Schizophrenia Research Forum - A Catalyst for Creative Thinking

Predicting the Future from First Psychotic Episodes

12 September 2006. From a first psychotic episode, equal numbers of patients improve or get worse. Finding a way to predict the path patients will follow is an area of intense research, with the ultimate goal of allowing physicians to offer the best possible treatment as early as necessary to individual patients.

A new study from Stephen Wood and colleagues at the University of Melbourne in Australia offer evidence that measurements of brain chemistry at first psychotic episode, using magnetic resonance spectroscopy (MRS), can predict disease outcome. The study, which appears in the September issue of the Archives of General Psychiatry, shows that lower n-acetylaspartate/creatine ratio (a marker of neuronal dysfunction) in the prefrontal cortex at the first occurrence of psychosis correlated with a poorer clinical picture 18 months later.

Another factor tied to poor outcomes in the short term is duration of untreated psychosis. A second new paper looks at the important question of whether that association holds up with longer follow-up. The study, from Eadbhard O’Callaghan and colleagues at University College Dublin, Ireland, shows that indeed, as long as four years later, a longer duration of untreated psychosis correlates with poorer functioning and more symptoms in patients. The work, which is published in the September issue of the British Journal of Psychiatry, strengthens the case for early intervention as a way to improve treatment outcomes.

The MRS study by Wood and colleagues builds upon previous work showing that reduction in n-acetylaspartic acid (NAA) in the prefrontal cortex in chronic schizophrenia is associated with poorer cognition, longer duration of illness, and greater negative symptoms. NAA is considered a marker of neuronal health, and is reduced in brain regions under conditions of neuronal loss. Reductions of NAA might also signal lower neuronal metabolism or problems with myelination, both of which could contribute to the prefrontal cortex abnormalities reported in schizophrenia.

However, studies from Wood and coworkers show that this marker, normally given as the n-acetylaspartate/creatine (NAA/Cr) ratio, is quite variable in early disease (Wood et al., 2003), and they wondered if this variation might presage later disease outcomes. To get at that question, the researchers measured NAA/Cr in two brain areas (left prefrontal cortex and left mediotemporal lobe) in 46 patients with first-episode psychosis who were treated at their center in Melbourne. The subjects were followed up with outcome measures after 18 months of comprehensive treatment. Outcomes were defined as scores on three standard evaluations: the Global Assessment of Functioning Scale (GAF), Clinical Global Impression Scale (CGI) and the Social and Occupational Functional Assessment scale (SOFAS). In addition, the researchers measured the number of in-patient admissions in the follow-up period.

A low NAA/Cr ratio in the left prefrontal cortex was significantly related to worse outcomes in all four measures. Even when adjusted for negative symptoms at baseline and premorbid GAF scores, which have been related to poorer outcomes, the NAA/Cr measure was still significantly associated with three of the four outcome measures, and was nearly significant for the fourth. The prefrontal cortex NAA/Cr ratio independently explained between 17 and 30 percent of the variance in the four different outcome measures, far more than age, duration of untreated psychosis, or baseline negative symptoms. Putting the NAA/Cr ratio together with premorbid GAF scores plus three other predictive factors (baseline negative symptoms, age at imaging, and duration of untreated psychosis) explained about half the variance in outcomes at 18 months.

In contrast to these results, NAA/Cr ratio in the mediotemporal lobe did not correlate with outcome. This supports the idea that changes in that region occur later in the disease progression.

These results suggest that impaired prefrontal function early in the course of schizophrenia may define a subset of patients with poor prognosis and poor response to treatment. The promise is that combining MRS with the other markers of negative symptoms, premorbid functioning, DUP, and age could help identify patients who would benefit from more intensive treatment early on. More studies will be needed, however, to find out if the association holds beyond the 18-month mark and persists over longer courses of disease.

Persistence is a critical question for all prognostic markers for long-term conditions like schizophrenia, and one that the Dublin group addresses in their study. To determine if the duration of untreated psychosis, which has been linked to short-term outcomes, is also tied to long-term outcome, first author Mary Clarke and colleagues followed up on a group of 166 patients 4 years after first presentation. The mean duration of the untreated psychosis was 17.9 months (s.d. = 32.1, range 0.25–240), with a median of 5 months. The mean prodrome, available for 152 patients, was 21.3 months (s.d. = 35.7, range 0–177), with a median of 3 months. At both study entry and follow-up, the researchers assessed psychopathology with the Positive and Negative Syndrome Scale (PANSS) and global functioning with the GAF scale.

Those patients with a longer duration of untreated psychosis had a reduced likelihood of remission, displayed poorer function, and increasing psychopathology, allowing the authors to conclude that, “The association between duration of untreated psychosis and functional outcome supports the likely benefits of early intervention in psychosis.”—Pat McCaffrey.

Wood SJ, Berger GE, Lambert M, Conus P, Velakoulis D, Stuart GW, Desmond P, McGorry PD, Pantelis C. Prediction of functional outcome 18 months after a first psychotic episode: a proton magnetic resonance spectroscopy study. Arch Gen Psychiatry. 2006 Sep ;63(9):969-76. Abstract

Clarke M, Whitty P, Browne S, McTigue O, Kamali M, Gervin M, Kinsella A, Waddington JL, Larkin C, O'callaghan E. Untreated illness and outcome of psychosis. Br J Psychiatry. 2006 Sep;189:235-40. Abstract

Comments on News and Primary Papers
Comment by:  Patricia Estani
Submitted 16 September 2006
Posted 16 September 2006
  I recommend the Primary Papers

Primary Papers: Untreated illness and outcome of psychosis.

Comment by:  Amresh Shrivastava
Submitted 23 September 2006
Posted 23 September 2006
  I recommend this paper

Several of these studies recently published appear to be milestones in early psychosis research, though the point which the authors are trying to make is clear: "catch them young." What we need is a very long term follow-up to examine that onset of psychosis has not only been delayed but actually averted. We need to move on to predictive and preventive psychiatry. Maybe the data from all three or four centers doing this kind of research need to be pooled and examined.

View all comments by Amresh Shrivastava

Comments on Related News

Related News: Attempts to Address Schizophrenia Prodrome Show Promise, Pitfalls

Comment by:  Thomas McGlashan
Submitted 18 May 2006
Posted 19 May 2006

I appreciate Dr. Yung's comments on our pharmacotherapeutic treatment trial in a sample of young persons with "prodromal" symptoms and high risk for becoming psychotic within a short period of time. It was her work with Pat McGorry that first demonstrated this population could be identified, thus opening up the potential for prospective study of the mechanisms of onset and the study of treatment as preventive as opposed to merely ameliorative. We were concerned about the high dropout rate for obvious reasons, but in retrospect we should not have been surprised. Our sample was young and perhaps more resistant for that reason, as Dr. Yung implies, but the fact is that 2 years is a very long clinical trail no matter what the age! In part we wanted to allow sufficient time to elapse to capture higher numbers of converting subjects, and that still seems to be a reasonable strategy insofar as the conversion rate in the placebo group had not clearly plateaued by 1 year. Nevertheless, in retrospect, a trial of 2 years was unrealistic.

The optimal design, clearly, would be larger samples treated for a shorter period, but recruiting larger samples proved to be very difficult, even with four sites, which gets to Dr. Yung's final point. The true positive prodromal person/patient emerges in the population at the incidence rate of schizophrenia which is not robust (one in 10,000 per year). Furthermore, the earliest symptoms are often negative in nature and hard to identify, especially if the person is no longer living at home with family, that is, with people who might be sensitive to nuance changes. The bottom line is that research in this field is an uphill battle vis-à-vis sampling and recruitment. Yet I feel strongly that such samples are extraordinarily valuable for studies of the pathophysiology and preventive treatment of schizophrenia because, unlike retrospective studies, predictions that are prospectively falsifiable can be made and tested.

Therefore, like Dr. Yung, I endorse current efforts to consolidate samples across sites and to plan studies that are multisite so that sufficient numbers of such potentially informative patients can be gathered and pooled. In North America, for example, eight sites have used a common prodromal assessment battery (the same assessment instruments used in the Lilly clinical trial) and have pooled their data with the help of supplemental funds from NIMH. This group, called the North American Prodromal Longitudinal Study (NAPLS), includes three of the sites from the Lilly trial (Yale, UNC, and Toronto) and five additional sites (Harvard, Hillside, Emory, UCLA, and UCSD). Together, the group has a consolidated sample of over 400 prodromal patients, thus demonstrating that the "prodromal recruitment problem" is not insurmountable.

View all comments by Thomas McGlashan

Related News: Attempts to Address Schizophrenia Prodrome Show Promise, Pitfalls

Comment by:  Patricia Estani
Submitted 28 September 2006
Posted 28 September 2006
  I recommend the Primary Papers