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

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 Maudsley

  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