The relation of antipsychotic and antidepressant medication with baseline symptoms and symptom progression: A naturalistic study of the North American Prodrome Longitudinal Sample

Abstract

A substantial number of patients who meet criteria for a prodromal syndrome for first psychosis are treated with antipsychotic and/or antidepressant medications. There is suggestive evidence that both classes of medication may reduce prodromal symptoms. This longitudinal study examined the relation of antipsychotic and antidepressant medication with prodromal symptom severity at baseline and 6-month follow-up. Participants met Structured Interview for Prodromal Syndromes (SIPS) criteria for the prodrome, and were evaluated at eight centers as part of the North American Prodrome Longitudinal Study (NAPLS). Symptom ratings (positive, negative, disorganized and general) and data on antipsychotics, SSRIs, and other antidepressant medications were obtained at baseline and 6-month follow-up. Analyses revealed that all symptom dimensions declined in severity over time, but there were differences in the magnitude of the decline as a function of antipsychotic medication. Those never on antipsychotics showed less reduction in positive and disorganized symptoms over time. SSRIs and other antidepressants were not linked with declines in symptom severity. Consistent with findings from small-sample, clinical trials, the present results suggest that atypical antipsychotics may be effective in reducing the severity of attenuated positive symptoms associated with the prodrome to psychotic disorders. Limitations of the present study are noted, including the fact that it is not a randomized trial, and data on duration and dosage of medication and 2-year follow-up were not available for most participants. The results are discussed in light of the relative risks and benefits of preventive interventions, both medication and cognitive therapies, and the importance of future clinical trials.

Introduction

Research has demonstrated that the onset of psychosis is typically preceded by a period of subclinical symptoms. This is referred to as the prodrome, with duration varying from one to six years (Cannon et al., 2008, Thomas and Woods, 2006). The onset of the prodrome is usually in the young adult period, and is characterized by behavioral dysfunction and subpsychotic symptoms that gradually increase in severity (Cannon, 2008, Sun et al., 2009, Walker, 2002). Interest in the prodrome has escalated recently in response to evidence that longer durations of untreated psychosis are associated with poorer prognosis. Thus, identifying individuals at risk for psychosis has the potential to hasten the provision of treatment if a psychotic episode occurs.

Several groups have developed structured interviews for assessing prodromal symptoms, and have significantly advanced the prediction of psychosis. Using the Comprehensive Assessment of At-Risk Mental States (CAARMS), researchers in Australia have conducted studies on prodromal individuals and initially reported that, within two years, 30 to 40% meet diagnostic criteria for a psychotic disorder (Yung and McGorry, 1996). In a more recent cohort from this project, a 2-year conversion rate of 16% was reported (Yung et al., 2008). It is suggested that this may reflect earlier detection of high risk individuals and/or greater provision or effectiveness of interventions in recent cohorts. Klosterkotter et al. (2001), in Germany, used another measure of prodromal symptoms, the Bonn Scale for the Assessment of Basic Symptoms (BSABS), to identify 110 prodromal patients who were followed for an average of 9.6 years. Of those with at least one prodromal symptom, 70% subsequently developed schizophrenia (within 4.3 years among women and after 6.7 years in men). In the US., McGlashan et al. (2006) developed the Structured Interview for Prodromal Syndromes (SIPS), as well as a severity scale, the Scale of Prodromal Symptoms (SOPS), and found that about 30% of individuals who meet criteria for attenuated positive symptoms manifest a psychotic disorder within 2 years (Miller et al., 2002). Most recently, a consortium has pooled data from prodromal studies conducted at eight sites, all using the SIPS. The sites comprising the North American Prodrome Longitudinal Study (NAPLS) ascertained clinical high-risk (CRH) individuals and followed them at regular intervals for up to 2 and 1/2 years (Addington et al., 2007). Approximately 35% of these subjects converted to psychosis over the 2 and ½ year period (Cannon et al., 2008).

A pivotal issue currently under discussion in the field is whether preventive intervention, especially antipsychotics, might be effective in delaying or reducing the onset of psychosis in prodromal individuals. Investigators have debated the potential benefits and risks in administering psychotropics to youth at risk for psychosis based on prodromal signs. Since 2000, several reports have been published on the effects of antipsychotics on prodromal symptoms and conversion to psychosis. The first, conducted by McGorry et al. (2002), in Australia, randomized prodromal patients to either usual care (n = 28) or open-label risperidone plus cognitive therapy and usual care (n = 31) for six months. Six month conversion to psychosis rates were 10% for the risperidone and therapy treatment versus 36% for usual care (p < .05), suggesting that the medication and cognitive therapy delayed onset of disorder, and possibly reduced incidence. In a follow-up of this sample 3–4 years later, however, there were no group differences in conversion or on any symptom measures (Phillips et al., 2007). A second study by the Yale group randomly assigned 60 prodromal youth to olanzapine or to placebo, with all receiving supportive psychotherapy (McGlashan et al., 2006, Woods et al., 2003). After one year, 16% of olanzapine-treated patients vs. 38% of placebo-treated patients had become psychotic. All of the conversions in the olanzapine group took place within the first month, while conversion continued beyond this period in the placebo group, suggesting a latency to the antipsychotic effect or doses that were too low. Treatment effects on symptoms were evident by eight weeks, with olanzapine producing greater symptom reductions, particularly in positive symptoms, than placebo. There was, however, significantly greater weight gain and fatigue among the olanzapine patients. In a treatment study from the German group, described above, prodromal individuals were randomly assigned to a needs-focused intervention without (n = 59) or with amisulpride (n = 65) (Ruhrmann et al., 2007). After 12 weeks, amisulpride plus the needs-focused intervention produced a greater reduction in symptoms, especially positive symptoms, as well as depression and functioning deficits. Although prolactin levels were higher with amisulpride, only a small number developed clinical elevations. Finally, in a nonrandomized clinical trial of risperidone with a small sample of youth yielded similar results, with greater reductions in positive prodromal symptoms (Cannon et al., 2002).

Subsequently, the Yale team completed an open-label, trial of aripiprazole in fifteen young prodromal patients (mean age 17.1 years) (Woods et al., 2007). The principal outcome was the reduction in the SOPS total score after 8 weeks. Improvement from baseline on the SOPS scores was statistically significant by the first week. Thirteen of 15 subjects (87%) completed the planned eight weeks of treatment. Weight gain averaged 1.2 kg over 8 weeks, and akathisia emerged in 8 of 15 patients, but mean akathisia ratings fell to baseline levels by the final visit. Adverse events were otherwise minimal. In summary, the findings from trials of antipsychotics with prodromal patients suggest conservative optimism about the potential benefits with respect to symptom reduction in the short term, but the findings are inconsistent with regard to prevention or delay of psychosis onset.

A recently reported naturalistic study indicates that antidepressants may also benefit clinical high risk youth (Cornblatt et al., 2007). The researchers examined non-randomly prescribed antidepressants (N = 20) and second-generation antipsychotics (N = 28). The two medication groups did not differ in baseline symptom profiles, with the exception of disorganized thinking, which was more severe in the second-generation antipsychotic group. Improvement in 3 of 5 positive symptoms over time was significant and similar for both medications. Disorganized thought, however, did not improve with either medication. Twelve of the 48 developed a psychotic disorder, with all converters having been on antipsychotics, and none on antidepressants. However, treatment outcome was confounded with medication adherence, in that 11 of the 12 converters were nonadherent, and participants were more likely to be nonadherent to second-generation antipsychotics than to antidepressants.

It should be noted that a randomized controlled trial of cognitive therapy (CT) was recently reported on a sample of prodromal subjects identified with the CAARMS (French et al., 2007, Morrison et al., 2007). Participants received either CT (n = 35) or monitoring (n = 23) over a 6 month period and 47% were followed up over a 3-year period. Within the first year, CT was associated with a greater reduction in positive symptoms (French et al., 2007). At the 3-year follow-up, CT significantly reduced the likelihood of being prescribed antipsychotic medication, but it did not affect transition to psychosis. Thus, to date, the limited findings on CT are similar to those on antipsychotic medication in showing reductions in positive symptom severity, but limited effect on conversion to psychosis.

In light of these findings, it is clear that additional research is needed on the relation between psychotropic medications and prodromal symptom progression. The NAPLS data set offers a unique opportunity for naturalistic investigations of this issue with a large sample. In this study, we examine the progression of prodromal symptoms in relation with the two most commonly prescribed classes of psychotropic medications: antipsychotics and antidepressants (SSRIs). Data on symptoms and medication status were collected at both baseline and follow-up. Based on past reports, it is predicted that prodromal patients on antipsychotics will show a more pronounced reduction in prodromal positive symptoms over time.