Schizophrenia Research Forum - A Catalyst for Creative Thinking

Attempts to Address Schizophrenia Prodrome Show Promise, Pitfalls

4 May 2006. Common sense says that early treatment of a disease provides a better chance of success. In schizophrenia, early intervention seems promising enough—studies show that getting patients under care early leads to better outcomes, and the longer psychosis goes untreated, the worse the outcome once treatment begins. But can this strategy be extended to the schizophrenia prodrome, the period of diminished functioning and mild symptoms that typically precedes a psychotic break? Several new papers highlight the promise and pitfalls of pre-psychosis treatment, which remains fraught with practical problems of recognizing impending illness, and controversy over the potential for unnecessarily medicating people who may not be on the road to psychosis. (Ed. Note: For a recent overview of this field, see the British Journal of Psychiatry’s August 2005 supplement, subscription required until August 2006.)

Thomas McGlashan of Yale University in New Haven, Connecticut, and collaborators in the U.S. and Canada, report in the May issue of the American Journal of Psychiatry that treatment of adolescents at high risk for developing schizophrenia with the antipsychotic drug olanzapine can relieve prodromal symptoms, and may delay a first episode of psychosis. Despite an impressive halving of the rate of progression to psychosis in the drug-treated group, the study was inconclusive because of a high dropout rate, with nearly half the subjects leaving the study during the year-long treatment phase. Fatigue and significant weigh gain were major adverse side effects.

The current issue of the American Journal of Psychiatry also features a report from Ingrid Melle of the University of Oslo and collaborators in the U.S. and Denmark on a community education program aimed at helping people identify the early symptoms of schizophrenia. Their results show that the program led to reduced suicidal behaviors in patients reporting to clinics. Both studies point to the benefits of getting patients into treatment at the earliest possible point, and will spur further research on the type and timing of interventions that yield the optimum risk-benefit ratio. A large part of that optimization requires the sensitive and accurate identification of adolescents on the verge of developing schizophrenia, and a study published online recently in Schizophrenia Research, from Alison Yung and Patrick McGorry’s group in Melbourne, Australia, shows that there is still some way to go on that count.

Message from olanzapine trial is promising, but incomplete
The olanzapine trial, undertaken at four centers in Connecticut, North Carolina, Ontario, and Alberta, and funded by a grant from Eli Lilly and Company (manufacturers of olanzapine, or Zyprexa®) recruited help-seeking individuals who were defined as possibly prodromal for schizophrenia. The original framework for such determinations was established by Yung and McGorry (Yung and McGorry, 1996), who identified three “syndromes”: mild positive symptoms, intermittent psychosis, or having a close relative with disease (genetic risk) plus deteriorating function. McGlashan and colleagues have subsequently modified these criteria in creating a data collection instrument (the Structured Interview for Prodromal Symptoms, or SIPS, version 4.0 available from McGlashan) to highlight recent change and to be able to track symptoms over time (see Miller et al., 2003). Most of the individuals in the current study met the attenuated positive symptoms syndrome criteria, meaning that they were experiencing positive symptoms of recent onset that were detectable and ratable but had not reached the clinical definition of psychosis.

Even though the prodrome condition is relatively uncommon (as is schizophrenia), the investigators managed to recruit 60 subjects who were randomized to receive olanzapine or placebo daily for one year, and then observed for an additional year of follow-up off the drug. The power of the study to detect differences in conversion to psychosis was seriously compromised, however, by a 45 percent dropout rate in the first year. Coupled with an average of 27 percent conversion to psychosis, that left only 17 patients completing the 2-year study, eight from the placebo group and nine from the olanzapine group.

Disregarding dropouts, in the first year, the rate of conversion to psychosis, the primary study measure, was 38 percent (11 patients) in the placebo group and 16 percent (five patients) in the drug group. The group difference barely missed statistical significance (p = 0.08), but the trend agrees with earlier studies showing that prodromal interventions, whether pharmacological or cognitive behavioral, do reduce the conversion to psychosis, at least in the short term (McGorry et al., 2002; Morrison et al., 2004). The drug seemed to delay, rather than prevent, conversion, since the rate of conversion in both groups equalized after treatment was discontinued, although the numbers of subjects left in the study by that time were too small to permit any statistical analysis. Consistent with a delay effect, olanzapine treatment significantly reduced some prodromal symptoms, and when the drug was stopped, symptoms worsened for all the patients still in the study.

Interestingly, the five conversions in the treatment group occurred within the first 4 weeks of treatment, and none were seen in the remaining 48 weeks. The five converters were also the most symptomatic, suggesting that perhaps they were too close to converting for the drug treatment to take effect.

According to McGlashan and colleagues, when patients in the study did convert to psychosis, the researchers were “surprised at how operationally benign the process was.” By that, they meant that whether coming from placebo or treatment group, in all cases the patients accepted open-label drug treatment, and complied without hospitalization, missing work or school, or disrupting their social networks. The smooth transition was attributed to the established physician-patient relationship, and the ability to start needed treatment as soon as psychosis appeared.

On the risk side of treatment, the most serious side effects of olanzapine were fatigue and weight gain. Olanzapine-treated patients gained an average of nearly 20 pounds, although this was not accompanied by metabolic disturbances in the first year. The possible long-term health consequences of weight gain and the sensitivity of adolescents to weight gain make this side effect troubling. Based on this study, the number needed to treat is 4.5, which means that between four and five people meeting the criteria for prodromal schizophrenia would need to be treated to prevent one conversion per year of treatment.

Despite the difficulties in recruitment and retention in this trial, the authors write that, “Overall, we feel that this clinical trial demonstrates that the benefits of pre-onset identification and treatment outweighs the risks to a degree sufficient to endorse future clinical trials (in academic centers with programs for early detection and intervention in psychosis) so that definitive recommendations on the use of antipsychotics to treat the prodromal phase of schizophrenia can be made.” (Ed. Note: McGlashan’s group is participating in the NIMH-funded North American Prodromal Longitudinal Study (NAPLS), described in the minutes of the September 2005 meeting of the National Advisory Mental Health Council.)

Testing the test Down Under
One way to improve the risk-benefit equation is to refine the identification of at-risk adolescents to home in on those most likely to progress to psychotic disease. That’s precisely the goal of Alison Yung, Patrick McGorry and colleagues, who started the first early intervention clinic in Melbourne a decade ago, and conducted the first randomized trial of intervention in a high-risk population (McGorry et al., 2002). They have worked to define a symptomatic profile of the “ultra-high risk”(UHR) population—patients with a high likelihood of progressing to a first psychotic episode within a short time. Like McGlashan and colleagues, they have developed a study tool, the Comprehensive Assessment of At Risk Mental States (CAARMS), to evaluate possibly prodromal patients. (For a comprehensive discussion of SIPS, CAARMS, and a third tool, the Bonn Scale for the Assessment of Basic Symptoms [BSABS], see Phillips et al., 2005) Studies employing these different assessment tools have found rates of conversion to psychosis of between 10 and 50 percent. However, as Yung and colleagues discuss in their current paper, published online April 19 in Schizophrenia Research, these studies have been done with subjects who were highly self- and/or clinician “selected.” That is, subjects often came from families with histories of mental illness, or were thought to be “prodromal” by someone—a mental health worker, general practitioner, school counselor, family member or even themselves. This contrasts with people who are not thought to be “prodromal” but who are found to have attenuated or subthreshold psychotic symptoms on routine enquiry.

In the general population or in other research populations, the positive predictive value of prodromal symptoms may be at the lower end of this range, according to new work from the Melbourne group. Using the CAARMS, Yung and coworkers identified UHR young people from a group of 292 15- to 24-year-olds who were referred to a general psychiatric service, not all of whom had primary complaints related to prodromal schizophrenia. They found that about 10 percent of subjects the researchers determined to be at ultra-high risk proceeded to psychosis over 6 months.

Somewhat more reassuring was the observation that only one person out of 173 judged to be at low risk progressed during the study. The authors conclude that UHR status is a sensitive (92 percent) predictor of impending progression, as most progressors (12 out of 13) were in the UHR category. But the specificity was only 62 percent, as the majority of UHR adolescents did not progress, at least in the 6-month time frame of the study. The study further identified low functioning as a factor that increased the risk of progression in the UHR group and the sample as a whole.

The results emphasize the need for additional screening criteria that accurately identify the appropriate treatment candidates for early intervention, given the side effects of medication and the potential for personal distress and lasting stigmatization that might occur from an inaccurate “prodromal” designation.

Communities that educate
Even without additional research, opportunities are all around for effective early intervention, if only communities can get the word out, according to a study from Ingrid Melle and colleagues in Oslo, Norway. Their study, also in the May American Journal of Psychiatry, shows that an educational campaign aimed at identifying and destigmatizing the early symptoms of schizophrenia resulted in a drop in the suicidal behaviors of patients in two communities that implemented the program compared to two that did not. The public information campaign resulted in patients appearing at clinics who were significantly younger, had milder symptoms, and a shorter duration of untreated psychosis. The patients reported significantly lower levels of suicidal behavior both in their lifetimes and in the month preceding first treatment contact. The difference was particularly apparent in reduced suicidal plans and attempts in the early-detection communities.

These results put hard numbers to the life-and-death struggle of many with schizophrenia, as outlined by Jill Harkavy-Friedman of New York State Psychiatric Institute in New York City, in an editorial accompanying the study by Melle and colleagues. She notes that suicide accounts for most of the excess mortality and premature death in schizophrenia, and the Melle study represents “an important first step in identifying individuals with psychotic disorders and implementing treatment earlier in the course of illness." Along with McGlashan’s work, she says, the studies “highlight the need for comprehensive universal public mental health interventions” with the goal of early detection and treatment.—Pat McCaffrey.

References:
McGlashan TH, Zipursky RB, Perkins D, Addington J, Miller T, Woods SW, A Hawkins K, E Hoffman R, Preda A, Epstein I, Addington D, Lindborg S, Trzaskoma Q, Tohen M, Breier A. Randomized, double-blind trial of olanzapine versus placebo in patients prodromally symptomatic for psychosis. Am J Psychiatry. 2006 May;163(5):790-9. Abstract

Melle I, Johannesen JO, Friis S, Haahr U, Joa I, Larsen TK, Opjordsmoen S, Rund BR, Simonsen E, Vaglum P, McGlashan T. Early detection of the first episode of schizophrenia and suicidal behavior. Am J Psychiatry. 2006 May;163(5):800-4. Abstract

Harkavy-Friedman JM. Can early detection of psychosis prevent suicidal behavior? Am J Psychiatry. 2006 May;163(5):768-70. Abstract

Yung AR, Stanford C, Cosgrave E, Killackey E, Phillips L, Nelson B, McGorry PD. Testing the Ultra High Risk (prodromal) criteria for the prediction of psychosis in a clinical sample of young people. Schizophr Res. 2006 Apr 19; [Epub ahead of print] Abstract

Comments on News and Primary Papers


Primary Papers: Randomized, double-blind trial of olanzapine versus placebo in patients prodromally symptomatic for psychosis.

Comment by:  Alison Yung (Disclosure)
Submitted 15 May 2006
Posted 15 May 2006
  I recommend this paper

Dr. McGlashan and the rest of the PRIME team are to be congratulated on their study. Having worked on similar studies myself, with the Ultra High Risk (or “prodromal”) population, I can attest to the difficulties of conducting such a trial. The high dropout rate from both the active medication group and the placebo group is of note. My experience working with young people in the UHR group, as well as young people with psychotic and non-psychotic disorders, is that they tend to be reluctant to take any medication for 12 months. So this finding from the PRIME study is not surprising. The high dropout rate does, however, have implications for the effectiveness (as opposed to efficacy) of using medication for the prodromal population. Additionally, the finding that cognitive therapy may significantly reduce the transition to psychosis rate in UHR individuals (Morrison et al., 2004) points to the need for the ongoing evaluation of which UHR patients should be medicated and when.

One area that needs ongoing investigation is the refinement of the UHR criteria, so that those who are at most risk can be targeted for preventive treatment. Demographic, psychopathological, neurocognitive, neurophysiological, and neurobiological variables could all be evaluated. Ideally, those at highest risk of transition could be detected and treated. Other targets for medication could be ongoing functional decline and suicidal and homicidal risk. I agree with the PRIME researchers’ recommendations that future trials are needed. An alternative strategy to a simple medication trial could be to have a medication-free period during which cognitive therapy versus supportive therapy could be assessed, followed by a medication trial in those who fail to respond to initial psychological treatment. The problems of low numbers and long recruitment phases continue to dog the area of UHR research. As the PRIME authors note, multisite trails and pooling of subjects would aid the endeavor.

View all comments by Alison YungComment 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 McGlashanComment by:  Patricia Estani
Submitted 28 September 2006
Posted 28 September 2006
  I recommend the Primary Papers

Comments on Related News


Related News: Predicting the Future from First Psychotic Episodes

Comment by:  Patricia Estani
Submitted 16 September 2006
Posted 16 September 2006
  I recommend the Primary Papers

Related News: Schizophrenia and Neurodegeneration—Case Bolstered by MRI, Electrophysiology

Comment by:  Dan Javitt, SRF Advisor
Submitted 29 May 2007
Posted 29 May 2007

Salisbury et al., in the May 2007 issue of Archives of General Psychiatry, demonstrate associated progressive reductions in mismatch negativity (MMN) amplitude and Heschl’s gyrus reduction in schizophrenia. These findings provide strong support for involvement of auditory cortex in the pathogenesis of schizophrenia, and demonstrate that pathological changes in the illness are not confined to specific brain regions, such as prefrontal cortex, that receive the preponderance of attention.

Further, the manuscript helps resolve an important current controversy in the MMN literature. Deficits in MMN generation have been among the most consistent findings in chronic schizophrenia, with a recent meta-analysis showing large (~1 sd unit) effect size MMN reductions across studies (Umbricht et al., 2005). As noted by Salisbury et al., however, deficits have not been observed in first-episode patients (Salisbury et al., 2002; Umbricht et al., 2006). An unknown issue was whether the discrepancy between first-episode and chronic patients was due to within-subject change (the “degeneration” hypothesis), or whether those patients with small MMN at entry tended to be retained disproportionately in chronic samples because of the relationship between MMN generation and global outcome (e.g., Light and Braff, 2005) (the “distillation” hypothesis).

The present study suggests that at least some patients show reductions of both MMN amplitude and left HG volumes over time, lending at least partial support for the degeneration hypothesis. This finding is important in that it shows that the pathological process contributing to cognitive impairment in schizophrenia continues beyond first episode, and may be a target for pro-cognitive interventions. It should be noted that the degeneration continued despite treatment with atypical, as well as typical, antipsychotic medication.

As noted by Salisbury et al., the change in MR volume in schizophrenia is best conceived as atrophy of neurons, rather than degeneration. On a histological level, the volume reductions noted on MR correspond with reduced pyramidal cell size in postmortem tissue (e.g., Sweet et al., 2004). Interestingly, postmortem studies have yet to show volumetric reductions in HG despite the change in some compartments, suggesting that MR may be detecting changes in tissue parameters that are not apparent in postmortem histological examination. This study also complements a recent diffusion tensor imaging (DTI) study that showed correlations between white matter changes in auditory projection pathways and auditory processing deficits in schizophrenia (Leitman et al., 2007). The relationship between white matter and grey matter pathology requires further investigation.

There are additional lessons hidden in the Salisbury et al. study. Given the relationship between reduced MMN generation (a functional measure) and cortical volume (a structural measure), there is a strong tendency to assume that structural changes are the cause of functional changes. The findings by Salisbury et al., as well as the extrapolation to postmortem histological studies, argue strongly against such an interpretation. For example, in the Salisbury et al. study, the change in left HG volume from time 1 to time 2 was only 6 percent, whereas MMN declined by 33 percent over the same period of time. At time 2, HG volumes were only 2 percent smaller in schizophrenia patients vs. controls, whereas MMN was 35 percent smaller. These findings suggest that simple volume loss does not cause the reduction in MMN. Further, even though MMN reduction seems to stabilize following the first 1.5 years (e.g., Umbricht et al., 2006; Javitt et al., 1995), this may not be the case with volumetric deficits. Thus, in a prior sample of chronic patients, this same group reported reductions of 13 percent in HG volume (Hirayasu et al., 2000), as opposed to the 2 percent reduction observed in patients following 1.5-year follow-up. Rather than suggesting a primary role of degeneration, this suggests a “use it or lose it” relationship within auditory cortex, wherein persistent reduction of activity may lead over time to structural involution. Even in postmortem studies (e.g., Sweet et al., 2004), pyramidal cell volumes are reduced by only 10 percent, whereas MMN in chronic schizophrenia may be reduced by 40 percent or more (e.g., Salisbury et al., 2002; Umbricht et al., 2006).

As noted by Salisbury et al., acute treatment with NMDA antagonists leads to reduced MMN amplitude in both human (Umbricht et al., 2000) and animal (Javitt et al., 1996) models. NMDA receptors also play a critical role in synaptic spine development and maintenance (Matsuzaki et al., 2004). A possible explanation, therefore, is that reduced NMDA activity in auditory cortex leads to both MMN reductions and reductions in spine density. Alternatively, primary alteration in subpopulations of cortical glutamatergic cells could trigger the sequence of events leading to reduced MMN generation.

There are several other intriguing features to the dataset. For example, at baseline, there were several controls who had larger than median HG volumes, but nevertheless failed to generate MMN (i.e., <1 μV). In schizophrenia patients, this sector of the plot was entirely empty and the only subjects who failed to generate MMN were those with small HG volumes. This suggests that there may be fundamental differences in structure/function relationships. It is almost as interesting to know why some controls fail to generate MMN despite having adequate HG size, as it is to know why HG is reduced in schizophrenia.

The finding that the relationships hold only for left, not right, HG, also is worthy of further investigation, as is the finding that right HG volumes are reduced even at first episode and do not decline further. Finally, the correlation on reduced MMN amplitude at Fz with reduced HG volume reiterates once again the role of auditory, rather than frontal, cortices in mediating MMN generation deficits in schizophrenia.

View all comments by Dan Javitt

Related News: Schizophrenia and Neurodegeneration—Case Bolstered by MRI, Electrophysiology

Comment by:  Lei Wang
Submitted 5 June 2007
Posted 5 June 2007

The authors reported a cross-sectional (first hospitalization or within 1 year of first hospitalization) and longitudinal (1.5-year follow-up) study of electrophysiologic testing (mismatch negativity, or MMN, amplitude) and high-resolution structural magnetic resonance imaging of Heschl gyrus and planum temporale gray matter volumes. Schizophrenia subjects showed longitudinal volume reduction of left hemisphere Heschl gyrus (P = .003), which was highly correlated with MMN reduction (r = 0.6; P = .04). The interrelated progressive reduction of functional and structural measures suggests progressive pathologic processes early in schizophrenia. The design of the study helped minimize the effect of medication, the authors commented, therefore allowing the interpretation that brain change is due to disease progression.

From an imaging perspective, this is a straightforward longitudinal study of brain structure following previously published image processing and measuring protocols (Kasai et al., 2003). T1- and T2-weighted MR scans were acquired using the same sequence and on the same scanner for all subjects and at all time points. All baseline and follow-up MR scans were bias-field corrected and used in a fully automated segmentation algorithm for tissue classification, and then realigned to standard coordinate space and re-sampled to isotropic voxel resolution for application of standard manual segmentation protocols. Intracranial content was also estimated. Inter-rater and intra-rater reliability for segmentation of the Heschl gyrus and planum temporale was very high (volume ICC ranging from 0.95 to 0.99) (Kasai et al., 2003).

The authors showed in their earlier paper (Kasai et al., 2003) that using this approach, the time-dependent change in the volume of intracranial content did not correlate with time-dependent volume changes of brain structures. While this is reassuring, a trend-level decrease of intracranial content in time (p = 0.065), however, does raise the possibility of some systematic bias such as scanner drift resulting in global scaling, especially considering the subjects’ ages of 21-24 years. Some solutions such as scaling the follow-up scans with respect to the baseline scans could be evaluated (Freeborough and Fox, 1997).

This well-designed and well-presented study adds to a growing body of evidence that longitudinal structural neuroimaging is an effective way to detect progressive changes in specific brain structure in patients with schizophrenia. The results of this study contribute to the debate over whether the pathogenesis of schizophrenia includes a neurodegenerative as well as neurodevelopmental component.

View all comments by Lei Wang

Related News: Schizophrenia and Neurodegeneration—Case Bolstered by MRI, Electrophysiology

Comment by:  Robert McClure (Disclosure)
Submitted 10 June 2007
Posted 10 June 2007

Longitudinal increases in volume of the lateral ventricles and decreases in brain volume—progressive changes—are often observed over time early in the course of schizophrenia. There is not uniform agreement over the proper interpretation of these changes, prompting vigorous, healthy debate among investigators. A major point of contention appears to be whether these volume changes actually constitute evidence of active disease progression.

In the current study, the authors seek to bolster the case for structural progression by demonstrating evidence of interrelated progressive functional impairment. They buttress the case for structural progression by demonstrating a relationship between worsening deficit in mismatch negativity and auditory cortex volume decreases.

Identification of a direct causal relationship between the underlying pathophysiology of schizophrenia and volume losses observed early in the illness would conclusively demonstrate structural progression. Such a direct link has not yet been established, so the results of this study constitute only indirect evidence that structural progression is tied to the emergence of functional impairment. Results of longitudinal MRI studies are useful for identify factors potentially associated with these volume changes, including altered neurodevelopment, disease progression, mismatch negativity, antipsychotic medications, and yet unidentified factors. Until the underlying etiology of schizophrenia is known, what underlies longitudinal volume change in schizophrenia is unlikely to be determined.

Future research should focus on specifying the neurodevelopmental mechanisms that contribute to the cortical pathology central to schizophrenia.

View all comments by Robert McClure

Related News: In Pursuit of Positive ID for Schizophrenia Prodrome—A Research Roundup

Comment by:  Patricia Estani
Submitted 31 May 2008
Posted 31 May 2008
  I recommend the Primary Papers

Related News: Thinking Outside the Pillbox: Fish Oil and Exercise for Schizophrenia?

Comment by:  William Carpenter, SRF Advisor (Disclosure)
Submitted 16 February 2010
Posted 16 February 2010

The most controversial recommendation being considered by the DSM-V Psychoses Work Group involves creating a risk syndrome section and placing psychosis risk as a class in this new section. The September 2009 issue of Schizophrenia Bulletin carried a concept piece on the risk syndrome by Heckers, a validity report by Woods et al., and an editorial detailing Work Group considerations by me. Reliability has been established among experts, but to eventually make this recommendation for DSM-V, we will have to demonstrate reliability in ordinary clinical settings by ordinary clinicians. Even then, substantial opposition is anticipated, and it seems more likely headed for the appendix (in need of further study) than prime time as a diagnostic class.

Opposition is based primarily on three concerns: 1) high false-positive rates, 2) harm related to stigma and excessive drug prescribing, and 3) lack of an evidence-based therapeutic approach with documented efficacy and effectiveness. The first two can be rebutted to some extent by giving emphasis to the potential advantages for the true positive cases. Regarding the false positive cases, it can be emphasized that distress, disability, and help-seeking are obligatory for the proposed criteria. Therefore, these persons would still be exposed to clinical care that might include excessive medication and stigma. Furthermore, they would still have the risk of an uninformative diagnosis.

On the third point, it is worth noting that the DSM is not a therapeutic manual. Nonetheless, as a practical matter, I have assumed that opposition would melt away if a safe and effective treatment for true positive cases were known, and if the treatment did more good than harm for false positive cases. Amminger et al. move the field a giant step forward in this regard. Omega-3 free fatty acids are thought to be associated with general health benefits without significant adverse effects. I take them daily and hope to live forever. Their report of substantially reduced conversion-to- psychotic-illness rates is reinforced by secondary analyses showing benefits for psychopathology. The number needed to treat is four, a very small number, and I assume the number needed to harm is very high (this could not be determined in the present study since adverse events did not exceed placebo, but infinity is not excluded).

This important report urgently calls for replication or refutation. If confirmed, it provides a basis for hope that therapeutics with a novel compound may substantially improve the fate of persons at risk for psychotic illness. If confirmed, I expect the opposition to formally identifying persons as at risk for psychosis will melt away. We may be closer to issues related to identifying and treating hypercholesterolemia than we are to the supposed harm associated with elevating the risk syndrome to the level of classification in DSM-V.

References:

Heckers S. Who is at risk for a psychotic disorder? Schizophr Bull. 2009 Sep;35(5):847-50. Epub 2009 Jul 24. Abstract

Woods SW, Addington J, Cadenhead KS, Cannon TD, Cornblatt BA, Heinssen R, Perkins DO, Seidman LJ, Tsuang MT, Walker EF, McGlashan TH. Validity of the prodromal risk syndrome for first psychosis: findings from the North American Prodrome Longitudinal Study. Schizophr Bull. 2009 Sep;35(5):894-908. Abstract

Carpenter WT. Anticipating DSM-V: should psychosis risk become a diagnostic class? Schizophr Bull. 2009 Sep;35(5):841-3. Abstract

View all comments by William Carpenter

Related News: Thinking Outside the Pillbox: Fish Oil and Exercise for Schizophrenia?

Comment by:  Stuart Maudsley
Submitted 19 February 2010
Posted 19 February 2010

The recent work of Pajonk and colleagues is one of the most recent demonstrations of the beneficial neurological actions of physical exercise. Physical activity not only can improve cardiovascular health directly, but also appears to engender a strong neurotrophic effect that can be isolated somewhat from the cardiovascular actions. Recreational physical activity has been demonstrated to improve learning and memory functions in healthy adults (Winter et al., 2007), reduce the risk of dementia in elderly patients (Karp et al., 2006; Vaynman and Gomez-Pinilla, 2006), attenuate progression and development of Alzheimer’s disease (AD) (Wilson et al., 2002), and productively increase brain volume in areas concerned with spatial memory and executive function (Colcombe et al., 2006; Erickson et al., 2009). This final aspect of physical exercise, i.e., actual increased central nervous system development, is the subject of the Pajonk et al. study. Rather than the neurological developmental effects of exercise upon healthy, aged, or AD patients, Pajonk and colleagues have studied the actions of exercise upon the hippocampal regions of schizophrenic patients.

Hippocampal function and structure are sensitive to the environment
The hippocampus, primarily concerned with the acquisition and transfer of short-term memories, has been demonstrated to be exceptionally sensitive to volume alteration with cognitive or physical exercise paradigms (Boyke et al., 2008; Erickson et al., 2009; Pereira et al., 2007). Although pathology of the hippocampus is primarily linked to AD (Maudsley et al., 2007), abnormalities in the structure of this brain region have been reported in schizophrenia (Reif et al., 2006) and may contribute to defects in neural plasticity in this area.

Pajonk et al. have attempted to apply the well-known effects of exercise upon hippocampal structure and volume to patients presenting with schizophrenia. This group recruited patients with schizophrenia along with a healthy control group. Half of the schizophrenic group was exposed to a coordinated and supervised physical exercise regimen (cycling), while the rest of the schizophrenic patients were occupied for a similar period of time with a hand-eye coordination skill that did not induce significant physical exertion (table football). The control individuals were also placed on an exercise regimen (cycling), but oddly, none was subjected to the table football task, a potential flaw in the study’s experimental design.

Physical exercise increases hippocampal volume in schizophrenic patients
Crucial neurophysiological measurements were made in all the experimental subjects at the beginning of the study and after three months of the protocols. One of the primary indices measured, using magnetic resonance imaging, was the change in relative hippocampal volume. As one would expect, the control patients experiencing the exercise paradigm demonstrated a significant increase in hippocampal volume. In the patients with schizophrenia, this was mirrored only in the exercise group; those who played table football failed to show any increase in hippocampal volume.

Here it would have been interesting to have investigated the table football-playing actions in the control patients, as learning coordinated motor skills (without significant physical strain), such as juggling, can increase hippocampal volume in healthy adults (Draganski et al., 2004). Nevertheless, the exercise-induced increase in relative hippocampal volume was clearly apparent in the exercising patients who had schizophrenia. Therefore, it seems likely that the complex physiological response mechanisms required for the translation of physical activity to neuromodulatory effects are still intact even in patients with schizophrenia. At a certain level, the brains of these patients could be considered still relatively healthy and normal.

Schizophrenic patients respond in a unique manner to exercise
To assess the functional integrity of the newly created neurons in the hippocampus, Pajonk et al. studied the ratio of N-acetylaspartate (NAA) to the metabolite creatine (Cr). High N-acetylaspartate levels are often associated with healthy functional neurons and were consistently increased in the exercising patients with schizophrenia. In exercising control patients, the NAA:Cr ratio was relatively unchanged, and some subjects showed a marked reduction. This difference could point to a potentially different mechanism by which patients with schizophrenia increase hippocampal volume compared to control patients who demonstrate the same physiological response to exercise.

Reinforcing the ultrastructural and biochemical effect of exercise upon the schizophrenic hippocampus improved its functional integrity as well. The group with schizophrenia demonstrated a profound increase in short-term memory, while the non-exercising patients with schizophrenia demonstrated a reduction. In addition to proving beneficial for memory function, the exercise paradigm improved schizophrenic symptomology. The non-exercising patients with schizophrenia experienced a worsening of their symptomology.

Physical exercise regimens may improve neurological health in schizophrenic patients
Taken together, these interesting findings indicate that, as with healthy control individuals, the incredibly complex endogenous response mechanism to the strains of exercise is intact and functional in patients with schizophrenia. This excellent news will potentially allow the use of this simple therapeutic paradigm to treat patients with schizophrenia and those with other neurological disorders.

There are likely to be multiple mechanisms by which physical exercise can be translated into improved neurological health. These may include enhanced stress responses, elevation of neurotrophic agents such as brain-derived neurotrophic factor or insulin-like growth factor-1, improvement of cellular metabolism, and angiogenesis. Considerable research has demonstrated that many of these factors are implicated, but in truth the effects of exercise are likely due to a complex interaction of all these factors. It is excellent news that patients with schizophrenia still possess this ability to benefit from the effects of exercise upon the central nervous system.

Potential of pharmacotherapeutics that can mimic exercise
One caveat in this story is familiar to everyone: exercise is a “medicine” that not everyone wants to take. If physical activity were considered a pharmacotherapeutic, it would possess one of the worst compliance rates of any drug. If we could start to understand the endogenous exercise translating mechanisms, we may be able to shortcut the need for many hours at the gym and tap into these mechanisms to enhance the actions of a short jog to those only previously generated by weeks of training (Stranahan et al., 2009).

Even with the potential ability to mimic the effects of exercise, we must remember that these effects do not happen in a simple linear manner. The effects of training are generated by the complex interaction of tens or hundreds of individual factors; if we can start to understand such an intricate interplay between our physiology at rest and during exercise, we may eventually be able to therapeutically exploit this evolutionarily conserved benefit of exercise.

References:

Boyke J, Driemeyer J, Gaser C, Büchel C, May A. Training-induced brain structure changes in the elderly. J Neurosci. 2008 Jul 9;28(28):7031-5. Abstract

Erickson KI, Prakash RS, Voss MW, Chaddock L, Hu L, Morris KS, White SM, Wójcicki TR, McAuley E, Kramer AF. Aerobic fitness is associated with hippocampal volume in elderly humans. Hippocampus. 2009 Oct;19(10):1030-9. Abstract

Pereira AC, Huddleston DE, Brickman AM, Sosunov AA, Hen R, McKhann GM, Sloan R, Gage FH, Brown TR, Small SA. An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus. Proc Natl Acad Sci U S A. 2007 Mar 27;104(13):5638-43. Epub 2007 Mar 20. Abstract

Colcombe SJ, Erickson KI, Scalf, PE, Kim JS, Prakash R, McAuley E, Elavsky S, Marquez DX, Hu L, Kramer AF. Aerobic exercise training increases brain volume in aging humans. J Gerontol A Biol Sci Med Sci. 2006;61:1166-70. Abstract

Vaynman S, Gomez-Pinilla F. Revenge of the "sit": how lifestyle impacts neuronal and cognitive health though molecular systems that interface energy metabolism with neuronal plasticity. J Neurosci Res. 2006;84:699–715. Abstract

Karp A, Paillard-Borg S, Wang HX, Silverstein M, Winblad B, Fratiglioni L. Mental, physical, and social components in leisure activities equally contribute to decrease dementia risk. Dement Geriat Cogn Disord. 2006;21:65–73. Abstract

Wilson RS, Mendes De Leon CF, Barnes LL, Schneider JA, Bienias JL, Evans DA, Bennett DA. Participation in cognitively stimulating activities and risk of incident Alzheimer disease. JAMA. 2002;287:742–8. Abstract

Winter B, Breitenstein C, Mooren FC, Voelker K, Fobker M, Lechtermann A, Krueger K, Fromme A, Korsukewitz C, Floel A, Knecht S. High impact running improves learning. Neurobiol Learn Mem. 2007;87:597-609. Abstract

Maudsley S, Martin B, Luttrell LM. G protein-coupled receptor signaling complexity in neuronal tissue: implications for novel therapeutics. Curr Alzheimer Res. 2007 Feb;4(1):3-19. Abstract

Reif A, Fritzen S, Finger M, Strobel A, Lauer M, Schmitt A, Lesch KP. Neural stem cell proliferation is decreased in schizophrenia, but not in depression. Mol Psychiatry. 2006 May;11(5):514-22. Abstract

Draganski B, Gaser C, Busch V, Schuierer G, Bogdahn U, May A. Neuroplasticity: changes in grey matter induced by training. Nature. 2004 Jan 22;427(6972):311-2. Abstract

Stranahan AM, Zhou Y, Martin B, Maudsley S. Pharmacomimetics of exercise: novel approaches for hippocampally-targeted neuroprotective agents. Curr Med Chem. 2009;16(35):4668-78. Abstract

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Related News: Thinking Outside the Pillbox: Fish Oil and Exercise for Schizophrenia?

Comment by:  Anthony Hannan
Submitted 19 February 2010
Posted 19 February 2010
  I recommend the Primary Papers

These important new papers (Amminger et al., 2010; Pajonk et al., 2010) suggest interesting approaches for delaying/preventing onset of, and treating, schizophrenia. As the interventions, and cohorts, are very different, it is likely the therapeutic mechanisms are distinct; however, in both cases neurobiological insights may be provided by animal models.

The exercise study (Pajonk et al., 2010) is supported by experimental studies involving environmental manipulations of animal models, which may provide some insight into underlying mechanisms. There is prior evidence, in a knockout mouse model of schizophrenia exhibiting predictive validity, that environmental enrichment (which enhances mental/physical activity levels) from adolescence onwards can ameliorate schizophrenia-like endophenotypes (McOmish et al., 2008). While this model does exhibit hippocampal dysfunction, these mutant mice are also known to have abnormal activity-dependent synapse formation and/or elimination in the postnatal neocortex (Spires et al., 2005), and, therefore, the enhanced mental and physical activity may be inducing its beneficial effects via additional areas outside the hippocampus. In another mouse model of schizophrenia, with a mutation in the neuregulin-1 gene, a minimal form of environmental enrichment provided throughout development can also modulate specific behavioral endophenotypes (Karl et al., 2007).

Environmental enrichment provides opportunities for enhanced sensory, cognitive, and motor activity (exercise), and has been shown to induce beneficial effects in various animal models of neurological and psychiatric disorders (reviewed by Laviola et al., 2008; Sale et al., 2009). Increased physical activity alone has a range of effects, at molecular, cellular, and systems levels, on brain function and cognition (reviewed by Cotman et al., 2007; Hillman et al., 2008). While Pajonk et al. (2010) have identified the hippocampus as a region of interest, enhanced exercise clearly has the potential to induce beneficial effects via additional systems outside the hippocampus. One key aspect of applying these environmental interventions in valid animal models is that we might identify the molecular/cellular mechanisms mediating the beneficial effects, and thus pave the way for the development and optimization of new therapeutic approaches.

References:

Amminger GP, Schäfer MR, Papageorgiou K, Klier CM, Cotton SM, Harrigan SM, Mackinnon A, McGorry PD, Berger GE. Long-chain Ω-3 fatty acids for indicated prevention of psychotic disorders: A randomized, placebo-controlled trial. Arch Gen Psychiatry. 2010 Feb;67(2):146-54. Abstract

Cotman CW, Berchtold NC, Christie LA. Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci. 2007 Sep;30(9):464-72. Abstract

Hillman CH, Erickson KI, Kramer AF. Be smart, exercise your heart: exercise effects on brain and cognition. Nat Rev Neurosci. 2008 Jan;9(1):58-65. Abstract

Karl T, Duffy L, Scimone A, Harvey RP, Schofield PR. Altered motor activity, exploration and anxiety in heterozygous neuregulin 1 mutant mice: implications for understanding schizophrenia. Genes Brain Behav. 2007 Oct;6(7):677-87. Abstract

Laviola G, Hannan AJ, Macrì S, Solinas M, Jaber M. Effects of enriched environment on animal models of neurodegenerative diseases and psychiatric disorders. Neurobiol Dis. 2008 Aug;31(2):159-68. Abstract

McOmish CE, Burrows E, Howard M, Scarr E, Kim D, Shin HS, Dean B, van den Buuse M, Hannan AJ. Phospholipase C-beta1 knockout mice exhibit endophenotypes modeling schizophrenia which are rescued by environmental enrichment and clozapine administration. Mol Psychiatry. 2008 Jul;13(7):661-72. Abstract

Pajonk F-G, Wobrock T, Gruber O, Scherk H, Berner D, Kaizl I, Kierer A, Müller S, Oest M, Meyer T, Backens M, Schneider-Axmann T, Thornton AE, Honer WG, Falkai P. Hippocampal plasticity in response to exercise in schizophrenia. Arch Gen Psychiatry. 2010 Feb;67(2):133-43. Abstract

Sale A, Berardi N, Maffei L. Enrich the environment to empower the brain. Trends Neurosci. 2009 Apr;32(4):233-9. Abstract

Spires TL, Molnár Z, Kind PC, Cordery PM, Upton AL, Blakemore C, Hannan AJ. Activity-dependent regulation of synapse and dendritic spine morphology in developing barrel cortex requires phospholipase C-beta1 signalling. Cereb Cortex. 2005 Apr;15(4):385-93. Abstract

View all comments by Anthony Hannan