Controversial issues in the management of schizophrenia

Controversial issues in the management of schizophrenia — brain shrinkage, dopamine supersensitivity, antipsychotic maintenance therapy, and treatment resistance — were examined in the light of the evidence by experts for a large audience at CINP 2018. The overall conclusions were: antipsychotics do not cause brain shrinkage; dopamine supersensitivity results from chronic treatment with D2 receptor antagonists and may be stabilized by D2 partial agonist antipsychotic therapy; maintenance antipsychotic therapy is necessary to prevent relapse and improve outcome; and more research is needed to understand treatment resistance, but it is important to exclude pseudo-resistance due to medication non-adherence.


Brain volume loss in schizophrenia is related to poor outcome

Brain shrinkage in schizophrenia is characterized by decreased gray matter and cortical volume and enlarged ventricles, explained Rene Kahn, professor of psychiatry, Icahn School of Medicine, Mount Sinai, NY; and it starts in childhood before the development of psychotic symptoms.

Over time, the brain shrinkage progresses much more rapidly in people with schizophrenia than in people without schizophrenia.

Professor Kahn provided data showing that among people with schizophrenia, more severe brain shrinkage is:

  • associated with a poor outcome (including cognitive decline) and a higher number of hospitalizations (generally due to relapse)
  • significantly correlated with the duration of psychosis despite antipsychotic treatment

All the evidence suggests that antipsychotics do not make the brain shrink, said Professor Kahn, and this has been confirmed by a recent study in bipolar patients (Abramovic L, in preparation).

Antipsychotic dose is, however, a marker for severity of psychosis or resistance to treatment, Professor Kahn added.

D2 receptor partial agonists may help to address dopamine supersensitivity

Over 50% of cases of treatment-resistant schizophrenia may be related to dopamine supersensitivity psychosis

Dopamine supersensitivity worsens the prognosis of schizophrenia

Upregulation of D2 receptors in response to long-term exposure to D2 antagonists results in dopamine supersensitivity and dopamine supersensitivity psychosis, explained Jun Soo Kwon, Republic of Korea, Professor of Psychiatry, Seoul National University Medical School, Republic of Korea.

In dopamine supersensitivity, withdrawal psychosis — acute relapse or exacerbation of psychosis following antipsychotic dose reduction or discontinuation — is observed.

Not only does dopamine supersensitivity worsen the prognosis of schizophrenia, but also over 50% of cases of treatment-resistant schizophrenia (TRS) may be related to dopamine supersensitivity psychosis, said Professor Kwon. 

Maintenance antipsychotic therapy prevents relapse and improves outcome  

Relapse prevention generally prevents a deterioration in psychosocial functioning

Are antipsychotics necessary for maintenance treatment in schizophrenia? asked Wolfgang Fleischhacker, professor and managing director, Department of Psychiatry and Psychotherapy, Innsbruck University Clinics, Austria.

First, he said, it is necessary to consider the many different definitions used to measure outcomes for patients with schizophrenia, including subjective and objective quality of life, symptomatic and functional recovery and remission, psychosocial integration, and mortality.

In terms of these outcomes:

  • a large meta-analysis of 65 randomized controlled trials involving 6493 patients with schizophrenia3 has demonstrated that antipsychotic medications significantly reduced relapse rates at 1 year vs placebo (27% vs 64%) — and for most patients, explained Professor Fleischhacker, relapse prevention translates into improved functional remission and recovery
  • a large registry review has demonstrated that cumulative moderate and high-dose exposure to antipsychotics is associated with a 15–40% lower overall mortality rate than for those with no exposure4

The evidence strongly supports the need for maintenance antipsychotic treatment for patients to remain well — both patients and families should be made aware of this, and also that side effects vary for different medications, Professor Fleischhacker said.

When asked how he would manage a patient who insisted on stopping their antipsychotic despite medical advice because they felt they were well and no longer needed it, Professor Fleischhacker cautioned against alienating patients so they do not return to the clinic. He advised requesting regular appointments for careful follow-up monitoring so an antipsychotic could be restarted as necessary in a timely fashion.

Exclude pseudo-resistant schizophrenia due to non-adherence

Positive symptoms (such as delusions, hallucinations) have been the main pharmacological treatment target but cognition, functioning, side effects and subjective perspectives also need to be taken into account.

Takefumi Suzuki, Professor Department of Neuropsychiatry and Clinical Ethics, University of Yamanashi, Japan, highlighted that although many patients with schizophrenia experience treatment resistance:

  • the lack of a universal definition means that the epidemiology has depended on the definition used
  • the exact mechanism is not known

A recently published consensus paper5 has, however, provided guidelines on the diagnosis of TRS and is expected to improve future understanding of TRS.

Positive symptoms have been the main treatment target in measuring treatment success, Professor Suzuki said, but other outcomes such as cognition, functioning, side effects and subjective perspectives also need to be taken into account.

In addition, non-adherence to oral antipsychotic treatment should be proactively monitored to rule out “pseudo-resistant” cases of TRS, said Professor Suzuki. He highlighted a study that showed that 35% per cent of antipsychotic plasma levels measured in a population of 99 patients with TRS were sub-therapeutic, and of these, 34% were undetectable.6


  1. Abramovic et al. In preparation.
  2. Oda Y et al. Int J Mol Sci 2015;16(12:30144-30163.
  3. Leucht S et al. Lancet 2012;379:2063-71.
  4. Tiihonen J et al. Am J Psych 2016;173:600-6.
  5. Howes O et al. Am J Psych 2016;174:216-29.
  6. McCutcheon R et al. Acta Psychiatr Scand 2018;137:39-46.