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Schizophrenia
to CVD and related conditions. The reduced level of healthcare valid. This realignment will have implications on treatment strategies for
received by this patient population indicates the need to revise and early response and non-responders in patients with schizophrenia.
implement preventative and therapeutic approaches towards CVD,
especially considering that the majority of cardiometabolic risk The Delayed Onset of Antipsychotic
factors prevalent in these patients are modifiable and potentially Action Hypothesis
reversible. The choice of antipsychotic drug may play a particularly Although the delayed-onset hypothesis has been widely recognised,
important role, as psychotropic medications can affect all risk questions remain since it has never been validated by clinical evidence.
factors of CVD aside from smoking. Different antipsychotics have Agid et al. carried out a meta-analysis to evaluate whether
varying effects on the level of risk of weight gain, dyslipidaemia and antipsychotics actually had a delay in their onset of action.
100,101
hyperglycaemia. Clinicians can beneficially modify patient risk The analysis included data from 42 double-blind active or
through the use of psychotropic medications that have lower placebo-controlled studies of antipsychotic response during the first
potential for adverse metabolic effects. Clinicians can also modify four weeks of treatment and included 7,450 patients, approximately 42%
patient risks through regular monitoring of weight, BMI, glucose of whom were from the US and 19% of whom were from Europe. There
levels, lipid profiles and interventions that include encouragement were some variations in diagnostic criteria over time; while earlier
of healthy lifestyle choices and activities. These preventation efforts studies generally used the International Classification of Diseases (ICD)
require increased awareness among not only psychiatrists, but also and Research Diagnostic Criteria for a Selected Group of Functional
primary care clinicians, endocrinologists and cardiologists, in order Disorders (6.9% of all studies), the newer studies used the diagnostic
to normalise disparities in the standard and quality of care for criteria from the Diagnostic and Statistical Manual of Mental Disorders
patients with mental illness. ■ (DSM)-III-R and the DSM-IV (93.1% of all studies). Nearly 77% of the
included studies had washout periods accounting for 62.8% of the
Implications of Early
patients included in the meta-analysis. The length of the washout period
varied between one day (in more recent studies) and 33 days (in earlier
Response and Non-response in studies). Almost half of the studies (47.4%) included only patients
Schizophrenia Pharmacotherapy
with schizophrenia, and the remainder included patients with
schizophrenia, schizoaffective disorder and schizophreniform disorder.
a report on presentations by The patients were typically in their 30s, with an age range of 16–72 years
Stefan Leucht
1
and Shitij Kapur
2
(mean 37.6 years), and 63.8% were male. More than half of the studies
(52.4%) involved inpatients only; the remainder included a mixture of
1. Assistant Professor, Department of Psychiatry and Psychotherapy, inpatients and outpatients. The studies included patients treated with
Technische Universität Munich; 2. Vice Dean, Professor and Head of Section of olanzapine (n=3,750), haloperidol (n=2,447), risperidone (n=8,96),
Schizophrenia, Imaging and Therapeutics, King’s College London chlorpromazine (n=95) and placebo (n=262). Symptoms were measured
using the Positive and Negative Syndrome Scale (PANSS) or the Brief
Antipsychotic drugs introduced more than 50 years ago have greatly Psychiatric Rating Scale (BPRS).
improved the treatment of patients with schizophrenia, but their precise
mechanism of action remains an issue of debate. There are two Placebo-adjusted results of this meta-analysis showed a substantial
competing hypotheses concerning the onset of action of antipsychotic reduction in the overall symptoms of schizophrenia after one week of
drugs, both of which are capable of explaining why it can take weeks antipsychotic drug administration, with a smaller but still substantial
before substantial clinical improvement is observed: the delayed onset reduction between weeks one and two followed by much smaller
of action theory and the early-onset hypothesis (see Figure 14).
100,101
reductions between weeks two and four (see Figure 15).
100
A similar
While both hypotheses can account for why it may take several weeks pattern was also seen when looking at the effect of antipsychotic
to achieve a substantial level of response, opposing predictions are treatment week on the psychotic symptom subscore. This meta-analysis
presented regarding what happens early in the course of treatment. provides clear evidence that antipsychotic action starts early in the
According to the delayed-onset hypothesis, after the drug reaches its treatment regimen, with the greatest response observed at weeks one
therapeutic level there is a period of ‘delay’ of approximately two to and two, which corresponds with the early-onset hypothesis.
three weeks before the initial clinical response is observed. However,
this hypothesis is based on expert opinion more than clinical evidence. These results are supported by data from a pooled post hoc analysis
In contrast, an early-onset hypothesis has been proposed that suggests using original patient data from seven randomised and double-blind
that the antipsychotic effect starts simultaneously with the acquisition studies on the efficacy of amisulpride in acutely ill patients with
of therapeutic drug levels within the first few days. According to this schizophrenia or schizophreniform disorder according to DSM-III-R or
theory, the greatest effect is seen earlier on in the treatment regimen, DSM-IV.
102
After exclusions, the database consisted of 1,708 patients
with the drug effect accumulating over time and eventually reaching a treated with amisulpride (n=1,042), haloperidol (n=367), flupenthixol
plateau. This idea corresponds to the delayed substantial clinical (n=47) or risperidone (n=252). Mean BPRS at baseline was 58.6±14.5, the
improvement whereby there is a long period before the antipsychotic mean psychotic subscore 18.1±3.2, the mean age 36.0±10.9 years and
exerts its full effect or until the patient is in full remission. Distinguishing the mean duration of illness 10.4±8.6 years (this information was not
between the two competing models of antipsychotic onset of action is recorded for 116 patients). At baseline, 1,136 participants were
not just of theoretical importance, but also of clinical significance. The inpatients, 156 were outpatients and 157 were being treated in day
two different time-scales will lead to different clinical expectations, hospitals; for 259 participants the treatment setting was not recorded.
different clinical trial designs and different kinds of mechanisms to
explain the effects of antipsychotic medications. Recent data indicate In a subsample treatment, responses were analysed over 51 weeks,
that a paradigm shift from the delayed- to the early-onset hypothesis is compared with the four-week response data utilised by Agid et al.
100
34 EUROPEAN PSYCHIATRIC REVIEW