Denise Evans

Reduced erythrocyte membrane essential fatty acids and increased lipid peroxides in schizophrenia at the never-medicated first-episode of psychosis and after years of treatment with antipsychotics.

Abnormal membrane phospholipid essential polyunsaturated fatty acid (EPUFA) metabolism (i.e., reduced incorporation into phospholipids and increased breakdown) has been suggested to contribute to the etiopathophysiology of schizophrenia. However, most of the published studies have reported changes in the levels of membrane EPUFA in chronic medicated patients or in drug-naive patients long after onset of illness (1-2 years). Since the EPUFA metabolism can be altered by years of untreated illness or differentially altered by various antipsychotics, the significance of EPUFA membrane status to schizophrenia psychopathophysiology is unclear. We report the erythrocyte membrane EPUFA levels in drug-naive patients within +/- 4.5 days of onset of psychosis from an Army Medical Center, and in patients treated years with antipsychotics from a Veterans Affairs Medical Center. The levels of plasma lipid peroxides (TBARS, thiobarbituric acid reactive substances), products of damaged EPUFAs, were also determined. The levels of EPUFAs, particularly arachidonic acid (AA) and docosahexaenoic acid (DHA) were significantly lower (P < 0.001) in drug-naive patients at the onset of psychosis compared to matched normal controls. These lower EPUFA levels were associated with significantly higher levels of TBARS in patients (P < 0.001). The levels of AA and DHA were also lower (P < 0.001) and TBARS higher in chronic medicated patients than normal controls. However, the EPUFA levels were higher in chronic medicated patients than drug-naive first-episode patients. These data indicate that lower membrane AA and DHA most likely predate the illness and probably contribute to the onset of illness, and furthermore treatment with some antipsychotics may increase the levels of EPUFAs. The lipid peroxidation data suggest that possible increased oxidative stress, either as a part of the illness and/or its treatment with antipsychotics, may be one of the mechanisms of reduced membrane EPUFAs. These findings may have a significant impact on improving strategies for supplementation of EPUFAs and antioxidants to improve the outcome of schizophrenia.

Oxidative stress and role of antioxidant and ω-3 essential fatty acid supplementation in schizophrenia

1. Schizophrenia is a major mental disorder that has a lifetime risk of 1% and affects at young age (average age at the onset 24 +/- 4.6 years) in many cultures around the world. The etiology is unknown, the pathophysiology is complex, and most of the patients need treatment and care for the rest of their lives. 2. Cellular oxidative stress is inferred from higher tissue levels of reactive oxygen species (ROS, e.g., O2*-, OH*, OH-, NO* and ONOO--) than its antioxidant defense that cause peroxidative cell injury, i.e., peroxidation of membrane phospholipids, particularly esterified essential polyunsaturated fatty acids (EPUFAS), proteins and DNA. 3. Oxidative stress can lead to global cellular with predominantly neuronal peroxidation, since neurons are enriched in highly susceptible EPUFAs and proteins, and damages DNA is not repaired effectively. 4. Such neuronal peroxidation may affect its function (i.e., membrane transport, loss of mitochondrial energy production, gene expression and therefore receptor-mediated phospholipid-dependent signal transduction) that may explain the altered information processing in schizophrenia. 5. It is possible that the oxidative neuronal injury can be prevented by dietary supplementation of antioxidants (e.g., vitamins E, C and A; beta-carotene, Q-enzyme, flavons, etc.) and that membrane phospholipids can be corrected by dietary supplementation of EPUFAs. 6. It may be that the oxidative stress is lower in populations consuming a low caloric diet rich in antioxidants and EPUFAs, and minimizing smoking and drinking. 7. Oxidative stress exists in schizophrenia based on altered antioxidant enzyme defense, increased lipid peroxidation and reduced levels of EPUFAs. The life style of schizophrenic patients is also prooxidative stress, i.e., heavy smoking, drinking, high caloric intake with no physical activity and treatment with pro-oxidant drugs. 8. The patients in developed countries show higher levels of lipid peroxidation and lower levels of membrane phospholipids as compared to patients in the developing countries. 9. Initial observations on the improved outcome of schizophrenia in patients supplemented with EPUFAs and antioxidants suggest the possible beneficial effects of dietary supplementation. 10. Since the oxidative stress exists at or before the onset of psychosis the use of antioxidants from the very onset of psychosis may reduce the oxidative injury and dramatically improve the outcome of illness.

Supplementation with a combination of ω-3 fatty acids and antioxidants (vitamins E and C) improves the outcome of schizophrenia

Reduced levels of membrane essential polyunsaturated fatty acids (EPUFAs), namely, arachidonic acid (AA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acids (DHAs), and their association with psychopathology have been consistently reported in both chronic-medicated schizophrenic patients as well as in never-medicated patients soon after the first episode of psychosis. Past supplementation studies with either omega-6 or omega-3 or both EPUFAs generally in chronic-medicated-older patients have reported varying degrees of therapeutic effects, and have suggested that supplementation with primarily omega-3 EPUFAs (EPA>DHA) may be preferable. We report the supplementation with a mixture of EPA/DHA (180:120 mg) and antioxidants (vitamin E/C, 400 IU:500 mg) orally morning and evening to schizophrenic patients (N=33) for 4 months. The red blood cell (RBC) membrane fatty acid levels, plasma lipid peroxides and clinical measures were carried out by established procedures at pretreatment, posttreatment and after 4 months of postsupplementation period to determine the stability of treatment effects within patients. Levels of fatty acids and lipid peroxides were compared with their levels in normal controls (NC) (N=45).Posttreatment levels of RBC EPUFAs were significantly higher than pretreatment levels as well as levels in normal controls without any significant increase in plasma peroxides. Concomitantly, there was significant reduction in psychopathology based on reduction in individual total scores for brief psychiatric rating scale (BPRS) and positive and negative syndrome scale (PANSS), general psychopathology-PANSS and increase in Henrichs Quality of Life (QOL) Scale. The EPUFA levels returned to pretreatment levels after 4 months of supplementation washout. However, the clinical improvement was significantly retained. Future studies need be done in placebo-controlled trials and also with a comparison group supplemented with fatty acids alone in a larger number of patients, both chronic as well as never medicated, and for a longer duration of treatment while the dietary intake is monitored. This may establish the EPUFA supplementation a very effective treatment to improve the outcome for an extended period of time.

Nerve growth factor in never-medicated first-episode psychotic and medicated chronic schizophrenic patients: possible implications for treatment outcome

Nerve growth factor (NGF) has been found to play a crucial role in the neuroplasticity of predominantly cholinergic neurons in brain development, and neuronal survival following brain injury, which reflect in cognitive performance. Wide ranges of neurodevelopmental abnormalities have been reported in schizophrenic patients, who also show poor cognitive performance. We report plasma NGF levels in never-medicated first-episode psychotic (FEP; N=24) and chronic medicated schizophrenic patients (N=24). NGF levels were determined in plasma by Enzyme-Linked ImmunoSorbent Assay (ELISA). Plasma NGF levels were significantly lower in both FEP and medicated chronic patients as compared to normal subjects (P<0.001). However, NGF levels were significantly higher in chronic schizophrenic patients, which were treated with antipsychotics as compared to FEP (P<0.05). Moreover, NGF levels in chronic patients treated with atypical antipsychotics were markedly higher as compared to patients treated with typical antipsychotics (P<0.05). Lower NGF levels in FEP patients at the onset of psychosis may have implications for the neurodevelopmental abnormalities. However, higher NGF levels in chronic patients treated with atypical antipsychotics may have implications for the treatment outcome.

Elevated plasma level of apolipoprotein D in schizophrenia and its treatment and outcome

Recently, apolipoprotein D (apoD), a protein that is involved in the essential polyunsaturated fatty acid (EPUFA) transport and metabolism, and neuronal growth and regeneration was reported to have increased in the postmortem brain and decreased in the serum of schizophrenia patients. We studied the plasma apoD levels in never-medicated schizophrenic patients at the onset of psychosis and in chronic patients with clozapine treatment. Plasma apoD levels were elevated in never-medicated patients at the first-episode of psychosis compared to normals (P = 0.047). Interestingly, the increase in apoD level was even more significant in chronic patients treated with clozapine compared to normals and first-episode patients (P = 0.008 and P = 0.03, respectively). The increased apoD level in never-medicated first-episode patients indicate that this increase probably predates the illness, since the duration of illness was < 5 days. Similarly, an even larger increase in apoD after clozapine treatment may be associated with its prophylactic effects, since the psychopathological scores were significantly reduced and the clozapine treatment has been found to increase the EPUFA membrane levels. These altered levels of apoD may help to understand the nature and possible mechanism of phospholipid membrane pathology in schizophrenia.

67. Neuroprotective actions of olanzapine in rat: cholinergic function

It has been hypothesized that schizophrenia arises from cell membrane abnormalities due to changes in phospholipid (PL) composition. Studies on erythrocytes and platelets suggest that alterations in membrane PL composition play a role in schizophrenia. It is essential to measure PL composition in the brain itself, which typically is only possible postmortem. In vivo P NMR of PL precursors and degradation products suggested changes in PL metabolism in the brain in schizophrenia, but solid-like PLs are not visible in typical in vivo NMR studies. Tissue PLs can be characterized according to headgroup and acyl-side-chain unsaturation usingin vitro P NMR. Postmortem brain tissue (gray matter) was obtained from left frontal cortex of 5 schizophrenics and 5 controls. High resolution P NMR spectra were obtained at 121.65 MHz. Phosphatidylinositol (PI) was significantly higher in the schizophrenic group relative to controls (p, 0.045). There were no differences between the two groups for other PL headgroups. The intensity of the PC peak representing molecular species with one saturated and one unsaturated acyl chain was higher in the schizophrenic group (p , 0.043). These results support the notion that PL abnormalities occur in the brain in schizophrenia, and that fatty acid metabolism may be abnormal. These observations have the advantage that they pertain to brain itself, and not peripheral tissue. However, the possible confounding effects of antipsychotic medication and perimortem factors must be considered.

Schizophrenia: Causes, course, and neurodevelopment

Schizophrenia, like other chronic medical conditions, is most likely the result of genetic and environmental risk factors. Whether these act independently or combine synergistically to confer “threshold liability” for the development of schizophrenia is presently undetermined and is a focus of intense research. The timing of pathogenic effects may also be crucial, both in terms of the expression and course of this illness. These aspects of the etiopathogenesis of schizophrenia and recent, pertinent publications are reviewed.

68. Neuroprotective actions of olanzapine in rat: mechanism

Psychotic patients treated with olanzapine (OLZ) do not exhibit extrapyramidal side-effects (EPS) similar to patients treated with haloperidol (HAL). Also, OLZ treated patients show significantly improved cognitive performance and negative symptoms, including patients previously treated with HAL. Haloperidol has been suggested to cause/exacerbate the neuropathological changes that are relevant to some of the sideeffects associated with its treatment. In animals, chronic HAL treatment has been found to cause neuropathology that is relevant to the behavioral effects, and this neuropathology is suggested to be a result of HAL associated free radical-mediated cellular damage. A possible mechanism of neuroprotection by OLZ against HAL induced neuropathology were studied in rats. Three groups of rats (CON, HAL, OLZ) were treated for 45 days and 90 days. After 45 days of treatment, one third (N 5 15) of the rats in each of the HAL and OLZ groups were switched to OLZ and HAL, respectively, in order to determine the protective/restorative actions of OLZ against HAL effects. The cellular effects were investigated by staining for DNA breaks that are often caused by free radical action and/or during replication/ translation. The cells were also stained with neuronal and glial markers to identify the cell types. After 45 days of treatment, a higher number of cells were labeled in cerebral cortex in OLZ group than HAL group, but fewer number of cells were labeled in caudate/putamen. The labeled cells were of both neuronal and glial types. There were no labeled cells in control group. The number of cells labeled decreased after 90 days of treatment proportionately in both drug groups but did not reach to the levels in controls. Preor the post-treatment with OLZ reduced the number of cells labeled compared to HAL treatment alone. The level of brain lipid peroxides, index of free radical damage, was higher in HAL group than OLZ group and was reduced by pre or post OLZ treatment, indicating that OLZ prevents the cellular neuropathology.