Preventing schizophrenia relapse key to optimizing outcome

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Sustained remission and good functional outcome depend on the interaction between factors we cannot control – such as pre-morbid hippocampal volume – and factors which we can control. Notable among these are early and specialized intervention and maintaining adherence to treatment. The symposium also discussed the link between absence of insight and abnormal brain function and structure.

In thinking of the outcome we want for patients, we should think of the outcome we would want for ourselves, said Ashok Malla (McGill University, Montreal, Canada). And that would include good functioning at work or education, social inclusion and the absence of stigma, independence, physical, psychological and spiritual well-being, and a coherent sense of self.

In thinking of the outcome for patients, we should think of the outcome we’d want for ourselves

The unwelcome fact is that – although around 80% of patients respond to treatment, and half have remission of both positive and negative symptoms – good functional recovery (in the sense described above) is achieved by no more than 10-25% of patients.

Modifiable and non-modifiable factors

Remission is highly predictive of function at two years, with non-remitted patients having little or no chance of meaningful symptom improvement. However, and while remission is necessary to the achievement of good function, it is not in itself sufficient.

A striking finding relating hippocampal tail volume to remission has now been replicated

Several factors prior to disease onset seem to favour a good outcome. These include cognitive capacity – with good verbal memory playing an important role – premorbid adjustment, and greater grey matter volume.

In a study comparing first-episode patients with healthy controls, a smaller hippocampal tail volume was associated with absence of remission after six months of treatment. This notable finding, relating anatomy to outcome, has been replicated.

There are also many factors that we do have power to influence. Modifiable factors that favour good functional outcome include a short duration of untreated psychosis, adherence to treatment, and avoidance of substance abuse.

Early intervention is also vital. Combining drug treatment (including long-acting injectables) with assertive case management, cognitive behavioral therapy, family psychoeducation and employment support can improve the chances that a patient will achieve remission, stay in treatment, and achieve good functional outcomes.

It now seems that gains achieved by two years of specialized early intervention can be sustained to five years, even if the continued support is less intensive.

Some predictive factors we cannot change. Others, such as the availability of specialized early intervention, are ours to control

It may also be possible to influence at least one seemingly less modifiable factor since there is evidence that hippocampal grey matter volume can increase during treatment with atypical antipsychotics.

Continuous treatment has major benefits

Preventing relapse is the key to optimizing outcomes, agreed Robin Emsley (Stellenbosch University, Cape Town, South Africa).

When patients receive treatment as prescribed, they do well. However, relapse rates are high when treatment is discontinued and we often have no warning signs of impending relapse. Further, there are currently no reliable means of predicting those patients who are not at-risk.

We do know that each episode of relapse has harmful psychosocial consequences. A prospective study by Professor Emsley and colleagues suggests that relapses are critical in the evolution of treatment-refractory disease. Compared with first episode patients, those with a first relapse are already substantially less likely to respond to treatment.

It is also probable that a relapse has adverse biological consequences.

Efforts to optimize outcome should focus on the active phase of the illness during which function declines rapidly with each episode of disease. Typically, this period is followed by a chronic phase when illness is relatively stable and there is a plateau in functioning.

It is when the disease is at its most aggressive that we should give patients the greatest chance of effective treatment. This means long-acting agents should not be considered a last option but our first. The question should not be “Who should be considered for a long-acting injectable?” but rather “Who would you not consider for an LAI?”, Professor Emsley argued.

Recovery means alleviation of symptoms but also social inclusion and a coherent sense of self

Impaired insight has a biological basis?

Robin Emsley also presented striking evidence that absence of insight – far from being solely a psychological defence mechanism – relates to a demonstrable abnormalities of brain function and structure.

In first-episode patients, poorer insight was predicted by lower fractional anistropy in white matter tracts associated with cortical midline structures. Further, when 92 first-episode patients were compared against matched controls, those with psychosis had reduced frontal cortical thickness in areas involved in self-monitoring.

Lack of insight linked to disconnectivity in white matter tracts

Any relapse is a relapse too many

Stephan Heres (Technical University of Munich, Germany) reinforced the themes discussed above, arguing that increasing adherence to existing agents could probably have at least as much benefit as the development of new ones.

Citing data from Weiden et al, he showed that the 6% rate of relapse and hospitalization seen in patients who had continuous medication rose to 22% in those who discontinued for more than thirty days in a year.

LAIs reduce the burden on the patient of ensuring adherence and help assure treatment delivery, Professor Heres said. And mirror image studies show reduced risk of hospitalization when compared against oral antipsychotics. He argued that patients should not have to suffer a relapse before being considered for long-acting therapies. Any relapse is a relapse too many, he concluded.

Improvements in functioning, QoL, and negative symptoms are important long-term treatment goals and recent data suggest emerging differences in efficacy between antipsychotic medications in achieving these outcomes

This report is from an Otsuka and Lundbeck-sponsored satellite symposium held during ECNP 2017.

Our correspondent’s highlights from the symposium are meant as a fair representation of the scientific content presented. The views and opinions expressed on this page do not necessarily reflect those of Otsuka and Lundbeck.

Symposium references
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  3. Cassidy CM, Norman R, Manchanda R, Schmitz N, Malla A. Testing definitions of symptom remission in first-episode psychosis for prediction of functional outcome at 2 years. Schizophr Bull. 2010 Sep;36(5):1001-8.
  4. Jordan G, Lutgens D, Joober R, Lepage M, Iyer SN, Malla A. The relative contribution of cognition and symptomatic remission to functional outcome following treatment of a first episode of psychosis. J Clin Psychiatry. 2014 Jun;75(6):e566-72.
  5. Alvarez-Jimenez M1, Priede A, Hetrick SE, Bendall S, Killackey E, Parker AG, McGorry PD, Gleeson JF. Risk factors for relapse following treatment for first episode psychosis: a systematic review and meta-analysis of longitudinal studies. Schizophr Res. 2012 Aug;139(1-3):116-28.
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  9. Leucht S, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, Samara M, Barbui C, Engel RR, Geddes JR, Kissling W, Stapf MP, Lässig B, Salanti G, Davis JM. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet. 2013 Sep 14;382(9896):951-62.
  10. Kishimoto T, Robenzadeh A, Leucht C, Leucht S, Watanabe K, Mimura M, Borenstein M, Kane JM, Correll CU. Long-acting injectable vs oral antipsychotics for relapse prevention in schizophrenia: a meta-analysis of randomized trials. Schizophr Bull. 2014 Jan;40(1):192-213.
  11. Heres S, Lambert M, Vauth R. Treatment of early episode in patients with schizophrenia: the role of long acting antipsychotics. Eur Psychiatry. 2014 Nov;29 Suppl 2:1409-13.
  12. Németh G, Laszlovszky I, Czobor P, Szalai E, Szatmári B, Harsányi J, Barabássy Á, Debelle M, Durgam S, Bitter I, Marder S, Fleischhacker WW. Cariprazine versus risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia: a randomised, double-blind, controlled trial. Lancet. 2017 Mar 18;389(10074):1103-1113.
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