Physical health

People with schizophrenia die earlier than the rest of the population. ^{Reference Walker, McGee and Druss5,Reference Brown, Kim, Mitchell and Inskip6} Studies from several countries show that the trend of mortality rates in people with psychosis has not followed the same downward course as that of the general population, resulting in a widening disparity. ^{Reference Hoang, Stewart and Goldacre7–Reference Laursen, Nordentoft and Mortensen10}

Suicide accounts for part of the excess mortality, although the most obvious remediable cause is the excessive use of tobacco; illicit drug use, poor diet and lack of exercise are also implicated. However, the possibility that antipsychotics also contribute has attracted much attention recently. Antipsychotics can cause cardiac arrhythmias ^{Reference Frommeyer and Eckardt11,Reference Ray, Chung, Murray, Hall and Stein12} and induce dyslipidaemia and obesity, with activation of the cascade towards insulin resistance and diabetes. ^{Reference Henderson, Vincenzi, Andrea, Ulloa and Copeland13–Reference De Hert, Detraux, van Winkel, Yu and Correll15} Most second-generation antipsychotics (SGAs) confer a higher cardiometabolic risk than first-generation antipsychotics (FGAs), and some authors point out that the switch to SGAs from the mid-1990s has paralleled the widening of the mortality gap. ^{Reference Saha, Chant and McGrath8}

However, there is still dispute over whether long-term antipsychotic prescription actually increases overall mortality. For example, data from Swedish nationwide registers show a lower mortality in patients with chronic schizophrenia receiving long-term antipsychotics than in those with similar duration of illness but no antipsychotic exposure. ^{Reference Torniainen, Mittendorfer-Rutz, Tanskanen, Bjorkenstam, Suvisaari and Alexanderson16} It could be that antipsychotics reduce suicides or facilitate better self-care – or simply, as Mace et al ^{Reference Mace, Dzahini, Cornelius, Anthony, Stewart and Taylor17} suggest, that taking antipsychotics ‘may be a surrogate marker for overall healthy behaviour’.

Structural brain changes

Many people with schizophrenia show subtle developmental brain abnormalities at the onset of their illness. ^{Reference Murray and Lewis18} However, further brain changes occur in the years following the onset of the illness. These were interpreted initially as reflecting an intrinsic degenerative schizophrenic process. ^{Reference van Haren, Cahn, Hulshoff Pol and Kahn19} However, a number of reports have concluded that the majority, if not all, of these brain changes are a consequence of environmental factors; among these factors are antipsychotic medication, ^{Reference Navari and Dazzan20–Reference Vita, De Peri, Deste and Sacchetti23} illicit drug use, ^{Reference Rais, Cahn, van Haren, Schnack, Caspers and Hulshoff Pol24} cigarette smoking, ^{Reference Karama, Ducharme, Corley, Chouinard-Decorte, Starr and Wardlaw25} obesity and diabetes. ^{Reference Katon, Pedersen, Ribe, Fenger-Gron, Davydow and Waldorff26} Animal studies have confirmed the effects of antipsychotics in decreasing cortical volume and have shown, at least in monkeys and rats, that the changes are not due to a loss of neurons. ^{Reference Dorph-Petersen, Pierri, Perel, Sun, Sampson and Lewis27–Reference Konopaske, Dorph-Petersen, Pierri, Wu, Sampson and Lewis29}

Do antipsychotics improve long-term outcomes?

Many RCTs have compared outcomes in those patients with schizophrenia continuing antipsychotics with those in whom the drugs were stopped. These ‘discontinuation’ studies uniformly show a greater likelihood of relapse in the latter group. ^{Reference Taylor, Cavanagh, Hodgson and Tiihonen36} Thus, a meta-analysis of 65 trials ^{Reference Leucht, Tardy, Komossa, Heres, Kissling and Salanti3} concluded that ‘antipsychotic maintenance treatment substantially reduces relapse risk in all patients with schizophrenia for up to 2 years of follow-up’. However, few studies have lasted longer than this, leading Leucht et al to point out that ‘nothing is known about the very long-term effects of antipsychotic drugs compared to placebo’. ^{Reference Leucht, Tardy, Komossa, Heres, Kissling and Davis37} Thus, long-term ‘maintenance’ treatment with antipsychotics is based on hope rather than evidence.

New studies have shed light on this issue. Harrow ^{Reference Harrow, Jobe and Faull38} repeatedly assessed the course of 70 young patients diagnosed with schizophrenia. Those 15 not prescribed antipsychotics over the 20 years showed significantly fewer psychotic symptoms than those 25 continuously on antipsychotics. Moilanen and colleagues, ^{Reference Moilanen, Haapea, Miettunen, Jaaskelainen, Veijola and Isohanni39} who followed up 74 patients with first-episode psychosis (FEP) in Finland, reported that after 10 years, the 24 not receiving medication had better clinical outcomes than those receiving antipsychotics. At the ten-year follow-up of 274 FEP patients in the UK ÆSOP sample, ^{Reference Morgan, Lappin, Heslin, Donoghue, Lomas and Reininghaus40} Morgan (personal communication, 2016) found that 18% of those who received a diagnosis of schizophrenia had not taken antipsychotics for two years and had no psychotic symptoms. Similarly, Wils & Nordentoft (unpublished, further details available from M.N. on request) followed up 496 patients from the Danish OPUS study for 10 years after their first episode of schizophrenia spectrum disorder; 30% had remission of psychotic symptoms and were not taking antipsychotics.

There is a major confounder in all these studies, in that they were without randomisation. Consequently, those patients who were able to stop their medication may have had a milder illness than those who continued. Nevertheless, these studies demonstrate that a significant proportion of patients with psychosis manage to come off antipsychotic medication without detriment in the long term.

In a study less open to bias, Wunderink and colleagues selected a group of FEP patients who had been initially treated successfully with antipsychotics. After 6 months of remission, they were randomised for 18 months to either (a) an approach encouraging antipsychotic dose reduction or discontinuation; or (b) standard maintenance treatment: 18 months later, as expected, twice as many people had experienced a relapse in the reduction/discontinuation group as in the maintenance group. ^{Reference Wunderink, Nienhuis, Sytema, Slooff, Knegtering and Wiersma41} However, by 7 years, the group who had been initially helped to reduce or discontinue their antipsychotics were reported to show twice the recovery rate of the maintenance patients. ^{Reference Wunderink, Nieboer, Wiersma, Sytema and Nienhuis42}

Dopamine receptor supersensitivity

The findings of Wunderink are curious and require some explanation. Why should antipsychotics be beneficial for up to 18 months but not at 7 years? Could it be that by then, antipsychotics have lost some of their effectiveness? To examine this possibility, we need to consider the mechanism of action of antipsychotics. All antipsychotics share the same essential property – they block D₂ and D₃ dopamine receptors. For many years, it was thought that the abnormality in schizophrenia lay in these receptors, and therefore it seemed logical to block them. However, it is now clear that most acutely psychotic patients show excessive presynaptic synthesis of dopamine in the striatum. ^{Reference Howes and Murray44} Thus, antipsychotics do not address the primary locus of abnormality but rather have their beneficial effects downstream of it. Is it possible that prolonged prescription of antipsychotics sometimes induces changes in the D₂/D₃ receptor, which diminish the effectiveness of the drugs?

Animal studies suggest that this may be the case. ^{Reference Smith and Davis45,Reference Grace46} Thus, Samaha et al found that, with continuous administration, haloperidol and olanzapine progressively lost their efficacy in suppressing amphetamine-induced locomotion and conditioned avoidance in rats; this was reversed temporarily by a further increase in antipsychotic dose. Antipsychotic failure was linked to a 20–40% increase in post-synaptic D₂/D₃ receptor density. ^{Reference Samaha, Seeman, Stewart, Rajabi and Kapur47} Ginovart et al ^{Reference Ginovart, Wilson, Hussey, Houle and Kapur48} subsequently showed that high-dose antipsychotics lead to such an upregulation of D₂/D₃ receptors in cats; however, this did not occur with occupancy below 80% or with transient occupancy. Thus, D₂/D₃ upregulation may be a consequence of high-dose treatment. ^{Reference Ginovart, Wilson, Hussey, Houle and Kapur48}

Post-mortem studies show increased D₂/D₃ receptor density in the brains of people with schizophrenia; however, most of the patients in these studies had been on long-term antipsychotics. ^{Reference Zakzanis and Hansen49} A meta-analysis of in vivo positron emission tomography (PET) and single-photon emission computed tomography (SPECT) studies ^{Reference Howes, Kambeitz, Kim, Stahl, Slifstein and Abi-Dargham50} demonstrated that patients who had previously received antipsychotics had an increase in D₂/D₃ receptor availability, but, importantly, antipsychotic-naive patients were no different from controls. One PET study showed D₂/D₃ receptor availability greater by 30% in patients who had received long-term dopamine antagonists relative to antipsychotic-naive patients. ^{Reference Silvestri, Seeman, Negrete, Houle, Shammi and Remington51}

There have only been two longitudinal studies. Konig et al showed a 10% increase in D₂/D₃ receptor availability over 2 months in one patient treated with huge doses of chlorpromazine. ^{Reference Konig, Benzer and Fritzche52} A more recent study, ^{Reference Mizrahi, Agid, Borlido, Suridjan, Rusjan and Houle53} which scanned eight antipsychotic-naive FEP patients, showed no elevation in D₂/D₃ receptor availability at baseline, but after 2–3 weeks of treatment (olanzapine 10 mg/day or risperidone 2–3 mg/day) there was an increase in D₂/D₃ receptors in some brain regions.

The idea that antipsychotics could induce supersensitivity of the D₂/D₃ receptor in some patients has been championed by Chouinard and colleagues, ^{Reference Chouinard, Jones and Annable54,Reference Chouinard and Chouinard55} who pointed out as early as 1978 that antipsychotics induce a syndrome of supersensitivity of the motor system – tardive dyskinesia – and described what they termed ‘drug-induced psychotic relapses’ associated with tardive dyskinesia after long-term high doses of FGAs. ^{Reference Chouinard, Annable and Ross-Chouinard56} They proposed that this supersensitivity causes tolerance to antipsychotics, such that eventually they no longer control psychotic symptoms. This is supported by a follow-up study of a cohort of 8620 patients, which reported worsening of psychosis with the onset of tardive dyskinesia. ^{Reference Tenback, van Harten, Slooff and van Os57}

The evidence of antipsychotic-induced changes in the D₂ receptor points to an intrinsic problem with discontinuation studies. This was noted by Carpenter and colleagues when they stated that ‘once patients are placed on medication, they are less vulnerable to relapse if maintained on neuroleptics. But what if these patients had never been treated with drugs to begin with? We raise the possibility that antipsychotic medication may make some schizophrenic patients more vulnerable to future relapse than would be the case in the natural course of the illness’. ^{Reference Carpenter, McGlashan and Strauss58}

Moncrieff, who carried out a meta-analysis of patient withdrawal studies, concluded that ‘antipsychotic discontinuation may also increase the risk of relapse over and above the risk because of the underlying disorder’. ^{Reference Moncrieff59} Interestingly, there have been occasional reports of withdrawal psychosis occurring in people who have never had psychiatric problems but have been prescribed D₂ blockers for other reasons. ^{Reference Roy-Desruisseaux, Landry, Bocti, Tessier, Hottin and Trudel60–Reference Seeman62}

Unfortunately, there are no clinical studies examining whether relapse following antipsychotic withdrawal is linked to D₂/D₃ receptor changes. However, Joyce, who gave haloperidol to rats for 9 months, showed that the increase in D₂ receptors persisted for at least 2 months after stopping antipsychotics. ^{Reference Joyce63} Converting rat months to their human equivalent, this would imply a period of increased vulnerability in patients following discontinuation of antipsychotics of more than a year. ^{Reference Quinn64} Such a vulnerability period would be consistent with views expressed by patient groups such as the Hearing Voices Network. ^{Reference Corstens, Longden, McCarthy-Jones, Waddingham and Thomas65} They remind us that that many people diagnosed as having schizophrenia have successfully come off their antipsychotics, ^{Reference Corstens, Longden, Rydinger, Bentall and van Os66} but point out that this can be initially difficult owing to agitation, insomnia and indeed recurrence of psychotic symptoms.

Treatment-resistant schizophrenia

In contrast to patients who respond to dopamine D₂ blockers, neurochemical imaging shows that a proportion of patients with TRS do not show any abnormality of dopamine synthesis. It appears that such patients have generally never responded to D₂ blockers because they have nothing intrinsically wrong with their dopamine system. ^{Reference Demjaha, Egerton, Murray, Kapur, Howes and Stone69,Reference Demjaha, Murray, McGuire, Kapur and Howes70}

A second group of TRS patients have initially responded to antipsychotics but gradually lose this responsiveness. Several Japanese groups ^{Reference Suzuki, Kanahara, Yamanaka, Takase, Kimura and Watanabe71,Reference Oda, Kanahara and Iyo72} have suggested that supersensitivity due to upregulation of D₂ receptors may be the cause of this treatment resistance. Here, it is worth pondering why clozapine is the most effective treatment for patients with TRS, when it is not especially effective for patients with FEP. ^{Reference Girgis, Phillips, Li, Li, Jiang and Wu73} Chouinard's idea that dopamine supersensitivity underlies both tardive dyskinesia and TRS reminds us that one of the most effective treatments for tardive dyskinesia is clozapine. Clozapine, of course, produces lower and more transient D₂/D₃ receptor occupancy than most other antipsychotics. ^{Reference Howes, Egerton, Allan, McGuire, Stokes and Kapur74} This allows the dopamine supersensitivity of the motor system to gradually resolve, and tardive dyskinesia to slowly fade. Is it possible that the effectiveness of clozapine for some patients with TRS relies on a similar mechanism?