Increasing expectations and knowledge require a more subtle use of prophylactic antipsychotics

Those who comment on the use of antipsychotics in 2018 face two challenges. The first stems from rising expectations. The move from incarceration of psychotic people in asylums to care in the community has transformed the lives of many in Western European countries. Undoubtedly, antipsychotics played a major role in facilitating this. Furthermore, there is overwhelming evidence that antipsychotics are essential in acute psychosis and that many patients will benefit from taking them for a period thereafter.

However, as care has improved, so expectations of recovery have increased. This has been accompanied by calls for patients and relatives to have a greater voice in planning care. In some countries, their representatives have been incorporated into policy making1. In others, patients have been relegated to shouting their criticisms from offstage. One example of the latter is the website “Mad in America” (https://www.madinamerica.com); a brief look should cause any psychiatrist to reflect on why antipsychotics attract such opprobrium from many of those they are intended to help.

It is in this context that the prescription of antipsychotics for prevention of recurrence, rather than treatment of active symptoms, should be considered. Drugs intended to be taken prophylactically need to be extremely safe and tolerable; witness the arguments concerning the pros and cons of statins. In recent years, concern has been raised about the risk/benefit ratio of prophylactic antipsychotics2. The paper by Correll et al3 is the second of two responses from the psychopharmacological establishment, and takes a less dogmatic approach than its predecessor4.

Correll et al accept that most antipsychotics increase the risk of obesity and the metabolic syndrome. Their review addresses, but fails to resolve, the paradox that we clinicians commonly see the adverse effects of antipsychotics on the physical health of our patients, yet mortality appears to be lower in those patients who take rather than do not take antipsychotics (at least for those who receive low or moderate doses)5. Fortunately, we are now better able to minimize metabolic effects by prescribing antipsychotics with lower propensity to weight gain.

The coverage of the worrying issue of the effects of antipsychotics on brain structure is less satisfactory. Correll et al too readily dismiss the evidence that prolonged antipsychotic use is associated with decreased grey matter and fail to cite the monkey and rodent studies in which administration of antipsychotics causes brain volume losses4. This is an unresolved issue that deserves intensive investigation rather than bland reassurances.

The second challenge to traditional practice comes from the explosion in knowledge about psychosis since the prophylactic use of antipsychotics was introduced in the 1970s. Then schizophrenia was considered a discrete neurodegenerative disease. Now we know that schizophrenia is the severe end of a continuum of psychosis, and that the final common pathway underlying positive symptoms is dopamine dysregulation6. We used to think that dopamine blockade addressed the locus of abnormality in the D2 receptor, but it is now clear that the primary problem in most patients is presynaptic: they synthesize excessive striatal dopamine. Antipsychotics block the effect of the released dopamine and thus diminish aberrant perceptions secondary to increased salience. They do little for established delusions; neither do they help negative symptoms or cognitive dysfunction: indeed, there is considerable evidence that high doses impair both of these.

We now also know that many of the environmental risk factors for psychosis (e.g., child abuse, migration) increase striatal dopamine synthesis, and that people with schizophrenia show greater dopamine release in response to everyday hassles6, 7. Furthermore, as people become ill, the stress caused by the psychosis itself (e.g., by beliefs that they may be harmed) and its consequences (e.g., compulsory hospitalization) likely result in further release of dopamine, and thus more abnormal salience and worsening psychosis6.

Care must therefore include efforts to minimize stresses and find an appropriate social niche for patients, to facilitate decrease in dopamine synthesis. Psychological treatments, including cognitive‐behavioural and cognitive remediation therapies, possibly the newer avatar therapy, and last but not least physical exercise, should also be available. Unfortunately, too often sufferers languish in hostels full of drug takers in the worst parts of town; or they are homeless or in jail, situations that we psychiatrists would have difficulty in coping with, let alone those with increased sensitivity to stress.

Advances in understanding the genetic architecture of schizophrenia have demonstrated shared genes with bipolar disorder and also with depression, post‐traumatic stress disorder and anxiety disorders8. This should not surprise clinicians who have noted that many people with a diagnosis of schizophrenia also suffer from mood swings, or find anxiety and depression as disabling as positive symptoms. Mood stabilizers, antidepressants and psychological treatments can ameliorate these and lessen the drive to psychosis.

Given that hard evidence for the benefits of antipsychotics extends only to about two years, what to do in the long‐term requires further research. Much effort has been expended by pharmaceutical companies emphasizing the importance of adherence to antipsychotics. Less attention has focused on the value of moderate and rational prescribing. As a result, many patients receive excessive doses of D2 blockers for prolonged periods. Correll et al note that many recovered patients are able to remain well on doses of antipsychotics smaller than that which was needed in the acute episode (though they say not less than 50%). Guidelines need to be developed on when and how slowly to reduce antipsychotics, and in whom it is appropriate to eventually stop them.

In their initial trial of the prophylactic use of antipsychotics, Leff and Wing9 reported that these were helpful to patients with a moderate, but not those with a very good, outlook. Similarly, Correll et al accept that a significant minority of people who receive the diagnosis of schizophrenia (perhaps up to 20%) will be able to come off the drugs without disadvantage, probably because they have milder illnesses.

Leff and Wing9 also noted that those with a very poor outcome do not benefit from continued antipsychotics. The reason that such individuals are treatment resistant is because they do not synthesize excessive striatal dopamine6. There appear to be two types of treatment resistance10. First, those who have never responded to antipsychotics and whose psychosis may not involve dopamine dysregulation. Second, those who once responded to D2 blockers but have lost this ability, possibly due to the development of dopamine supersensitivity. Correll et al ignore the evidence that prolonged administration of antipsychotics to animals cause an increase in D2 receptor numbers, and that the resultant dopamine supersensitivity causes antipsychotics to lose their efficacy2. They do, however, cite reports that partial dopamine agonists may have less propensity to cause dopamine supersensitivity. Once again this is an issue that demands further investigation.

Finally, we psychiatrists need to reach out to our patients and to those groups critical of antipsychotic prescribing. Doctors and patients may have different priorities; patients may put more emphasis on remaining slim rather than having voices totally eradicated, or may consider it more important to be alert enough to work rather than to have conventional thoughts. In the absence of such conversations, patients may become disillusioned with psychiatry and rely on alternatives such as the Hearing Voices Network or therapies without any evidence base.

Robin M. Murray, Marta Di Forti
Institute of Psychiatry, Psychology and Neuroscience, King's College, London, UK