Schizophrenia Research Forum - A Catalyst for Creative Thinking

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

15 February 2010. Antipsychotic drugs help many people with diagnosed schizophrenia, but they have significant side effects. The idea of trying to use them to prevent psychosis in high-risk individuals makes many people nervous. Fortunately, two new studies in the February Archives of General Psychiatry test other ways to ward off psychosis and to improve brain structure and function in schizophrenia. A randomized, placebo-controlled trial by G. Paul Amminger and colleagues suggests that taking fish oil capsules containing omega-3 fatty acids prevents, or at least delays, psychosis in the most vulnerable teens and young adults, with benefits that linger months after the end of treatment. In another trial, Frank-Gerald Pajonk and colleagues find that participating in a three-month aerobic exercise program increases hippocampal volume in male patients with chronic schizophrenia and improves their short-term verbal memory.

The resistance of long-untreated psychosis to eventual treatment underscores the need to identify as early as possible anyone at high risk of becoming psychotic. It also raises the issue of how to stop people in the prodromal stage from developing frank psychosis. There is no conclusive evidence that antipsychotic drugs prevent conversion to schizophrenia in high-risk populations (see SRF related news story). However, even if such evidence was found, using the drugs for this purpose risks causing metabolic harm, along with other known and unknown side effects, in young people who might not even develop psychosis, much less schizophrenia (see SRF related news story; see SRF related news story).

Keeping psychosis at bay
Studies evaluating whether omega-3 fatty acids can prevent or treat schizophrenia have produced mixed results (see Peet, 2008). Humans obtain them mostly from food, particularly fatty fish such as salmon and mackerel. These polyunsaturated fatty acids, present in high concentrations at synaptic membranes, may play a role in neurodevelopment, synaptic pruning, and neuroplasticity, processes that may be impaired in schizophrenia (see Berger et al., 2006).

Amminger, of the Orygen Youth Health Research Centre in Melbourne, Australia, and colleagues tested whether fish oil capsules high in omega-3 fatty acids would prevent the transition to psychotic disorder. They enrolled subjects, 13 to 25 years old, who met criteria for being at ultra-high risk of developing psychosis. These criteria included transient psychosis, sub-threshold positive symptoms of psychosis, or genetic risk for psychosis plus decreased functioning. To identify subjects who met either of the first two criteria, the researchers used the Positive and Negative Syndrome Scale (PANSS). They defined genetic risk as having schizotypal personality disorder or a first-degree relative with psychotic disorder. They considered subjects to have decreased functioning if their scores on the Global Assessment of Function Scale (GAF) declined by 30 percent or more within the prior year.

Using a double-blind design, the researchers randomized 81 subjects to receive capsules containing either fish oil or placebo for 12 weeks. The daily fish oil dose contained about 1.2 grams of omega-3 fatty acids, including 700 mg of eicosapentaenoic acid, 480 mg of docosahexaenoic acid, and 7.6 mg of tocopherol. The placebo consisted of coconut oil capsules that looked and tasted like the fish oil ones. The researchers chose coconut oil for the placebo because it contains no polyunsaturated fatty acids and does not affect the body’s use of omega-3 fatty acids. To control for the effects of depression on the course of psychosis, the researchers stratified randomization based on subjects’ scores on the Montgomery Asberg Depression Rating Scale (MADRS). Subjects could not take antipsychotic medication or mood stabilizers, but could take other psychiatric medication.

A few patients, three in the fish oil group and two in the placebo group, stopped treatment before the end of the study, leaving 76 subjects who completed the intervention. After randomization, subjects underwent evaluations weekly for the first month, followed by further testing at eight and 12 weeks, and at six and 12 months. The main outcome, the development of a psychotic disorder that lasted at least a week, was based on PANSS scores and confirmed by psychiatrists who were not involved with the study. All analyses used the intent-to-treat approach.

At baseline, the two treatment groups appeared similar on sociodemographic and psychiatric measures, but their paths later diverged. At 12 months, well after the intervention ended, 4.9 percent (two of 41 subjects) of the omega-3 group and 27.5 percent (11 of 40) of the placebo group had developed outright psychosis, generally schizophrenia or schizophreniform disorder. The risk of psychosis in the two groups differed by 22.6 percent (p = .007). The researchers found that, for every four people who received the fish oil treatment, one would be spared from developing psychosis over the course of a year.

Repeated measures analyses of variance showed that the fish oil relieved psychotic symptoms and improved functioning, too. Subjects who took it scored significantly lower than those assigned to placebo on PANSS total scores, positive symptoms, negative symptoms, and general psychopathology symptoms at 12 weeks, six months, and 12 months (all p <.05). On overall functioning, as measured by the GAF, the fish-oil group improved over time relative to control subjects, as shown by a significant interaction between treatment group and measurement at 12 weeks, six months, and 12 months (all p <.03).

People generally tolerate fish oil supplements well, but some experience gastrointestinal side effects. In this study, the two treatment groups experienced adverse effects at similar rates, suggesting that the benefits of omega-3 supplementation outweigh any risks.

In short, this study suggests that 12 weeks of treatment with fish oil capsules produces benefits that persist many months later. However, Amminger and colleagues caution, “In some individuals, the transition to a first episode of psychosis may have been delayed rather than prevented.”

Bulking up the hippocampus
Besides fish oil, another heart-healthy intervention may prove useful for schizophrenia. Pajonk, of Dr. K. Fontheim’s Hospital for Mental Health, Liebenburg, Germany, and colleagues find that exercise may grow the hippocampus, even in subjects with chronic schizophrenia. Most imaging studies find a disproportionately small hippocampus, relative to the rest of the brain, in subjects with schizophrenia (see Gur et al., 2007; see also recent SRF Hippocampus in Schizophrenia Roundtable). This finding does not seem to result from antipsychotic medication.

Research suggests that exercise improves brain structure and function. In fact, a recent review (van Praag et al., 2009) concluded that it fosters neurodevelopment in rodents, including in the hippocampus, where processes related to learning and memory occur. To see if exercise would increase hippocampal volume in human subjects with schizophrenia, Pajonk and colleagues conducted a proof-of-concept study.

The study enrolled men with chronic schizophrenia who ranged from 20 to 51 years old. All had been taking stable doses of antipsychotic medication for at least six weeks. They were randomly assigned to participate in either an exercise or a non-exercise group. A group of eight control subjects, matched to the schizophrenia exercise group on demographic characteristics, verbal intelligence, body mass index, and weight-adjusted peak oxygen uptake, also received the exercise training.

The exercise group bicycled indoors under supervision for 30 minutes daily, three times a week, for 12 weeks. Subjects in the control group spent the same amount of time playing tabletop football. The researchers explain that the latter does not affect aerobic fitness, but does improve coordination and concentration. No subjects in either group experienced adverse events.

Magnetic resonance imaging at baseline and three months later supplied the data needed to compute hippocampal volume as a percentage of total brain volume. Repeated-measures analysis of variance weighed the effects of time and treatment on relative hippocampal volume.

In both exercise groups combined, those who completed the intervention increased their relative hippocampal volume by 14 percent (p <.001 for time effects) over three months. Subjects with schizophrenia and healthy controls changed equally on this measure. In neither group did exercise change the volume of the whole brain or the gray matter alone.

Looking only at subjects who had schizophrenia revealed that those who exercised grew their hippocampus by 12 percent. In contrast, this brain region actually shrank by 1 percent in those who played the tabletop game (p = .002 for the group-by-time interaction). Analyses performed without subjects who were taking antidepressants revealed that these drugs did not account for the findings.

Exercise did more than enlarge the hippocampus; it also improved memory and symptoms. On a measure of short-term memory based on the Rey Auditory Verbal Learning Test, exercise produced opposite effects in subjects with schizophrenia versus healthy controls (p = .007). It enhanced the performance of subjects with schizophrenia by 34 percent, but worsened that of control subjects by 17 percent. It had no clear effect on measures of long-term memory or visuospatial short-term memory.

The bicycling sessions also relieved symptoms of schizophrenia, at least as measured by PANSS total scores (p = .02). Subjects with schizophrenia reported 9 percent lower symptoms after the exercise intervention. The symptoms of those who did not exercise increased by 13 percent.

Next, Pajonk and colleagues turned to magnetic resonance spectroscopy to learn how exercise affected the ratio of N-acetylaspartate (NAA) to creatinine, two hippocampal metabolites. NAA, made mostly in neurons, serves as a marker for their loss or dysfunction. The researchers found a significant time-by-diagnosis interaction (p = .01), in which this ratio rose 35 percent in subjects with schizophrenia and dropped 16 percent in control subjects. To the authors, this finding suggests that physical activity may spur hippocampal growth through different mechanisms in subjects with schizophrenia compared to healthy subjects. For instance, exercise alters glutamatergic neurotransmission via N-methyl D-aspartate receptors (Praag et al., 2009). Brain-derived neurotrophic factor, also of interest in schizophrenia, appears crucial for producing the benefits of exercise on the nervous system (Stranahan et al., 2009).

Taking a broader view of their findings, Pajonk and colleagues write, “The change in volume related to exercise in schizophrenia indicates that this type of plasticity remains relatively intact.” Future research will need to confirm these findings in men and determine whether they also apply to women. In any case, these two studies point to ways to address neuropsychiatric functioning in schizophrenia while at the same time, perhaps, address the cardiovascular disease and lipid abnormalities often seen in the disease.—Victoria L. Wilcox.

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

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

Comments on News and Primary Papers
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 CarpenterComment 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

View all comments by Stuart MaudsleyComment 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

Comments on Related News


Related News: Some Antipsychotic Drugs Impair Glucose Metabolism

Comment by:  James Manning IV
Submitted 25 November 2005
Posted 25 November 2005

This study is thoughtful and balanced, and driven by evidence.

View all comments by James Manning IV

Related News: Some Antipsychotic Drugs Impair Glucose Metabolism

Comment by:  Patricia Estani
Submitted 27 November 2005
Posted 28 November 2005
  I recommend the Primary Papers

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

Related News: Children and Teens Gain Weight Quickly on Second-generation Antipsychotics

Comment by:  William Carpenter, SRF Advisor (Disclosure)
Submitted 29 October 2009
Posted 29 October 2009

It has been known for years that some—not necessarily all—second-generation drugs have severe metabolic side effects. These effects are common, not rare. Metabolic changes induced will increase risk of an early death substantially unless persons receiving these treatments are immune to effects observed in the general population. In fact, cardiovascular disease, stroke, diabetes, and pulmonary disease are already associated with early death of persons with schizophrenia where mortality rates are already two to six times standard mortality rates (see SRF related news story). The fact that these populations have increased risk from other lifestyle problems (e.g., diet, sedentary lifestyle, smoking, and stress) increases the need for clinicians to minimize risk from iatrogenic sources. The importance of the report by Correll et al. is not based on surprising new data. Rather, it is the ability to bring extensive attention to this problem to the broad medical field and the public.

The increased safety and efficacy of second-generation antipsychotic drugs was debunked before the turn of the century, and the value of the CATIE and CUtLASS studies was more in their ability to spark the public discussion than in surprising new data (Lieberman et al., 2005; Jones et al., 2006). In young people, the antipsychotic drugs with serious metabolic adverse profiles should rarely be considered. Clozapine for some childhood-onset schizophrenia patients may be one of the exceptions. Antipsychotic drugs are usually prescribed with long-term use in mind. If a clinician considers this essential therapy—as it often is in schizophrenia, less so in bipolar disorder, where effective and safer drugs are available—selection of compounds based on safety and tolerability is essential. In this regard, prescribing drugs such as olanzapine is very difficult to defend. The importance of this report being published in JAMA is underscored by the reports of Lilly directing representatives to market olanzapine to primary care providers who are less aware of the metabolic effects (see, e.g., Attorney General’s Settlement).

View all comments by William Carpenter

Related News: Signs of Things to Come? Seeking Biomarkers for the Schizophrenia Prodrome

Comment by:  Thomas McGlashan
Submitted 21 January 2012
Posted 21 January 2012

Three very recent publications have detailed that biomarkers can identify and quantify high-risk or prodromally symptomatic subjects who subsequently undergo conversion to psychosis. McGuire and his group (Howes et al., 2011) used fluoro-dopa positron emission tomography scanning to measure dopamine synthesis. Koutsouleris et al. (Koutsouleris et al., 2011) used structural MRI data to develop a neuroanatomical classification system for predicting psychosis conversion, and Amminger et al. (Amminger et al., 2011) used capillary gas chromatography of erythrocyte membrane fatty acid levels to provide information about brain phospholipids. All measures were significantly successful in identifying high-risk or prodromally symptomatic subjects who went on to develop a first episode of psychosis.

These papers point to an exciting future in our efforts to elaborate easily identifiable risk factors that can pinpoint among clinically identified "prodromal" subjects those who are most likely to become psychotic. That such diverse measures proved to be successful in identifying "true positives" can be regarded as a milestone in this line of investigation. It represents a quantitative leap forward in our ability to reduce the uncertainty of predicting psychosis, and hints at the day when tragedies such as the one occurring in Tucson, Arizona, become a thing of the past.

References:

Howes OD, Bose SK, Turkheimer F, Valli I, Egerton A, Valmaggia LR, Murray RM, McGuire P. Dopamine Synthesis Capacity Before Onset of Psychosis: A Prospective [18F]-DOPA PET Imaging Study. Am J Psychiatry. 2011 Dec 1; 168: 1311-1317. Abstract

Koutsouleris N, Borgwardt S, Meisenzahl EM, Bottlender R, Möller HJ, Riecher-Rössler A. Disease Prediction in the At-Risk Mental State for Psychosis Using Neuroanatomical Biomarkers: Results From the FePsy Study. Schizophr Bull. 2011 Nov 10. Abstract

Amminger GP, Schäfer MR, Klier CM, Slavik JM, Holzer I, Holub M, Goldstone S, Whitford TJ, McGorry PD, Berk M. Decreased nervonic acid levels in erythrocyte membranes predict psychosis in help-seeking ultra-high-risk individuals. Mol Psychiatry. 2011 Dec 20. Abstract

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