Research by Andreasen et al. published in American Journal of Psychiatry in June of 2013 reported that the dosage of antipsychotic medication correlated with the reduction in the cortex volume; higher dosage was associated with greater reduction. In that same article, the authors suggested that, since they found brain shrinkage correlated with duration of relapse, curtailing or preventing the relapse would probably decrease damage. Their suggested mechanism for shortening the relapse process was to prescribe more drugs. The validity of Andreasen et al.’s advice rests on two assumptions: (1) psychotic symptoms are signals that a volume reducing process is occurring; (2) anti-dopaminergic drugs actually prevent the brain-volume-reducing process as opposed to merely masking downstream manifestations of this process. There is some support in the literature for the first assumption. However, there is reason to believe that while antipsychotic drugs can mask symptoms, they don’t touch the processes that cause the damage and may, in fact, exacerbate the damaging processes. Thus, using antipsychotic drugs to reduce symptoms of physiological damage is analogous to the fire department disconnecting the smoke detector but doing nothing to put out the fire.
Oxidative stress, that is too many free radicals with an unpaired electron, has been implicated in schizophrenia. Oxidative stress as well as the chemicals that rid the body of free radicals (e.g., uric acid and glutathione) can be measured in blood, in the cerebrospinal fluid, and in the brain. A number of investigators have found elevations in free radicals and lower levels of antioxidants in persons exhibiting psychosis who were not taking medications (Arvindakshan, et al., 2003; Khan et al., 2002; Li et al., 2011; Mahadik et al., 1998; Owe-Larsson, et al., 2011; Yao et al., 1998; Zhang et al., 2009). Furthermore, the level of oxidative stress in unmedicated persons with psychosis correlates with level of negative symptoms (Arvindakshan et al., 2003; Li, Zheng, Xiu 2011) and positive symptoms (Mahadik et al., 1998; Zhang et al., 2009). Moreover, alleles for genes involved in production of glutathione are associated with risk for psychosis (Carter, 2006). Free radicals can damage all kinds of molecules. Presumably, the free radicals are the proximal cause of cortex damage. The correlation between symptoms and increased levels of free radicals is consistent (although not definitive proof) that symptoms reflect an acute process of damage.
Getting from free radicals to psychosis: Animal research illuminates the link between the free radicals and the creation of symptoms. The free radicals impair the function of an enzyme that makes GABA and eventually kills the GABA interneurons (Sorce et al., 2010). In fact, alterations in chandelier cells, a type of GABAergic interneuron, have been identified in the brains of schizophrenics at autopsy (Lewis, 2011). The interneurons, when functioning properly, place a break on the release of glutamate and dopamine (Nakazawa et al., 2013, p. 8; Schwartz, Sachdeva, & Stahl, 2012; Sorce et al., 2010). The case for hallucinations being caused by excessive dopamine release in the Nucleus Accumbens is pretty strong (Nakazawa et al., 2013). Cocaine and amphetamines which increase levels of dopamine in the Nucleus Accumbens reliably cause psychotic symptoms, as anyone who works in emergency rooms knows.
What the antipsychotic drugs do: Antipsychotic drugs displace dopamine from its receptor sites on the post-synaptic neuron. The signaling that dopamine would otherwise induce in the post-synaptic neuron does not occur. In the presence of the antipsychotic drug, the downstream effects of excessive dopamine, psychotic symptoms, are precluded. However, the damage to the cortex is not caused by the dopamine signaling; it is caused by free radical excess and in some theories inflammatory processes, which the antipsychotic drugs may fail to influence. The data on how antipsychotics influence oxidative stress is inconclusive and some have argued that the medications enhance oxidative stress (Ng et al., 2008; Mahadik, et al., 2006).
Caveat: Admittedly, much of this story is speculative. Schizophrenia is diagnosed on the basis of psychotic symptoms. There are probably multiple pathways to the same endpoint of too much dopamine signaling. Some pathways may be associated with brain volume reduction whereas others are not. Moreover, the story on interneurons is complex. GABA, generally known as an inhibitory neurotransmitter, may have differing effects on various cell subtypes. There are many types of GABA interneurons, although most theories identify basket cells and chandelier cells as relevant to schizophrenia (Chattopadhyaya & Di Cristo, 2012; Lewis, 2011). There are multiple pathways to disturbance of the interneurons, including low levels of stimulation of these neurons at their membrane NMDA receptors (Nakazawa et al. 2012). Moreover, interneurons play a role in both brain development and brain function. In the fetus, they help to set up the developing brain architecture. Obviously identifying proximal causes for various symptoms and possible brain volume reduction in unmedicated persons with schizophrenia will be difficult. I am also aware that Moncrieff has argued that brain volume reduction is not a component of the natural history of schizophrenia; so this also is controversial. However, if one assumes that the unmedicated trajectory of schizophrenia entails brain damage at least for some subtypes of schizophrenia, problems remain with Andreasen et al.’s recommendation. Proof is required that the antipsychotic drugs influence the mechanism for creating brain volume reduction.
Bottom Line: Before advising fellow physicians to increase the dosage of antipsychotic drugs to prevent brain volume reduction, it is important to show the following: first, demonstrate that symptoms, in fact, reflect the occurrence of a damaging process; second, demonstrate that any treatment intervention actually targets the damaging process itself and not just the downstream symptoms of this process. Hopefully, in future research, Andreasen et al. will measure free radicals to determine their correlation with symptoms of florid psychosis, brain shrinkage, and how antipsychotic drugs influence the free radicals. Before acting, it is important to “first do no harm”.
Arvindakshan, M., Sitasawad, S., Debsikdar, V., Ghate, M., Evans, D., Horrbin, D. F., Bennett, C., Ranjekar, P. K., & Mahadik, S. P. (2003). Essential polyunsaturated fatty acid and lipid peroxide levels in never-medicated and medicated schizophrenic patients. Biological Psychiatry, 53, 1, 56-64.
Carter, C. J. (2006). Schizophrenia susceptibility genes converge on interlinked pathways related to glutamateric transmission and long-term potentiation, oxidative stress, and oligodendrocyte viability. Schizophrenia Research, 86, 1-14.
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Khan, M. M., Evans, D.R., Guanna, V., Scheffer, R. E., Parikh, V.V., & Mahadik, S. P. (2002). 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 anti-psychotics. Schizophrenia Research, 58 (1), 1-10.
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Owe-Larsson, B., Ekdahl, K., Edbom, T., Ösby, U., Karlsson, H., Lundberg, C., & Lundberg, M. (2011). Increased plasma levels of thioredoxin-1 in patients with first episode psychosis and long-term schizophrenia. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 35 (4), 1117-1121.
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Sorce, S., Schiavone, S., Tucci, P. Colaianna, M., Jaquet, V., Cuomo, V., Dubois-Dauphin, M., Trabace, L., & Krause, K-H. (2010). The NADPH oxidase NOX2 controls glutamate release: a novel mechanism involved in psychosis-like ketamine responses. Journal of Neuroscience, 30(34), 11317-11325.
Yao, J. K., Reddy, R., & van Kamman, D. P. (1998). Reduced level of plasma antioxidant uric acid in schizophrenia. Psychiatry Research, 80, 29-39.
Zhang, X. Y., Chen, D. C., Xiu, M. H., Wang, F., Qi, L. Y., Sun, H. Q., Chen, S., He, S. C., Wu, G. Y., Haile, C. N., Kosten, T. A., Lu, L., & Kosten, T. R. (2009). The novel oxidative stress marker thioredoxin is increased in first-episode schizophrenic patients. Schizophrenia Research, 113, 2-3, 151-157.
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