1 Boring Old Man

At clinical high risk for psychosis: outcome for nonconverters.
^{by Addington J, Cornblatt BA, Cadenhead KS, Cannon TD, McGlashan TH, Perkins DO, Seidman LJ, Tsuang MT, Walker EF, Woods SW, and Heinssen R.}
American Journal of Psychiatry. 2011 168(8):800-5.
[full text on-line]

^{OBJECTIVE: A major focus of early intervention research is determining the risk of conversion to psychosis and developing optimal algorithms of prediction. Although reported rates of non-conversion vary in the literature, the non-conversion rate always encompasses a majority (50%-85%) of the sample participants. Less is known about the outcome among this group, referred to as false positive individuals.
METHOD: A longitudinal study was conducted of more than 300 prospectively identified treatment-seeking individuals meeting criteria for a psychosis-risk syndrome. Participants were recruited and evaluated across eight clinical research centers as part of the North American Prodrome Longitudinal Study. Over a 2.5-year follow-up assessment period, 214 (71%) participants had not made the transition to psychosis.
RESULTS: The sample examined included 111 individuals who had at least 1 year of follow-up data available and did not transition to psychosis within the study duration. In year 1, there was significant improvement in ratings for attenuated positive and negative symptoms. However, at least one attenuated positive symptom was still present for 43% of the sample at 1 year and for 41% at 2 years. At the follow-up time points, social and role functioning were significantly poorer in the clinical sample relative to non-psychiatric comparison subjects.
CONCLUSIONS: Help-seeking individuals who meet prodromal criteria appear to represent those who are truly at risk for psychosis and are showing the first signs of illness, those who remit in terms of the symptoms used to index clinical high-risk status, and those who continue to have attenuated positive symptoms.}

^{In summary, we found that help-seeking individuals who met attenuated positive symptom risk criteria appeared to cluster into several groups over a 2.5-year period. Among the 255 participants with 1 year of follow-up data in the North American Prodrome Longitudinal Study, approximately 35% developed a psychotic illness, 24% remitted their attenuated symptoms, 20% retained attenuated positive symptoms at lower levels of severity than those present at baseline, and 21% received an antipsychotic drug while in the prodromal phase and therefore could not be used to represent the natural course. Thus, prodromal attenuated positive symptoms may predict a more severe condition in some but by no means all cases. Thus, better prediction requires a range of both clinical and biological marker-predictors in the future. Overall, our results suggest that persons who meet symptom and functional criteria for a psychosis-risk syndrome represent a collection of the following groups: [1] those who are truly at risk for psychosis and are showing the first signs of disorder, [2] those who remit in terms of the symptoms used to index clinical high-risk status, and [3] those who continue to have attenuated positive symptoms. Future work is needed not only to replicate these findings but to extend them over much longer follow-up periods and with more comprehensive assessments that were beyond the scope of this project.}

Early Intervention for Schizophrenia:
The Risk-Benefit Ratio of Antipsychotic Treatment in the Prodromal Phase
^{by Mark Weiser, M.D.}
American Journal of Psychiatry 2011 168:761-763.

^{In schizophrenia, once psychosis and negative symptoms have manifested, most patients will suffer from persistent illness and declining social and vocational functioning; hence prevention has been contemplated for many years. In the early 1990s, the perception that second-generation antipsychotics improved the risk-benefit ratio of antipsychotic treatment was the impetus for investigators to attempt to diagnose and treat the illness before the appearance of full-blown psychosis. It was hypothesized that early intervention, including supportive therapy and treatment with antipsychotics, might prevent or delay the first psychotic episode and the subsequent deterioration. In order to identify these future patients, diagnostic criteria for this prodromal phase of the illness were developed and agreed upon, based on the presence of attenuated or brief positive symptoms or decreased functioning in persons with a first-degree relative with schizophrenia. Initial results indicated that 40% of patients who met these criteria transitioned to full-blown psychosis within a year. Specialty clinics were established, professional organizations were formed to promote investigation in this field, and new assessment tools were developed to quantify prodromal symptoms. The National Institute of Mental Health funded the North American Prodromal Longitudinal Study, in which the leading prodromal researchers in the United States and Canada pooled their data to further the study of the prodromal phase. Impressive prediction models were published in prestigious journals, positive treatment trials encouraged the use of second-generation antipsychotics in these patients, and more and more clinicians began to administer antipsychotics to patients with attenuated psychotic symptoms. However, as time went on, the rates of transition from prodrome to psychosis dropped below a range of 15%–20%. There are several possible explanations for the decline. Publicity and increased awareness led to earlier referrals, and hence patients were assessed earlier in the period of risk, leading to the recruitment of a more dilute sample, including more false positives. In addition, increased exposure of putative prodromal patients to pharmacological and psychosocial interventions might result in fewer transitions to psychosis. Around the same time, it became clear that the second-generation antipsychotics were marginally if at all more efficacious than the old drugs and had significant metabolic side effects, which led to a reshifting of the risk-benefit ratio.}

^{This issue of the Journal includes an important article by Addington et al. that sheds light on this pioneering project. The authors reported on the patients in the North American Prodromal Longitudinal Study clinics who did not receive antipsychotic medication and did not transition to full-blown psychosis over 2 years. It turns out that the clinical status of the majority of these patients was improved, with fewer positive symptoms and somewhat better functioning. First and foremost, this finding encourages clinicians treating patients with these symptoms not to initiate antipsychotic treatment, as the majority of them are not on their way to a psychotic disorder. Second, these findings force us to reconsider the validity of this diagnostic category, including the members of the DSM-5 Task Force, who are contemplating inclusion of a diagnostic category of an "at risk" syndrome based on these criteria in DSM-5…}

One of the consequences of the invasion of the pharmaceutical industry into academic psychiatry is that it stifles genuine research. Beside the mythology that clinical drug trials are anything more than marketing research, there’s the notion of translation – that all research must have some immediate clinical application. And while it is fashionable to start articles with the public health burden meme and end with a pressing call for more research, not many of our current studies end up refining our understanding or asking new more relevant questions. This simple report did that. It told me something I didn’t know – that the identified group contains a subgroup that improves, but has persistent "schizophrenia-ish" symptoms or characteristics even though they didn’t become psychotic. Are they survivors? near-misses who have the diathesis, but didn’t become frankly psychotic? In the search for biomarkers, this could also be an important group to study further – a call for more research that might actually go somewhere. Good show.

Like many, I’m primarily opposed to pre-medicating the UHR patients with antipsychotics because of the potential for unnecessary harm. But there’s another point. We’ve had the antipsychotic medications for 60 years, and I’m not sure that we’ve learned a great deal about Schizophrenia since they were introduced. So, another thing I liked about this article was this statement, "…and 21% received an antipsychotic drug while in the prodromal phase and therefore could not be used to represent the natural course." And speaking of natural course, the intrusion of profit-driven pharmaceutical influence has created too many neuroscientists more interested in resume building, grantsmanship, pseudo-expertise, and drug promotion than creative observation. The resurgence of neoKraepelinian biological psychiatry thirty years ago created a space that was way too quickly filled with many of the wrong kind of scientists, contaminating the whole enterprise.