The Long-Term Effects of Antipsychotic Medication on Clinical Course in Schizophrenia

Since their introduction in the 1950s, antipsychotic drugs have been an integral part of the treatment of schizophrenia because of their ability to alleviate psychotic symptoms and prevent relapse. Recently, the widely accepted recommendation that all individuals with new-onset schizophrenia should receive acute and maintenance antipsychotic treatment (1) has been challenged by concerns that antipsychotics might adversely affect long-term outcomes (2–5). Two possible mechanisms for a putative negative long-term effect have been proposed. One is antipsychotic-induced dopamine D₂ receptor sensitization, by which antipsychotics might produce an iatrogenic vulnerability to psychosis and relapse, thus necessitating long-term antipsychotic treatment and creating a pattern of recurrent relapses in individuals who might have had better outcomes if never or only minimally exposed to antipsychotics. Second, the association of brain volume loss with antipsychotic treatment in neuroimaging studies has raised questions about whether antipsychotics could have a neurotoxic effect; two studies in animal models have also found antipsychotic-associated brain volume loss. While clinical correlates of medication-related neurotoxicity have not been well defined, possible consequences include cognitive deficits, negative symptoms, and functional decline. The clinical evidence cited in support of these potential long-term adverse effects has included naturalistic observational studies of individuals who recovered without antipsychotic treatment or who did well following antipsychotic discontinuation compared with individuals who remained on treatment. More recently, the results of a 7-year follow-up study, conducted by Wunderink and colleagues (6), of individuals who participated in a randomized antipsychotic discontinuation trial have been cited as additional evidence for the adverse long-term effects of medication. A definitive answer to the question of whether antipsychotics adversely affect the long-term course of the illness can only come from placebo-controlled trials in medication-naive individuals followed for an extended period. The study of medication-naive individuals reduces the risk of sampling bias, since the decision to participate in a clinical trial is not influenced by prior treatment experience, and eliminates potential confounding of results by persistent antipsychotic-induced dopamine receptor sensitization from prior treatment. Such trials have not been attempted in the modern era because they have been considered unethical, as well as unfeasible. While several studies conducted in the decade after the introduction of antipsychotics provide relevant data, most have serious methodological limitations. In the absence of data from definitive clinical trials, assessment of whether antipsychotics might have a negative effect on clinical course requires a synthesis of evidence from multiple convergent approaches, including clinical trials, postmortem studies, imaging studies, and preclinical animal studies.

To help clinicians, patients, and family members faced with difficult decisions regarding antipsychotic treatment and to identify questions requiring further research, we convened an international panel of experts in antipsychotic pharmacology, neuroimaging, and neuropathology to review the preclinical and clinical evidence supporting potential adverse effects of antipsychotics on long-term outcomes. We present here a synopsis and analysis of evidence that has been cited in support of long-term negative effects of antipsychotics on clinical course, including studies of early and maintenance treatment effects, and preclinical and clinical evidence for neurotoxicity and dopamine sensitization; this evidence was identified from recent journal articles, books, and online sources (2–5). We place these findings within the context of results from systematic meta-analyses of relevant randomized controlled trials of antipsychotic efficacy and relapse prevention, systematic meta-analyses of antipsychotic-related brain volume changes, and a systematic review of longitudinal controlled trials of antipsychotic treatment of medication-naive first-episode psychosis. The primary clinical outcome for this review is psychosis, since the dopamine supersensitivity model predicts a loss of antipsychotic efficacy and increased risk of psychotic relapse. When available, long-term effects on cognition, negative symptoms, and social functioning were also reviewed, since these effects could reflect either neurotoxicity or neuroprotection. Although not covered in this review, medical morbidity and mortality associated with antipsychotic use is highly relevant to decisions about long-term treatment. Many antipsychotics increase risk for metabolic syndrome and thus the risk of heart disease, diabetes, and stroke (7), which are among the common causes of premature mortality in schizophrenia (8). However, much of the roughly 3.5-fold increase in mortality rates in schizophrenia compared with the general population appears to be attributable to cigarette smoking, alcohol, accidents, and suicide (8). Furthermore, in a large naturalistic study of schizophrenia, low and moderate exposure to antipsychotics was associated with lower overall mortality compared with no antipsychotic exposure (9).

1. What is the Clinical Evidence That Initial Treatment With Antipsychotics Affects Long-Term Outcomes?

Evidence for the Effectiveness of Initial Antipsychotic Medication

Psychosis can be extremely distressing to patients and their families and is associated with serious consequences, including self-injury, violence, incarceration, and disruption of social relationships. Whereas benefit for negative symptoms and cognitive deficits is not well established (10–12), the effectiveness for psychosis has been well established in randomized controlled trials; a systematic meta-analysis of 38 placebo-controlled trials of second-generation antipsychotics calculated a moderate effect size of 0.51 and a response rate of 41% with antipsychotic treatment compared with 24% with placebo (13). This magnitude of therapeutic effect compares favorably with many of the most effective treatments in nonpsychiatric fields of medicine (14). The effect size of antipsychotic efficacy compared with placebo has decreased over the past several decades, reflecting increased placebo response and possibly reflecting a decrease in drug response (15, 16), although the therapeutic effect size remains in the moderate range. Publication bias does not appear to have had a large effect on meta-analysis results (17).

Do All Patients With First-Episode Psychosis Require Initial Antipsychotic Treatment?

An older literature described spontaneous improvement rates of approximately 20%−30% in the preantipsychotic era, when Kraepelinian diagnostic criteria were employed (18), and sustained remission in approximately 15% (19). Kraepelinian criteria, similar to contemporary diagnostic criteria, required persistence of illness prior to diagnosis. Other studies of psychosocial alternatives to antipsychotics have claimed higher rates of remission, but results are difficult to interpret due to highly selective patient samples, diagnostic heterogeneity, and high attrition rates (20, 21). While no placebo-controlled trials have been reported in first-episode psychosis patients, the National Institute of Mental Health (NIMH) Collaborative Study of Phenothiazine Treatment in Schizophrenia (22) studied acutely ill inpatients with schizophrenia, 50% of whom were in their first episode. Twenty-nine percent of placebo-treated patients were dropped prior to completing the 6-week trial due to treatment failure; of the placebo completers, 23% (or 16% of the intent-to-treat sample) were much or very much improved compared with 75% of patients treated with antipsychotics. In contrast, two recent studies of intensive individual and family psychotherapeutic approaches (23, 24) reported sufficient response in 35% and 37% of individuals with first-episode nonaffective psychosis such that elective antipsychotic medication was not administered during a 2-year follow-up. These studies did not employ epidemiologic catchment-area based sampling, and thus it is unclear whether subjects are representative. Attempts to identify clinical predictors of response in the absence of antipsychotic treatment have not produced consistent findings (25, 26), and thus currently it is unclear what proportion of individual patients experiencing a first episode of nonaffective psychosis will remit without medication, who they may be, and how long the remission will last.

Is There a Negative Long-Term Impact of Initial Treatment With Antipsychotics?

From prior systematic reviews (27–29), we identified nine studies that compared antipsychotic treatment versus no pharmacotherapy in medication-naive first-episode psychosis patients with follow-up lasting at least 1 year; for studies utilizing mirror image historical controls treated in the preantipsychotic era, we required that the two treatment groups be treated within a 10-year period at the same facility. Because these studies were conducted before the practice of maintenance treatment with antipsychotics was widely adopted, in most cases patients received antipsychotics during hospitalization and subsequently were followed medication-free (28). Six of these studies utilized a mirror image design and compared longitudinal outcomes over periods of 1–5 years in a total of 7,161 first-episode psychosis patients treated in the preantipsychotic era compared with 3,510 first-episode psychosis patients treated in the antipsychotic era. Because findings from these mirror image studies are potentially confounded by factors that may have changed during the interval of time between treatment cohorts, firm conclusions cannot be drawn; however, no study reported poorer long-term outcomes in patients initially treated with antipsychotics. The three studies that focused on hospitalization rates (30–32) found increased rates of discharge and reduced rates of hospitalization associated with initial antipsychotic treatment, whereas the three studies (26, 33, 34) that measured functional outcomes reported higher rates of remission and lower rates of deterioration in the group initially treated with antipsychotics. Three additional studies provided longitudinal follow-up of medication-naive first-episode or early-course patients randomly assigned to medication compared with no medication—a design that avoids the potential limitations of nonrandomized mirror image studies using historical controls. In the first, May and colleagues (35) randomly assigned 228 first-admission patients with schizophrenia to psychotherapy, milieu treatment, antipsychotic, ECT, or antipsychotic plus psychotherapy for 1 year, after which nonresponders were openly treated with antipsychotics. Patients assigned to antipsychotic (alone or in combination) or to ECT spent less time in the hospital over the subsequent 3 years and exhibited superior social functioning; the improved outcome associated with initial antipsychotic treatment appeared to dissipate after 3 years of follow-up (36). The dissipation of the effect of initial medication status may reflect that, by the end of year 3, maintenance antipsychotic treatment was common (100% in the medication group and 85% in the psychotherapy group), consistent with clinical practice in the mid-1960s. Two other studies have been cited as evidence for negative long-term effects of initial antipsychotic treatment, but both involved sampling bias that may have confounded the results. In the first, Schooler and colleagues (37) conducted a 1-year follow-up of the 299 participants who were successfully discharged in the NIMH Collaborative Study of Phenothiazine Treatment in Schizophrenia (22) and found that individuals who received placebo during the initial 6-week trial were less likely to relapse after hospital discharge compared with individuals who received phenothiazine. Because dropout rates due to nonresponse during the initial randomized trial differed substantially between treatment groups (2% in the phenothiazine group compared with 29% in the placebo group), it is highly likely that the sample for the follow-up study of discharged patients contained a disproportionate number of poor-prognosis subjects in the phenothiazine group, since these subjects would not have achieved discharge if treated with placebo. Similarly, in a study of acutely psychotic patients, most of whom were medication naive, Rappoport and colleagues (38) reported poorer outcomes over a 3-year follow-up in patients who initially were randomly assigned to treatment with chlorpromazine compared with patients randomly assigned to placebo during the hospitalization. This design is also confounded by unequal attrition rates during the initial treatment phase—45% of placebo-treated patients dropped out compared with 26% of patients treated with chlorpromazine. After correction for the unequal loss of poor-prognosis patients in the placebo group, differences in outcomes were no longer significant between groups.

Additional information about the long-term effect of antipsychotic exposure has come from two contemporary analyses. Hegarty and colleagues (18) performed a meta-analysis comparing individuals diagnosed with schizophrenia by decade from 1895 to 1992 and found that outcomes substantially improved following the introduction of antipsychotic medication midcentury. However, outcomes became less positive following the introduction of more restrictive Kraepelinian diagnostic definitions in the 1980s, which by requiring a duration of illness of at least 6 months, decrease the likelihood of spontaneous remission. Kraepelinian diagnostic systems were similarly associated with more negative outcomes when applied in the preneuroleptic era (1895–1925). Finally, recent naturalistic studies in rural areas of China provide an opportunity to examine individuals with long durations of illness who have remained medication naive and are diagnosed using contemporary criteria. In a 14-year follow-up study comparing medicated with never-medicated individuals with schizophrenia, outcomes were poorer in the never-medicated group, including rates of partial and complete remission, homelessness, and mortality (39). Approximately 10% of individuals who had never been treated achieved remission, and approximately 8% were partially remitted compared with 30% and 37%, respectively, in individuals who regularly took medication. Because factors such as family involvement and characteristics of illness may have influenced medication status in these subjects, conclusions regarding the causal role of antipsychotics in improved long-term outcomes must be tempered. Nevertheless, this study and similar studies (40–42) do not provide evidence for a long-term negative effect of medication.

Is a Delay in Initial Antipsychotic Treatment Harmful?

A recent meta-analysis of 33 studies found consistent although relatively modest positive correlations between a longer duration of untreated psychosis and residual positive and negative symptoms and impairments in social functioning (43). One quasi-experimental study also found that a reduction in the gap between onset of psychotic symptoms and treatment with antipsychotics was associated with improved long-term outcome (44). The relationship between the duration of untreated psychosis and outcome remains significant after controlling for variables known to influence prognosis (45), but it is not certain that the relationship between duration of untreated psychosis and outcome is causal, since no contemporary randomized placebo-controlled studies have assessed the long-term consequences of withholding antipsychotic treatment. Nevertheless, this association argues against an initial negative effect of medication and suggests that antipsychotics may have an early protective effect that persists over time.

Summary.

The efficacy of antipsychotics for the initial treatment of psychosis is well established. Early initiation of antipsychotics in first-episode psychosis may improve the long-term course of the illness, although this has not been firmly established by randomized trials. More research is needed to determine whether some individuals may respond to alternative pharmacologic or nonpharmacologic treatments for a first episode of psychosis and if so, how to identify them. Currently, there is not compelling evidence from controlled clinical trials that initial antipsychotic treatment worsens the long-term course of the illness.

2. What is the Clinical Evidence That Maintenance Treatment With Antipsychotics Affects Long-Term Outcomes?

Evidence for the Impact of Maintenance Antipsychotic Treatment on the Course of Illness

Questions have also been raised about the value of maintenance antipsychotic treatment based on longitudinal naturalistic studies of patients with schizophrenia conducted in the United States by Harrow and colleagues (46) and in Finland by Moilanen and colleagues (47) that found superior outcomes in individuals who were previously treated but not taking medication at the time of assessment compared with individuals taking medication. However, nonmedicated patients had more favorable premorbid characteristics in the study by Harrow and colleagues (48) and had less severe illness in the study by Moilanen and colleagues (47), suggesting that in naturalistic uncontrolled studies, medication status may in part be the consequence of whether patients are doing well or poorly rather than the cause. Other naturalistic studies have found improved outcomes in individuals with schizophrenia who continued antipsychotic treatment compared with those who did not (49, 50). It is not possible to draw conclusions from these studies due to the substantial risk of confounding (51). It is clear, however, from placebo-controlled trials that maintenance treatment with antipsychotics reduces the risk of relapse. A meta-analysis of 65 randomized trials of maintenance treatment demonstrated a large reduction in relapse rates with antipsychotic maintenance compared with placebo at the 1-year follow-up (27% compared with 64%) and better quality of life (52). The effectiveness of antipsychotics in the prevention of relapse was consistent regardless of duration of illness, duration of clinical stability prior to medication discontinuation, or the use of first-generation compared with second-generation agents (52).

Studies of the Discontinuation of Maintenance Medication

Several naturalistic studies have reported that a subgroup of patients, possibly as large as 20%−30%, maintain remission and function relatively well for sustained periods after discontinuing antipsychotics (6, 53–55). In a randomized trial in stabilized first-episode patients, Wunderink and colleagues (6, 56) found that a strategy of lowering antipsychotic doses and discontinuing antipsychotics when possible resulted in higher relapse rates (43% compared with 21%) over 18 months compared with treatment as usual, consistent with prior studies of targeted treatment in which medication discontinuation resulted in high rates of relapse (57). When followed naturalistically for an additional 5 years after completion of the randomized trial, rates of relapse no longer differed between experimental and control groups (61.5% compared with 68.6%) and functional remission was greater in the experimental group (46.2% compared with 19.6%), although rates of symptomatic remission did not differ (69.2% compared with 66.7%). This finding is difficult to interpret and requires replication, especially given that during the 5-year follow-up, the original randomized treatment allocation was not retained and further treatment was not controlled. Mean doses of antipsychotics (in haloperidol equivalents) were only marginally lower in the treatment discontinuation group (2.8 mg/day) compared with the standard care group (4.0 mg/day) during the final 2 years of follow-up. It is noteworthy that under the closely monitored dose reduction protocol employed by Wunderink and colleagues (56), the increase in relapse rates during the first 18 months was not associated with an increase in hospitalization or with negative outcomes, in contrast to naturalistic studies in which relapse has been associated with worsening of negative symptoms and poorer functional outcomes (58). The Wunderink study (6, 56) illustrates the difficulty of balancing the risk of relapse associated with antipsychotic dose reduction or discontinuation compared with the potential for minimizing adverse effects. Notably, one meta-analysis found that maintenance treatment with moderately low doses (50%−100% of World Health Organization-defined standard doses) was comparable in preventing relapse to standard doses, whereas very low doses (less than 50% of standard doses) increased the risk of relapse (59).

Summary.

The effectiveness of maintenance treatment for prevention of relapse is well established. A subgroup of patients, which may be as large as 20%, may maintain remission or partial remission for extended periods off medication. The use of low doses or of medication discontinuation may have long-term benefits for some patients, but a weighing of the relative risks of relapse compared with exposure to higher doses of medication remains to be clarified.

3. What is the Evidence From Neuroimaging and Preclinical Studies That Antipsychotics are “Neurotoxic” or “Neuroprotective”?

Evidence From Imaging and Postmortem Studies of Antipsychotic-Related Brain Volume Loss

Structural abnormalities in the brains of schizophrenia patients have been well documented, particularly reductions in prefrontal cortex and temporal lobes. Brain volume is reduced in patients at ultra-high risk and is further reduced with progression to the first episode of psychosis, prior to exposure to medication (60). Unaffected twins in monozygotic and dizygotic twin pairs discordant for schizophrenia also exhibit reductions in gray matter and, based on these data, it has been estimated that most of the gray matter loss in schizophrenia is explained by genetic liability, although environmental factors also contribute (61). Whether medication plays a role in gray matter volume change, either protective or causative, remains uncertain. Antipsychotic drug dose at the time of scanning and duration of illness correlated significantly with gray matter volume loss in a meta-analysis of over 18,000 subjects with schizophrenia (62), but because medication dose may be a marker for severity of psychosis or refractoriness to treatment, correlations between medication dose and brain volume loss are difficult to interpret. Similarly, because brain regions associated with volume loss during antipsychotic treatment also are reduced in medication-naive patients, it is difficult to determine whether brain volume loss reflects progression of illness compared with a medication effect, or an interaction between the two (63). Moreover, postmortem studies prior to the use of antipsychotics showed abundant evidence of brain structural abnormalities (64), mirroring structural abnormalities found in postmortem studies of patients having received antipsychotics (65).

Along these lines, in a 5-year longitudinal study, left frontal cortical density loss correlated with the number of hospitalizations (66), consistent with a negative effect of psychosis. The duration of relapses was also found to correlate with a reduction in brain volume in a longitudinal study of first-episode patients (67), although whether associations between relapse and brain volume reduction are causal cannot be determined from naturalistic studies. In another approach to addressing this question, a study of nonrandomized medication discontinuation in stabilized first-episode psychosis patients found that gray matter volume loss over a 12-month period did not differ between medicated and nonmedicated patients, whereas both groups displayed significant brain volume loss compared with healthy controls (68), consistent with the possibility that volume changes reflect progression of illness rather than a medication effect.

Finally, it remains unclear whether brain volume changes during treatment are associated with clinical worsening. In general, gray matter volume correlates with IQ, although the pattern of relationships between brain regions and cognitive domains may be altered in schizophrenia (69). Gray matter volume loss during the course of illness has been associated with cognitive impairment and functional deficits in most studies (70, 71) but not all (72). However, studies of first-episode psychosis consistently find improvement of cognition with antipsychotic treatment, consistent with symptom reduction and practice effects on cognitive tests (73). Most evidence indicates that cognitive impairment in schizophrenia occurs prior to initiation of antipsychotic treatment and then remains stable (73); however, a subgroup of patients may exhibit cognitive decline in the latter stages of the illness (74). In addition, clozapine treatment has been associated with gray matter volume loss that occurred concurrently with clinical improvement (75, 76), suggesting a complex relationship between brain volume changes and clinical course.

Proposed Mechanisms of Antipsychotic-Related Volume Change With First- and Second-Generation Agents

The question of whether antipsychotics protect against or contribute to gray matter loss is hindered by a lack of understanding of the molecular mechanisms underlying gray matter loss in schizophrenia. Postmortem brain studies in schizophrenia patients have failed to find histopathological evidence of a neurodegenerative or neurotoxic process, including neuronal loss, ubiquitination, dystrophic neurites, astrocytosis, or microglial infiltrates (77), whereas evidence for oxidative stress is more compelling (78). Most volume changes that occur appear to be the result of reduction in neuropil related to less dendritic branching, lower spine density, and smaller cell body size (79).

A large literature has compared first- and second-generation antipsychotics on the basis of potential effects on oxidative stress, excitotoxicity, and inflammation, and these findings have generally favored second-generation agents (80). However, clinical comparisons of these two somewhat arbitrarily defined classes of antipsychotics have produced inconsistent results for both comparative efficacy and association with gray matter loss, although reduced neurologic side effects with second-generation agents is a consistent finding (81, 82). Tardive dyskinesia, which may be a marker for neurotoxicity, is more common with first-generation agents (83) and has been linked to excessive glutamate transmission and oxidative stress (84). In an early study by Lieberman and colleagues (85), haloperidol was associated with greater gray matter volume loss than olanzapine in a randomized trial in first-episode psychosis patients; the degree of gray matter loss correlated with clinical outcome. In contrast, other studies have found gray matter volume loss associated with cumulative exposure to either first- or second-generation agents, without evidence of a significant difference between the two (62, 86). One meta-analysis found that higher doses of first-generation agents were associated with greater volume loss, whereas higher doses of second-generation agents were associated with less volume loss (87); this effect may be largely attributable to clozapine (71). Because of the substantial heterogeneity among drugs within the category of second-generation antipsychotics, as well as potential effects of dosing, no definitive conclusions can be drawn about relative effects, nor are mechanisms of brain volume loss related to illness or medication clearly established.

Evidence From Preclinical Animal Models of Antipsychotic-Related Brain Volume Loss

Studies of antipsychotic exposure in animal models have drawn attention to possible neurodegenerative effects. In one study, 18 macaque monkeys were treated with vehicle, haloperidol, or olanzapine for 18–24 months administered at doses calculated to approximate typical therapeutic blood levels (88). At the end of the study, monkeys exposed to both haloperidol and olanzapine had a statistically significant 10% reduction in brain volume compared with vehicle-treated monkeys; examination of parietal cortex revealed decreased numbers of astrocytes, but not pyramidal neurons or oligodendroglia compared with monkeys in the control group (89). While of great interest, the results of this study require replication given the cross-sectional design, the small sample size, and the focus on a brain region (parietal cortex) not generally considered to be central to the disease process of schizophrenia. In a second study, rats treated with haloperidol and olanzapine demonstrated significant gray matter volume loss at 8 weeks; postmortem examination revealed a loss of neuropil but no change in the number of cells (90), suggesting that possible early effects on brain volume do not involve neuronal loss. The relevance of findings in rodents and monkeys to the treatment of psychosis in humans is uncertain, both due to species-related differences and because animals lack the pathophysiology of schizophrenia. It is possible that antipsychotics may have deleterious effects on normal brain but protective effects in the presence of schizophrenia-related neuropathology (91).

Summary.

Evidence linking brain volume changes to antipsychotic treatment is potentially confounded by the underlying illness and by uncertainty whether higher antipsychotic dosing is a response to, or a contributor to, progressive brain volume loss. Evidence for negative effects of antipsychotics in some animal models supports the need for more controlled trials addressing this issue in humans. Second-generation antipsychotics have been associated with less brain volume loss in some clinical studies and more favorable effects in some animal models, but the evidence for overall clinical superiority of second-generation agents remains mixed.

4. What is the Evidence From Preclinical and Clinical Studies Regarding Possible Antipsychotic-Related Dopamine Sensitization?

Soon after the introduction of chlorpromazine and related phenothiazines, concerns were raised about whether antipsychotic treatment, particularly at high doses, might make some patients more vulnerable to relapse following discontinuation. It was observed that patients who were treated with high doses of antipsychotics were more likely to relapse when switched to placebo compared with patients who were treated with low doses or compared with patients who were medication-free at the time of discharge (37, 92). Although interpreted as possibly reflecting a sensitization effect of high-dose antipsychotics, this finding may reflect different subgroups of patients identified by clinician-determined medication dosing; patients who were successfully treated with low doses and patients who could be discharged without having received treatment may have been less ill or may have been more stable independent of drug effects. No trial has examined randomized assignment to high- compared with low-dose treatment prior to placebo substitution. A recent meta-analysis found no difference in relapse rates following abrupt compared with gradual discontinuation of first- or second-generation antipsychotics, and the relative risk benefit of drug over placebo remained similar after eliminating subjects who relapsed during the first 3, 6, or 9 months of follow-up, which strongly argues against iatrogenic relapse resulting from antipsychotic withdrawal, since sensitization effects would be expected to attenuate over time (52).

In 1980, Chouinard and Jones (93) introduced the term “supersensitivity psychosis” to describe cases in which patients appeared to develop tolerance to antipsychotic treatment defined by an increasing dose requirement over time and an increased risk for rapid relapse following antipsychotic discontinuation. The dopamine supersensitivity model was based in part on observations in rats that antipsychotic exposure increased dopamine D₂ receptor density in mesolimbic pathways (94), and with repeated administration of antipsychotics, increasing doses were required to block the behavioral effects of apomorphine (95). Concerns regarding potential adverse consequences of D₂ receptor supersensitivity led to an exploration of intermittent dosing strategies. Studies in which medication was administered at least 4 days per week found antipsychotic efficacy to be similar between intermittent and daily dosing (96, 97), whereas longer drug-free periods were consistently associated with higher relapse rates (98–101). In no study has intermittent dosing improved efficacy.

In addition to a rapid increase in D₂ receptor density, antipsychotics, including clozapine, produce a delayed down-regulation of cortical D₁ receptors (102). In monkeys, treatment with haloperidol for 1–4 months at doses that produced blood levels consistent with clinical practice were associated with significant impairment of working memory, which was attenuated by short-term administration of a D₁ agonist (103). The impairment and normalization of working memory in this study were interpreted by the investigators as evidence of D₁ desensitization by chronic haloperidol treatment, although evidence from behavioral response was indirect. While this study raises concern about potential consequences of chronic D₂ blockade, the relevance to patients with schizophrenia is not clear; studies of cognition during the first year of treatment in first-episode psychosis have not found an evolution of similar cognitive deficits (73).

Summary.

Despite evidence that antipsychotics can produce D₂ receptor sensitization and D₁ receptor desensitization in animal models, clinical studies have not provided compelling evidence that treatment with antipsychotics worsens the course of illness, increases risk of relapse, or causes cognitive deficits.

Conclusions

Results from many randomized clinical trials strongly support the benefit of antipsychotic drugs for the initial treatment of psychosis and for the prevention of relapse. While naturalistic studies suggest that a small number of patients may recover from a first episode of psychosis without pharmacologic treatment or may discontinue medication and remain stable for extended periods of time, we do not have clinical measures or biomarkers that allow us to identify them prospectively. Because relapses and delays in the treatment of psychosis have been associated with poorer outcomes, there may be risk associated with withholding or discontinuing medication. Evidence from preclinical animal models is mixed regarding whether antipsychotics have “neuroprotective” compared with “neurodegenerative” effects, and it is not possible to conclude from available clinical imaging studies whether the brain volume loss observed during the course of illness is attributable to antipsychotics or to the underlying illness. More research is needed to clarify long-term effects of antipsychotics on brain volume and their consequences. Existing clinical evidence for a negative long-term effect of initial or maintenance antipsychotic treatment is not compelling. Patients and their families should be made aware of the strong evidence supporting antipsychotic efficacy and of the side effects that vary between drugs. Additional research is needed to help quantify the risk-benefit ratio associated with continuation compared with discontinuation of antipsychotic treatment and to identify predictive biomarkers in order to facilitate shared decision making and a personalized medicine approach.