Are structural brain changes in schizophrenia related to antipsychotic medication? A narrative review of the evidence from a clinical perspective

Abstract

Some observational studies and literature reviews suggest that antipsychotic drug use is associated with loss of grey or white matter in patients with schizophrenia, whereas others have contradicted this finding. Here, I summarize and critique the available evidence and put it in the context of clinical practice. This narrative review pools evidence from observational and experimental studies in humans and animals on the relationship between antipsychotic medication use and brain structure and function in patients with schizophrenia. To summarize, the observational evidence in patients with schizophrenia and the experimental evidence in animals suggest that antipsychotic drugs can cause reductions in brain volume, but differ as to where those effects are manifest. The experimental evidence in patients is inconclusive. There is stronger and more consistent evidence that other factors, such as alcohol and cannabis use, are likely causes of progressive brain changes in schizophrenia. Overall, I argue the case against antipsychotics is not proven and the jury is out on any significance of putative antipsychotic-induced brain changes. Taken in the context of strong evidence from clinical trials that antipsychotic drugs have beneficial effects on symptoms, function, relapse and cognition, and observational evidence that treatment normalizes other imaging indices and reduces mortality, the balance of probabilities is that antipsychotic drugs do not cause adverse structural brain changes in schizophrenia.

Keywords

antipsychotic drugs magnetic resonance imaging outcome schizophrenia

Introduction

Schizophrenia has a variable presentation, course and outcome. Up to one half of patients can be held to have a good outcome ¹ but a meta-analysis of 50 naturalistic follow-up studies concluded that only 13.5% of patients with schizophrenia recover in the long term.² This figure is very similar to the repeated findings from prospective longitudinal studies that about one fifth of people diagnosed with schizophrenia will be symptom free without antipsychotic medication on long-term follow up. For example, the AESOP-10 study showed that approximately 20% of people with schizophrenia had no psychotic symptoms and were not taking antipsychotics at 8 years or more of follow up.³

Antipsychotic benefits

Antipsychotic medication can have dramatic benefits in acute schizophrenia. In a systematic review and meta-analysis, Leucht and colleagues⁴ included 167 double-blind, randomized controlled trials (RCTs) with 28,102 participants, mainly with chronic disease. At least a ‘minimal’ response occurred in 51% of the antipsychotic-treated group versus 30% in the placebo group, and 23% versus 14% had a ‘good’ response. Quality of life and functioning also improved, even in the short term. Antipsychotics are also very effective at relapse prevention,⁵ and the effect size is strong and greater even than seen for most drugs in general medicine.⁶ A meta-analysis of 65 studies reported that 27% of patients with schizophrenia receiving antipsychotic medication had relapses at 7–12 months compared with 64% of patients who had medication withdrawn and switched to placebo.⁵ Patients with stable disease for 3–6 years still relapsed after antipsychotic withdrawal. Sensitivity analysis to address supersensitivity/rebound psychosis showed that even when only patients who had not relapsed for 3, 6 or 9 months after study start were included, antipsychotics were still more efficacious than placebo.

Based on available evidence on relapse prevention, patients with first-episode psychosis should receive antipsychotics for 1 year, and those with multiple episodes should receive medication for 3–6 years (because there are no longer-term trial data).^5,7 The duration of treatment needs to be individualized and based on the severity of psychotic episodes and side effects. Overall, however, there is a good deal of evidence that antipsychotic drugs improve long-term outcome in schizophrenia,⁸ and very little evidence that they lead to a poor outcome. It has therefore become commonplace for patients with schizophrenia to remain on the same or similar doses of antipsychotic medication for years and even decades. A natural conservatism amongst clinicians, keen to avoid relapse and further hospitalization, is compounded by pressures on services that can make regular review difficult. Moreover, after referral of patients back to primary care, GPs are afraid to change the antipsychotic dose, let alone stop it.

Antipsychotic harms

Antipsychotic drugs also have a propensity to cause troublesome adverse effects. About 5% will have one or more adverse effects, such as movement disorder, sedation or weight gain, which can be attributed to the drug.⁵ Patients do not like taking antipsychotic medication long term and some recent evidence suggests that doing so can impair the prospects of recovery⁹ and potentially reduce brain volume (see below).

The open, randomized controlled MESIFOS trial⁹ found that patients with remitted first-episode psychosis who continued on maintenance antipsychotic therapy were initially functioning better at 18 months than those who underwent dose reduction or discontinuation. In addition, relapse rates were 20% higher in patients who discontinued antipsychotics compared with patients who continued to take them. However, by 7 years, after 5 years of unspecified treatment, those in the dose-reduction/discontinuation arm were functioning better than those in the maintenance arm. They had a higher rate of recovery (symptomatic and functional remission: 40.4%) than those who had originally received maintenance therapy (17.6%). Notably, however, only 20% of patients could discontinue antipsychotics successfully and the doses of antipsychotic drugs were similarly low in the two arms of the study, making the findings difficult to interpret.

Antipsychotic-associated structural brain changes

It has been clear for 20 years or so that schizophrenia is associated with widespread reduction in brain volume compared with groups of healthy controls, particularly in prefrontal and medial or superior temporal lobes. Some of these studies also suggested an association between first-generation antipsychotic drug use and increases in the volume of parts of the basal ganglia, especially the globus pallidus, which might be reversed upon switching to second-generation drugs and clozapine.^10–12

Initially, these differences were interpreted as developmental but it is now clear that there are progressive reductions in both grey and white matter in patients with schizophrenia. Olabi and colleagues¹³ systematically reviewed the literature and found that the differences between patients and controls in annualized percentage volume change were −0.07% for whole brain volume, −0.59% for whole brain grey matter, −0.32% for frontal white matter, −0.32% for parietal white matter, −0.39% for temporal white matter, and +0.36% for bilateral lateral ventricles.

Gradually, evidence began to accrue that antipsychotic drugs were associated with progressive reduction in grey matter volume, but relationships with the type or dose of drug, illness duration and site of apparent changes were very variable across studies. Very few studies had the power to detect the size of the effect.^14,15

One particularly notable study substantially added to the evidence that antipsychotic drugs might actually cause structural brain changes in schizophrenia. Ho and colleagues¹⁶ examined no fewer than 211 patients who each had an average of three structural magnetic resonance imaging (MRI) scans over an average of 7 years. These sequential MRI scanning investigations showed that patients with schizophrenia had an increase in lateral ventricular volume and a reduction in grey matter volume over time that was associated with increasing antipsychotic dose and the researchers could not find a similar relationship with illness features. There was also an apparent dose–response effect for lateral ventricular volumes, but the correlation between time on treatment and grey matter volume was stronger in those on an ‘intermediate dose’ (mean 392 mg chlorpromazine equivalents) than those on higher or lower doses.¹⁶

There are several other problems with this and similar studies. Such naturalistic studies may be subject to bias because patients with the best outcome may selectively stop antipsychotic treatment. In other words, antipsychotic dose and duration is increased in the most ill patients, who are also those most likely to show the greatest brain changes over time. Indeed, there is a well replicated association between progressive loss of grey matter and poor outcome, but none of those studies have examined any potentially mediating effect of antipsychotic drugs (see below).

Experimental evidence

Clearly, the only means by which to know for sure whether antipsychotic drugs cause structural brain changes in schizophrenia, over and above those associated with the illness and associated factors, is to conduct a RCT in patients and include serial structural MRI. This is however far easier said than done. To my knowledge, there are two such published accounts and both attest to the difficulties of such studies rather than delivering clear results. Leiberman and colleagues¹⁷ randomized 263 patients with first-episode psychosis to haloperidol or olanzapine and attempted to follow them up over two years. Haloperidol was associated with reduced whole brain and prefrontal grey matter volumes whereas olanzapine was not, and healthy controls showed some increases over time, but attrition from the trial was so high as to make the results impossible to interpret.

Roiz-Santianez and colleagues¹⁸ investigated the effects of risperidone (n = 16), olanzapine (n = 18) and low doses of haloperidol (n = 18) on cortical thickness changes during a 1-year follow-up period in a relatively small sample of patients with schizophrenia spectrum and found no significant differences between groups. Post hoc comparisons indicated that a control group had a thicker cortical thickness than the risperidone treatment group.

For ethical reasons, neither of these studies was able to include an untreated patient control group. These days, given the overwhelming evidence for the benefits of antipsychotic drugs in schizophrenia, it is only animal (or perhaps cellular) models that can incorporate such an untreated control arm. In a series of studies, researchers in Pittsburgh gave adolescent or young adult macaque monkeys differing antipsychotic medications for up to 2 years using drug administration paradigms at doses that produce trough serum drug levels in the range known to be therapeutic in humans.¹⁹ Chronic administration of either haloperidol or olanzapine was associated with smaller grey matter volume, lower glial cell number, and higher neuron density without a difference in total neuron number in the cerebral cortex, findings that parallel the results of postmortem schizophrenia studies.^20,21 These similarities support the interpretation that some of the alterations in brain morphology reported in schizophrenia are attributable to the effects of antipsychotic medication, but the changes (of about 8–10%) were greater than those typically reported even in chronic schizophrenia, the differences many other studies note between first- and second-generation antipsychotics were not evident, and one cannot rule out species effects.

Studies of rats have reached similar but different conclusions. Chronic (8 weeks) exposure to both haloperidol and olanzapine resulted in significant decreases in whole-brain volume (6–8%) compared with vehicle-treated control subjects, driven mainly by a decrease in frontal cerebral cortex volume (8–12%). Hippocampal, corpus striatum, lateral ventricles, and corpus callosum volumes were not significantly different from control subjects, suggesting a differential effect on the cortex. These results were corroborated by ex vivo MRI scans and decreased cortical volume was confirmed postmortem by stereology. However, further examination showed that in the anterior cingulate cortex (ACC) treatment had no effect on the total number of neurons or S100β+ astrocytes in the ACC; rather, an increase in the density of these cells was observed. Thus, whilst the available animal literature generally suggests an adverse effect of antipsychotic drugs on grey matter, the available studies do not agree on the cell populations implicated.^22,23

Known influences on brain structure in schizophrenia

One further group of studies is relevant; those that show the effects of other factors associated with schizophrenia on the structure of the brain. These factors include pre-illness developmental influences and risk factors for schizophrenia, as well as post-illness factors. There are in fact many of these and some of them have considerably stronger evidence for their effects on the brain in health and illnesses such as schizophrenia.

In our own work, as part of the Edinburgh High Risk Study of Schizophrenia (EHRS), we have shown the effects of family history, childhood maltreatment, alcohol and cannabis use on differences in several brain volumes between young people at elevated familial risk and healthy controls.^24–26 We have also shown, in a total of 434 structural MRI scans collected over 10 years, that reductions in prefrontal and temporal lobe volumes of about 1% per year are evident in those who go on to develop International Classification of Diseases (ICD)-10 schizophrenia from an average of 2.5 years before the onset of diagnosable disorder and that such changes correlate strongly with increasing symptom severity.²⁷ All of these changes occurred in untreated at risk individuals and so antipsychotic medication cannot be invoked as an explanation.

Longitudinal twin studies from Utrecht have also shown that whole brain volume reductions in patients are at least partly due to the heritability of the condition.²⁸ In addition, patients with first-episode psychosis who use cannabis show a greater grey matter volume reduction at 5-year follow up than patients who are nonusers and healthy controls.²⁹

It is also now clear that alcohol causes cortical shrinkage in healthy individuals even at low dosage.³⁰ Two notable studies have shown that effects are if anything greater in people with schizophrenia who drink to excess, especially in the prefrontal cortex.^31,32 Two recent systematic reviews strongly suggest that chronic cannabis use reduces grey matter in both healthy and clinical populations, especially in the CB1 receptor rich prefrontal cortex.^33,34 In addition, substance misuse (alcohol or drugs) in patients with schizophrenia has been shown to wipe out the relapse prevention benefits of adherence to antipsychotic medication.³⁵

The deleterious impact of relapses and the other benefits of antipsychotics

It is important that clinicians and patients realize the ongoing benefits of antipsychotic medication in schizophrenia and the dangers of stopping treatment.

It would be a great shame if, at most, suggestive evidence of grey matter reductions led to systematic undertreatment and an increase in attendant risks.

Psychiatrists tend to overestimate patients’ adherence to antipsychotic medication and numerous data suggest that 50% or more of patients with schizophrenia are poorly adherent or nonadherent.³⁶ Patients with partial or full nonadherence to antipsychotics are at significant risk of relapse. Discontinuation of antipsychotic medication after remission of first-episode psychosis or in established illness significantly increases the risk of relapse compared with maintenance therapy. Indeed, stopping antipsychotic medication is the most powerful predictor of relapse.³⁷

Gradual discontinuation may be associated with a lower rate of relapse compared with abrupt discontinuation³⁸ but even low doses of antipsychotics are associated with greater relapse rates than higher doses^39,40 and relapse rates are higher with intermittent treatment than continuous treatment.⁴¹

Relapse has a major negative impact on patients with schizophrenia and is associated with worse prognosis, worse cognitive function, risk of injury to self and others, risk of hospitalization, decreased quality of life and self-esteem, and reduced ability to regain previous levels of health, functioning and support.^42,43 For example, the diagnosis of schizophrenia at a young age makes it difficult to enter work, and frequent absences jeopardize job prospects. Having a job improves general and mental health and wellbeing, and people with schizophrenia who are employed are much more likely to achieve functional remission than those who are not.^44,45 Repeated relapses may also lead to reduced responsiveness or refractoriness to antipsychotic medication.^46,47 Relapse can therefore have devastating clinical consequences, which are likely to be of much greater consequence than some possible antipsychotic drug-mediated reduction in grey matter. Indeed, relapse and rehospitalization are themselves also associated with greater brain tissue loss.^48,49

One other major benefit of antipsychotic medications in schizophrenia deserves special mention: they save lives! On average, people with schizophrenia die 14.5 years earlier than the general population, with 60% of excess deaths due to suicide and accidents, and 40% to natural causes.⁵⁰ Reasons for the excess natural deaths include lifestyle issues (e.g. high rates of smoking, possible self neglect, lack of exercise), and reduced access to healthcare services.⁵¹ The available RCT evidence suggests antipsychotic treatment reduces mortality overall,^5,52 but death is thankfully such a rare event in trials that observational studies have to be relied upon to answer this question. Several longitudinal studies in several countries and healthcare settings have found a lower risk of mortality in antipsychotic-treated patients with schizophrenia compared with untreated patients.^53,54

Concluding remarks

RCTs have established beyond any reasonable doubt that antipsychotic medication is highly effective in treating the acute symptoms of schizophrenia and reducing relapse. They also seem highly likely to generally improve function and quality of life, and prolong life, despite notable adverse effects. Overall, antipsychotic drugs do far more good than harm in patients with schizophrenia. They also have an increasingly clear role in the management of bipolar disorder.

However, antipsychotics are often inappropriate and may be damaging if used in some other psychotic disorders (e.g. brief psychotic disorder, psychotic disorder due to a general medical condition, substance-induced psychotic disorders), and approximately 20% of patients with schizophrenia do not need antipsychotic treatment beyond at most a short period. Predicting which patients fall into this category is at present not possible. The judicious management of patients with schizophrenia remains, therefore, aiming to maintain patients on the lowest possible effective dose. RCT evidence supports treating most patients for 1–2 years after they have responded to treatment for an acute episode. Clinical practice suggests that once they are stable the dose can be reduced cautiously, perhaps in increments every 3 months or so, to allow time for the dose to be increased again if needed. Patients with schizophrenia should be made aware that stopping antipsychotic medication is the most powerful predictor of relapse.

Systematic reviews and meta-analyses have established that there is progressive loss of grey and white matter in patients with schizophrenia, and suggest that antipsychotic medication may contribute to this. However, the available patient studies are inconsistent as to whether grey or white matter is particularly affected and whether first- or second-generation antipsychotic drugs are implicated. Such observational studies are prone to many biases and, unlike RCTs, cannot show a causal relationship. Experimental studies in animals suggest an effect, but the cell populations affected are inconsistent. Overall, the evidence is inconclusive. There is much more consistent and convincing evidence that other factors, including stress, alcohol and cannabis, contribute to progressive loss of brain substance in humans and animals.

The broader literature on the cognitive and imaging effects of antipsychotics in schizophrenia also argues against a generally noxious influence. Systematic reviews have shown that initiating antipsychotic treatment in patients with first-episode psychosis produces sustained cognitive improvement for up to 2 years.^55,56 Similarly, the bulk of the functional imaging literature suggests that antipsychotics normalize activation and connectivity patterns in patients with schizophrenia.^57,58

The same benefits seems to accrue in spectroscopy studies.^59,60 It is difficult to see how antipsychotic medication can normalize functional measures and yet have an apparently adversely impact on brain structure, but some studies suggest exactly that.⁶¹ One possible interpretation is that brain structure actually increases during an acute psychotic episode, possibly through inflammatory processes, and that a reduction is in fact a normalization. Another is that there may be a subgroup who show reductions, possibly those who do not benefit clinically from antipsychotic drugs because they have a different (nonhyper-dopaminergic) pathophysiology or because they have dopamine supersensitivity.

Or perhaps it is those on the highest doses who are rendered so immobile or sedated as to be able to do little in the way of everyday activities and therefore show a ‘disuse atrophy’ of grey and white matter through reduced dendritic arborization or myelin sheath thickness.

Another critical piece of the puzzle, is that (as far as I am aware) there have been no studies which have shown antipsychotic drugs to adversely impact on brain structure and to have adverse functional effects. It is clear that patients with schizophrenia who have the greatest loss of grey matter over time tend to have the worst outcome,^62,63 but there is no clear evidence that antipsychotic medication rather than some other factors are responsible.

To sum up, there is currently insufficient evidence to conclude that antipsychotics cause brain tissue loss in schizophrenia. There are other more likely causes. There is no clear relationship between antipsychotic-induced brain changes and cognitive impairment or functional decline. The matter can likely only be finally settled by suitably large and placebo-controlled trials of patients on or off antipsychotic medication with serial imaging investigations.

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement

The authors declare that there is no conflict of interest.

ORCID iD

Stephen M. Lawrie

References

van Os

Kapur

Schizophrenia. Lancet 2009; 374: 635–645.

Jääskeläinen

Juola

Hirvonen

et al . A systematic review and meta-analysis of recovery in schizophrenia. Schizophr Bull 2012; 39: 1296–1306.

Morgan

Lappin

Heslin

et al . Reappraising the long-term course and outcome of psychotic disorders: the AESOP-10 study. Psychol Med 2014; 44: 2713–2726.

Leucht

Huhn

et al . Sixty years of placebo-controlled antipsychotic drug trials in acute schizophrenia: systematic review, Bayesian meta-analysis, and meta-regression of efficacy predictors. Am J Psychiatry 2017; 174: 927–942.

Leucht

Tardy

Komossa

et al . Antipsychotic drugs versus placebo for relapse prevention in schizophrenia: a systematic review and meta-analysis. Lancet 2012; 379: 2063–2071.

Leucht

Hierl

Kissling

et al . Putting the efficacy of psychiatric and general medicine medication into perspective: review of meta-analyses. Br J Psychiatry 2012; 200: 97–106.

Leucht

Tardy

Komossa

et al . Maintenance treatment with antipsychotic drugs for schizophrenia. Cochrane Database Syst Rev 2012; 5: CD008016.

Ran

M-S

Weng

Chan

CL-W

et al . Different outcomes of never-treated and treated patients with schizophrenia: 14-year follow-up study in rural China. Br J Psychiatry 2015; 207: 495–500.

Wunderink

Nieboer

Wiersma

et al . Recovery in remitted first-episode psychosis at 7 years of follow-up of an early dose reduction/discontinuation or maintenance treatment strategy: long-term follow-up of a 2-year randomized clinical trial. JAMA Psychiatry 2013; 70: 913–920.

10.

Lawrie

Abukmeil

SS.

Brain abnormality in schizophrenia. A systematic and quantitative review of volumetric magnetic resonance imaging studies. Br J Psychiatry 1998; 172: 110–120.

11.

Wright

Rabe-Hesketh

Woodruff

et al . Meta-analysis of regional brain volumes in schizophrenia. Am J Psychiatry 2000; 157: 16–25.

12.

Haijma

Van Haren

Cahn

et al . Brain volumes in schizophrenia: a meta-analysis in over 18 000 subjects. Schizophr Bull 2012; 39: 1129–1138.

13.

Olabi

Ellison-Wright

McIntosh

et al . Are there progressive brain changes in schizophrenia? A meta-analysis of structural magnetic resonance imaging studies. Biol Psychiatry 2011; 70: 88–96.

14.

Fusar-Poli

Smieskova

Kempton

et al . Progressive brain changes in schizophrenia related to antipsychotic treatment? A meta-analysis of longitudinal MRI studies. Neurosci Biobehav Rev 2013; 37: 1680–1691.

15.

Vita

De Peri

Deste

et al . The effect of antipsychotic treatment on cortical gray matter changes in schizophrenia: does the class matter? A meta-analysis and meta-regression of longitudinal magnetic resonance imaging studies. Biol Psychiatry 2015; 78: 403–412.

16.

B-C

Andreasen

Ziebell

et al . Long-term antipsychotic treatment and brain volumes: a longitudinal study of first-episode schizophrenia. Arch Gen Psychiatry 2011; 68: 128–137.

17.

Lieberman

Tollefson

Charles

et al . Antipsychotic drug effects on brain morphology in first-episode psychosis. Arch Gen Psychiatry 2005; 62: 361–370.

18.

Roiz-Santiáñez

Tordesillas-Gutiérrez

de la Foz

VO-G

et al . Effect of antipsychotic drugs on cortical thickness. A randomized controlled one-year follow-up study of haloperidol, risperidone and olanzapine. Schizophr Res 2012; 141: 22–28.

19.

Dorph-Petersen

K-A

Pierri

Perel

et al . The influence of chronic exposure to antipsychotic medications on brain size before and after tissue fixation: a comparison of haloperidol and olanzapine in macaque monkeys. Neuropsychopharmacology 2005; 30: 1649–1661.

20.

Konopaske

Dorph-Petersen

K-A

Pierri

et al . Effect of chronic exposure to antipsychotic medication on cell numbers in the parietal cortex of macaque monkeys. Neuropsychopharmacology 2007; 32: 1216–1223.

21.

Konopaske

Dorph-Petersen

K-A

Sweet

et al . Effect of chronic antipsychotic exposure on astrocyte and oligodendrocyte numbers in macaque monkeys. Biol Psychiatry 2008; 63: 759–765.

22.

Vernon

Natesan

Modo

et al . Effect of chronic antipsychotic treatment on brain structure: a serial magnetic resonance imaging study with ex vivo and postmortem confirmation. Biol Psychiatry 2011; 69: 936–944.

23.

Vernon

Crum

Lerch

et al . Reduced cortical volume and elevated astrocyte density in rats chronically treated with antipsychotic drugs—linking magnetic resonance imaging findings to cellular pathology. Biol Psychiatry 2014; 75: 982–990.

24.

Welch

Moorhead

McIntosh

et al . Tensor-based morphometry of cannabis use on brain structure in individuals at elevated genetic risk of schizophrenia. Psychol Med 2013; 43: 2087–2096.

25.

Welch

McIntosh

Job

et al . The impact of substance use on brain structure in people at high risk of developing schizophrenia. Schizophr Bull 2010; 37: 1066–1076.

26.

Barker

Bois

Johnstone

et al . Childhood adversity and cortical thickness and surface area in a population at familial high risk of schizophrenia. Psychol Med 2016; 46: 891–896.

27.

McIntosh

Owens

Moorhead

et al . Longitudinal volume reductions in people at high genetic risk of schizophrenia as they develop psychosis. Biol Psychiatry 2011; 69: 953–958.

28.

Brans

van Haren

van Baal

GCM

et al . Heritability of changes in brain volume over time in twin pairs discordant for schizophrenia. Arch Gen Psychiatry 2008; 65: 1259–1268.

29.

Rais

Cahn

Van Haren

et al . Excessive brain volume loss over time in cannabis-using first-episode schizophrenia patients. Am J Psychiatry 2008; 165: 490–496.

30.

Topiwala

Allan

Valkanova

et al . Moderate alcohol consumption as risk factor for adverse brain outcomes and cognitive decline: longitudinal cohort study. BMJ 2017; 357: j2353.

31.

Mathalon

Pfefferbaum

Lim

et al . Compounded brain volume deficits in schizophrenia-alcoholism comorbidity. Arch Gen Psychiatry 2003; 60: 245–252.

32.

Sullivan

Pfefferbaum

Neurocircuitry in alcoholism: a substrate of disruption and repair. Psychopharmacology (Berl) 2005; 180: 583–594.

33.

Rapp

Bugra

Riecher-Rossler

et al . Effects of cannabis use on human brain structure in psychosis: a systematic review combining in vivo structural neuroimaging and post mortem studies. Curr Pharmac Des 2012; 18: 5070–5080.

34.

Batalla

Bhattacharyya

Yücel

et al . Structural and functional imaging studies in chronic cannabis users: a systematic review of adolescent and adult findings. PLoS One 2013; 8: e55821.

35.

Hunt

Bergen

Bashir

Medication compliance and comorbid substance abuse in schizophrenia: impact on community survival 4 years after a relapse. Schizophr Res 2002; 54: 253–264.

36.

Kane

Kishimoto

Correll

CU.

Non-adherence to medication in patients with psychotic disorders: epidemiology, contributing factors and management strategies. World Psychiatry 2013; 12: 216–226.

37.

Robinson

Woerner

Alvir

JMJ

et al . Predictors of relapse following response from a first episode of schizophrenia or schizoaffective disorder. Arch Gen Psychiatry 1999; 56: 241–247.

38.

Viguera

Baldessarini

Hegarty

et al . Clinical risk following abrupt and gradual withdrawal of maintenance neuroleptic treatment. Arch Gen Psychiatry 1997; 54: 49–55.

39.

Kane

JM.

Schizophrenia. N Engl J Med 1996; 334: 34–42.

40.

Wang

C-Y

Xiang

Y-T

Cai

Z-J

et al . Risperidone maintenance treatment in schizophrenia: a randomized, controlled trial. Am J Psychiatry 2010; 167: 676–685.

41.

Gaebel

Riesbeck

Wölwer

et al . Relapse prevention in first-episode schizophrenia–maintenance vs intermittent drug treatment with prodrome-based early intervention: results of a randomized controlled trial within the German Research Network on Schizophrenia. J Clin Psychiatry 2011; 72: 205–218.

42.

Almond

Knapp

Francois

et al . Relapse in schizophrenia: costs, clinical outcomes and quality of life. Br J Psychiatry 2004; 184: 346–351.

43.

Taylor

Chaudhry

Cross

et al . Towards consensus in the long-term management of relapse prevention in schizophrenia. Hum Psychopharmacol 2005; 20: 175–181.

44.

Taskila

Steadman

Gulliford

et al . Working with schizophrenia: experts’ views on barriers and pathways to employment and job retention. J Vocat Rehabil 2014; 41: 29–44.

45.

Haro

Novick

Bertsch

et al . Cross-national clinical and functional remission rates: Worldwide Schizophrenia Outpatient Health Outcomes (W-SOHO) study. Br J Psychiatry 2011; 199: 194–201.

46.

Emsley

Oosthuizen

Koen

et al . Comparison of treatment response in second-episode versus first-episode schizophrenia. J Clin Psychopharmacol 2013; 33: 80–83.

47.

Ohmori

Ito

Abekawa

et al . Psychotic relapse and maintenance therapy in paranoid schizophrenia: a 15 year follow up. Eur Arch Psychiatry Clin Neurosci 1999; 249: 73–78.

48.

van Haren

Pol

HEH

Schnack

et al . Focal gray matter changes in schizophrenia across the course of the illness: a 5-year follow-up study. Neuropsychopharmacology 2007; 32: 2057–2066.

49.

Andreasen

Liu

Ziebell

et al . Relapse duration, treatment intensity, and brain tissue loss in schizophrenia: a prospective longitudinal MRI study. Am J Psychiatry 2013; 170: 609–615.

50.

Hjorthøj

Stürup

McGrath

et al . Years of potential life lost and life expectancy in schizophrenia: a systematic review and meta-analysis. Lancet Psychiatry 2017; 4: 295–301.

51.

Lawrence

Coghlan

Health inequalities and the health needs of people with mental illness. NSW Public Health Bull 2002; 13(7): 155–158.

52.

Isaac

Koch

The risk of death among adult participants in trials of antipsychotic drugs in schizophrenia. Eur Neuropsychopharmacol 2010; 20: 139–145.

53.

Tiihonen

Lönnqvist

Wahlbeck

et al . 11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study). Lancet 2009; 374: 620–627.

54.

Vermeulen

van Rooijen

Doedens

et al . Antipsychotic medication and long-term mortality risk in patients with schizophrenia; a systematic review and meta-analysis. Psychol Med 2017; 47: 2217–2228.

55.

Bora

Murray

RM.

Meta-analysis of cognitive deficits in ultra-high risk to psychosis and first-episode psychosis: do the cognitive deficits progress over, or after, the onset of psychosis?

Schizophr Bull 2013; 40: 744–755.

56.

Karson

Duffy

Eramo

et al . Long-term outcomes of antipsychotic treatment in patients with first-episode schizophrenia: a systematic review. Neuropsychiatr Dis Treat 2016; 12: 57.

57.

Davis

Jeste

Eyler

LT.

Review of longitudinal functional neuroimaging studies of drug treatments in patients with schizophrenia. Schizophr Res 2005; 78: 45–60.

58.

Schmidt

Smieskova

Aston

et al . Brain connectivity abnormalities predating the onset of psychosis: correlation with the effect of medication. JAMA psychiatry 2013; 70: 903–912.

59.

Jayakumar

Gangadhar

Venkatasubramanian

et al . High energy phosphate abnormalities normalize after antipsychotic treatment in schizophrenia: a longitudinal 31 P MRS study of basal ganglia. Psychiatry Res 2010; 181: 237–240.

60.

Schwerk

Alves

Pouwels

et al . Metabolic alterations associated with schizophrenia: a critical evaluation of proton magnetic resonance spectroscopy studies. J Neurochem 2014; 128: 1–87.

61.

Lesh

Tanase

Geib

et al . A multimodal analysis of antipsychotic effects on brain structure and function in first-episode schizophrenia. JAMA Psychiatry 2015; 72: 226–234.

62.

Lieberman

Chakos

et al . Longitudinal study of brain morphology in first episode schizophrenia. Biol Psychiatry 2001; 49: 487–499.

63.

Dazzan

Arango

Fleischacker

et al . Magnetic resonance imaging and the prediction of outcome in first-episode schizophrenia: a review of current evidence and directions for future research. Schizophr Bull 2015; 41: 574–583.