Determinants of Attention and Mood Disorder in Tardive Dyskinesia. Myslobodsky, M. Brain and Cognition 23 (1993):88-101.
e) Cognitive Dysfunction in Schizophrenia. Waddington, J. Brain and Cognition 23 (1993):56-70.
f) The Effect of Atypical versus Typical Antipsychotics on Tardive Dyskinesia. De Leon, J. Eur. Arch. Psychiatry Clinical Neurosciences 257 (2007):169-172.
g) The Neuropathologic Effects of Antipsychotic Drugs. Harrison, P. Schizophrenia Research 40 (1999):87-99.
Over the long term, antipsychotics may cause dopaminergic pathways in the brain to become permanently dysfunctional. They may lead to movement disorders (tardive dyskinesia), severe psychotic symptoms (tardive psychosis), and global cognitive decline (tardive dementia).
15. Harrow/Jobe longitudinal study
a) Factors Involved in Outcome and Recovery in Schizophrenia Patients Not on Antipsychotic Medications. Harrow, M. Journal of Nervous and Mental Disease 195 (2007):407-414.
b) Do all schizophrenia patients need antipsychotic treatment continuously throughout their lifetime? A 20-year longitudinal study. Harrow, M. Psychol Med 42 (2012):2145-55.
c) Does treatment of schizophrenia with antipsychotic medications eliminate or reduce psychosis?” Harrow, M. Psychol Med 44 (2014):3007-16.
d) Does long-term treatment of schizophrenia with antipsychotic medications facilitate recovery? Harrow, M. Schizophr Bull 39 (2013):962-5.
NIMH-funded researchers followed the long-term outcomes of schizophrenia patients diagnosed at two Chicago-area hospitals in the 1980s, and they found that at the end of 15 years, 40% of the schizophrenia patients who had stopped taking antipsychotics were recovered, versus 5% of those who had stayed on the drugs. They also found that those off medication fared better in every domain measured over the long-term: Presence of psychotic symptoms, relapse rates, anxiety levels, cognitive functioning, and employment rates.
Most notably of all, patients with a milder psychotic diagnosis at the start of the study who stayed on their antipsychotic medication fared worse, over the long-term, than those diagnosed with schizophrenia — a more severe diagnosis — who were off antipsychotics.
16. Wunderink’s randomized drug-tapering study
a) Recovery in remitted first-episode psychosis at 7 years of follow-up of an early dose reduction/discontinuation of maintenance treatment strategy. Wunderink, L. JAMA Psychiatry 70 (2013):913–20.
Lex Wunderink from the Netherlands randomized 128 patients who had recovered from a first episode of psychosis to “treatment as usual” with the drugs or to a drug-tapering program. At the end of seven years, the recovery rate for those randomized to the drug-tapering group was twice that of the treatment as usual group (40% vs. 18%).
17. Finnish birth-cohort study
Moilanen, J. European Psychiatry 28 (2013):53-58. In this study, Finnish researchers identified 70 patients born in 1966 who were diagnosed with schizophrenic psychoses. They assessed the status of the patients in 2000, when they were 34 years old (with a mean duration of illness of 10.4 years.) At that time, the 24 patients off medication were doing much better than the 46 patients on antipsychotics: they were more likely to be working, more likely to be in remission, and had better clinical outcomes.
18. Australian medication compliance study a) A randomized controlled trial of relapse prevention therapy for first-episode psychosis patients. Gleeson, J. Schizophrenia Bulletin 39 (2013):436-48.
In Australia, 81 first-episode patients stabilized on medications were randomized to treatment as usual or to a “specialized therapy” designed to increase medication adherence. Although the therapy did increase compliance over the 30-month study, the increased use of medication was associated with “decreases in psychosocial functioning and increases in negative symptoms.”
19. Denmark’s OPUS trial
a) Antipsychotic medication and remission of psychotic symptoms 10 years after a first-episode psychosis. Wils, R. Schizophrenia Research 182 (2017):42-48.
b) Cognitive functioning following discontinuation of antipsychotic medication. A naturalistic sub-group analysis from the OPUS II trial. Albert N. Psychological Medicine 49 (2019):1138-1147.
This Danish study followed 496 first-episode schizophrenia-spectrum patients diagnosed for 10 years. At the end of that period, there were 303 patients still in the study, 121 of whom were deemed “non-compliant” and off medication. The non-compliant patients were more likely to be in remission (74% vs. 49%), and more likely to be working (37% vs. 16%). There were no differences at baseline between the two groups. In a second analysis of their outcomes data, the OPUS researchers reported that those off medication had better cognitive functioning, lower positive and negative symptoms, and were more likely to have a romantic partner.
20. German review of longer term outcomes
a) Symptoms, functioning and coping strategies in individuals with schizophrenia spectrum disorders who do not take antipsychotic medication: a comparative interview study. Jung, E. Psychological medicine 46 (2016):1-10.
In a study of 48 patients with schizophrenia spectrum disorder, German researchers found that those off medication (23 of 48) had significantly higher levels of general functioning, and that the longer they had been off, the higher their level of functioning.
21. The patients’ perspective a) Antipsychotic treatment–a systematic literature review and meta-analysis of qualitative studies. Bjornestad, J. Journal of Mental Health (2019):1-11.
Studies of patients’ perspective of antipsychotics revealed that they found that long-term use of the drugs was a barrier to recovery.