Hindsight meets foresight: balancing long-term antipsychotic benefits and harms

Think about the future

The central theme of a popular symposium on Sunday was trying to describe and tease out factors that may contribute to brain atrophy in patients with schizophrenia and whether such factors and changes have an impact on patient outcomes.

Almost all speakers acknowledged that schizophrenia may not be one single entity and the term may in fact encompass a number of different pathologies including neurodevelopment or recreational-drug induced aetiologies.

Professor Andreas Heinz of the Department of Psychiatry and Psychotherapy, Charité - University Medicine Berlin, Germany began by reminding delegates that schizophrenia appears to be characterized by a dysfunction of critical processing associated with imbalances in glutaminergic and gabaminergic control systems leading to disinhibition and disruption in dopaminergic signalling.  He said that while neuronal processing pathways appear to work the same as in normal subjects, in schizophrenia the context of the signal is lost.

Prof Heinz described a cognitive model that has been studied in schizophrenia – which has some parallels with Pavlovian responses and behaviours – in which patients receiving typical antipsychotic drugs showed some degree of  motivational deficit not seen in untreated controls. He commented that trying to understand what brain changes are due to disease and which may be due to treatments can be messy.

Brain atrophy – what does it mean for the patient?

While the debate goes on about whether or not schizophrenia is a neuroprogressive disease, there has been evidence from some quarters that our approaches to treatment might sometimes fuel rather than dampen progressive atrophy. In a systematic review of longitudinal studies, Dr Volkmar Aderhold of the Institute for Social Psychiatry, University of Greifswald in Germany was somewhat circumspect about what the evidence can tell, particularly with regards any impact on clinical outcomes. His systematic review tried to correlate drug exposure with frontal lobe volume reductions and identified 10 studies spanning follow-up periods of 1 to 7 years.

In patients with first episode disease, he said some studies suggested a correlation between cumulative daily dose exposure and brain volume changes,  while other studies found no such relationship. And again while it has been suggested that there might be a difference between older and newer generation drugs, of three studies looking at this, all had differing results.

In patients with multiple episodes, first generation drugs appeared to affect cortical thickness and studies of second generation drugs showed some suggestion that frontal density was affected by dose of drug but there was no evidence that such structural changes correlated with clinical outcomes such as disease relapse.

Dr Adelhold and others in the faculty nevertheless consider that a prudent approach to long-term drug treatment of schizophrenia should be to use the lowest possible effective dose of therapy.

Are our guidelines adequate on long-term dosing?

Indeed Dr Hiroyoshi Takeuchi, of the Schizophrenia Division, Centre for Addiction and Mental Health, Toronto in Canada highlighted that current clinical guidelines on long term maintenance therapy in schizophrenia are far from aligned – some supporting dose tapering and reductions, others advising continuation of effective treatment doses. 

The symposium ended with a presentation by Dr Lex Wunderink of the Friesland MHS/UMCG Groningen, Leeuwarden, The Netherlands who reported the results of a small-scale study assessing 7-year outcomes in two groups of patients managed for 2 years either on maintenance dose therapy or reduced dose therapy. He said that while initially relapse-rates in the reduced dose group were higher, these equalled those in the maintenance therapy group from 3 years to the end of the study.