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.
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