Brain changes in people never medicated for mental illness and those who have been medicated
Some people have suggested that there is no difference in structure of the brain in people with mental illness; and those that do exist are caused by the medications. Some claim medications cause mental illness. Two papers are presented to address these beliefs.
The first summarizes research on people with mental illness who have never been medicated and shows that many exhibit brain abnormalities. This research on “medication-naïve patients shows these illnesses are real illnesses and are not caused by medications.
The second paper summarizes the research on people who have been medicated and shows they too have changes in brain structure. Some may be associated with the illness, others with the efficacy (or side-effects) of the medications.
Both papers are by Dr. E. Fuller Torrey
Brain structure in people with mental illness who have never been treated
There is a lot of misinformation regarding what is wrong with the brain in schizophrenia. Dr. Thomas Szasz has claimed that nothing is wrong and that schizophrenia is merely a “myth.”1 Dr. Peter Breggin has argued that people with schizophrenia bring the symptoms on themselves because of “cowardice” or “failure of nerve.”2 Dr. Daniel Fisher says schizophrenia is merely “severe emotional distress and loss of social role” brought on by “trauma.”3 Scientologists even claim that the symptoms of schizophrenia are caused by the drugs that are used to treat it.
All such statements indicate a profound ignorance about schizophrenia. Research has now clearly demonstrated that schizophrenia is caused by changes in the brain and that these can be measured by changes in both brain structure and brain function. Over 1,000 such research studies have been published. Schizophrenia is thus a disease of the brain in exactly the same sense that Parkinson’s disease, multiple sclerosis, epilepsy, and Alzheimer’s disease are diseases of the brain.
The same thing can be said about some other severe psychiatric disorders, specifically bipolar disorder (manic-depressive illness), schizoaffective disorder, severe depression, autism, and severe obsessive-compulsive disorder. Research studies indicate that all of these are also diseases of the brain, although far fewer such studies have been done on these disorders than on schizophrenia.
The following sections will briefly review the evidence for schizophrenia as a brain disease. The only studies included will be studies carried out on individuals with schizophrenia who, at the time of the study, had never received any antipsychotic medication. Such individuals are often referred to by researchers as being neuroleptic-naïve. Thus, these studies prove that the changes in brain structure and function seen in schizophrenia are clearly caused by the disease process, not by the medications used to treat the disease.
Since 1975, there have been at least 107 such studies. They can be divided into research on structural abnormalities, neurological abnormalities, neuropsychological abnormalities, neurophysiological abnormalities, and cerebral metabolic abnormalities.
The modern era in schizophrenia research can be dated to 1976, with the publication of the first research using the newly developed computerized axial tomography (CT) brain scans, which showed that the brains of individuals with schizophrenia have significantly larger fluid-filled spaces (cerebral ventricles) compared to unaffected controls. The CT scan was the first technology allowing for visualization of brain structures in living patients that could be used to statistically distinguish those with schizophrenia from unaffected controls.4 Following the introduction of CT scans, magnetic resonance imaging (MRI) scans also became widely available for studying brain structures.
Since 1976, a total of thirty-five studies of brain structure have been done on individuals with schizophrenia who had never been medicated.5
All six studies that measured the size of the brain ventricles found them to be significantly enlarged. For example, Gur et al. reported a 16 percent increase in ventricular volume in thirty-three never-treated patients compared to sixty-five unaffected controls. Similarly, McCreadie et al. reported a 20 percent increase in ventricular volume in forty-two patients compared to thirty-one unaffected controls. In addition to ventricular size, abnormalities in brain structure in never-treated individuals with schizophrenia have been reported for the frontal cortex, temporal cortex, hippocampus, amygdala, cingulate, thalamus, cerebellum, corpus callosum, and septum pellucidum. The only brain area that has been extensively studied and for which the results of different studies have been contradictory is the basal ganglia, especially its caudate subdivision.
Since 1976, at least thirty-three studies have reported significantly more neurological abnormalities in individuals with schizophrenia who had never been treated with antipsychotic medications compared to unaffected controls.
The neurological abnormalities include abnormal spontaneous movements called dyskinesias, parkinsonian signs, neurological soft signs, and cerebellar signs.
Dyskinesias are spontaneous movements, usually involving the tongue, facial muscles, or arms. Eleven studies have demonstrated that such movements occur more often among never-treated individuals with schizophrenia than among unaffected controls.6 For example, Fenton et al. found that 23 percent of never-treated patients exhibited some form of spontaneous dyskinesia. Eight recent studies have also reported that never-treated patients with schizophrenia have neurological abnormalities resembling those seen in Parkinson’s disease, including rigidity, tremor, and slowing of movements.7 Combining the studies, 91 out of 394 (23 percent) never-treated patients showed parkinsonian signs.
Neurological abnormalities called soft signs have also been extensively investigated in individuals with schizophrenia. Soft signs include such things as being unable to identify the type of coin placed in the hand without looking at it. Since 1992, fourteen research groups have assessed the presence of neurological soft signs in never-medicated patients with schizophrenia.8 Finally, a recent study compared neurological signs of cerebellar dysfunction in 155 never-treated individuals with schizophrenia to 155 matched unaffected controls. Among the patients, 21 percent had signs of cerebellar dysfunction, such as having an abnormal gait, whereas only 5 percent of the unaffected controls had such abnormalities.9
For almost two centuries, it has been observed that individuals with schizophrenia have deficits in some neuropsychological functions, especially memory, attention, and planning (also called executive function).
Since 1994, ten studies have been carried out on patients who had never received antipsychotic medications confirming these observations. For example, Brickman et al. compared twenty-nine never-medicated adolescents with schizophrenia to seventeen matched unaffected controls and reported that the patient group performed significantly worse than the unaffected controls, especially on memory, attention, and executive functioning.10
In addition to these ten studies, three other research groups studied individuals with first-episode schizophrenia, some of whom had never been medicated and some of whom had been briefly medicated, and reported that the never-medicated patients had significant neuropsychological deficits.11
Electrical impulses are one method used to communicate between brain cells. As noted previously, electroencephalograms (EEGs) have been used for many years to assess brain function in schizophrenia.
Consistent with past studies, two recent studies used EEGs to examine sleep patterns in never-medicated individuals with schizophrenia, and both reported more abnormalities in the patients compared to the unaffected controls.12
Another technique commonly used in psychiatric research to measure neurophysiological function is a type of electrical impulse called an evoked potential, elicited by auditory, visual, or sensory input. For example, a startle reflex, measured electrically, may be evoked by a loud sound.
Three recent studies of evoked potentials have been carried out on never-medicated individuals with schizophrenia; all three showed significantly more abnormalities in the patients than in unaffected controls.13 Another measure of neurophysiological brain function is the recently developed transcranial magnetic stimulation (TMS), in which the brain is stimulated using magnets.
A study of twenty-one neuroleptic-naïve individuals with schizophrenia reported them to be significantly different from twenty-one unaffected controls on some TMS measures.14 These studies suggest abnormal electrical and magnetic circuits in the brains of individuals with schizophrenia, evidence of neurophysiological dysfunction.
Cerebral Metabolic Abnormalities
The measurement of cerebral metabolic activity is comparatively new and technically complex. Three ways of doing this are by positron emission tomography (PET), single photon emission computed tomography (SPECT), and functional magnetic resonance imaging (fMRI). Since it is known that antipsychotic medications can affect these tests,15 it is important to use individuals who have not been treated whenever possible.
Since 1991, twenty-one studies have examined cerebral metabolic abnormalities in individuals with schizophrenia never treated with antipsychotic medications. Representative of these studies is one by Braus et al., in which twelve never-medicated patients with schizophrenia were compared to eleven unaffected controls by functional MRI. According to the researchers: “In comparison with control subjects, patients showed reduced activation in the right thalamus, the right prefrontal cortex, and the parietal lobe . . . bilaterally.”16 Of the twenty-one studies reported to date, all except one found more cerebral metabolic abnormalities in the individuals with schizophrenia compared to the controls.
In summary, since 1975 at least 107 separate studies have demonstrated that individuals with schizophrenia, who have never been treated with antipsychotic medications, have significant abnormalities in brain structure and function. This listing of studies includes only those related to brain abnormalities; additional studies have been carried out on antipsychotic-naïve patients with schizophrenia that have demonstrated other types of abnormalities such as altered interleukins, nerve growth factor, and red blood cell membrane essential fatty acids.17
Studies of medication-naïve patients thus demonstrate that abnormalities in schizophrenia are part of the disease process, not a result of medication being taken to treat the disease.
For neurological, neuropsychological, neurophysiological, and metabolic abnormalities of cerebral function, in fact, there is evidence suggesting that antipsychotic medications decrease the abnormalities and return the brain to more normal function.18 This is consistent with the known effectiveness of antipsychotic medications in reducing the clinical symptoms of schizophrenia.
The 107 studies cited, which were restricted to those in which the patients had not previously taken antipsychotic medication, are part of a much larger cohort of studies of cerebral structure and function in patients who had been medicated. Studies of neurologic soft signs in schizophrenia, for example, number over 50, and studies of neuropsychological abnormalities number well over 200.19
Altogether, there are now over 1,000 published studies on brain structure and function in individuals with schizophrenia.
It should also be emphasized that none of the cerebral abnormalities cited above are specific to schizophrenia. All of them can be found in some other brain diseases and occasionally in normal individuals, although they occur statistically more frequently in individuals with schizophrenia. Thus, the brain abnormalities found in schizophrenia are similar to the tremor seen in many patients with Parkinson’s disease. Tremor may also be found in other brain diseases; it occurs in some normal individuals [benign intention tremor], but it occurs statistically much more frequently in Parkinson’s disease.
- 1 Szasz TS. Schizophrenia: The Sacred Symbol of Psychiatry (Syracuse: Syracuse University Press, 1976).
- 2 Breggin PR, The Psychology of Freedom (Buffalo: Prometheus Books, 1980).
- 3 Condon G, quoting Daniel Fisher on WTIC-TV, Hartford, Connecticut, April 6, 2005.
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- 10 See Brickman AM et al., Neuropsychological functioning in first-break, never-medicated adolescents with psychosis, J Nerv Ment 2004;192:615–622. See also Saykin AJ et al., Neuropsychological deficits in neuroleptic naïve patients with first-episode schizophrenia, Arch Gen Psychiatry 1994;51:124–131; McCreadie RG et al., Poor memory, negative symptoms and abnormal movements in never-treated Indian patients with schizophrenia, Br J Psychiatry 1997;171:360–363; Lussier I, Stip E, Memory and attention deficits in drug naïve patients with schizophrenia, 2001;48:45–55; Schuepbach D et al., Selective attention in neuroleptic-naïve first-episode schizophrenia: a two-year follow-up (abstract), Biol Psychiatry 2002;51;118S; Kerns JG et al., Context-processing deficits and decreased prefrontal cortex activity: specific associations with unmedicated, first-episode Schizophrenia and with disorganization symptoms (abstract), Schizophr Res 2003;60:225; Hill SK et al. Impairment of verbal memory and learning in antipsychotic-naïve patients with first-episode schizophrenia, Schizophr Res 2004;68:127–136; Good KP et al., The relationship of neuropsychological test performance with the PANSS in antipsychotic naïve, first-episode psychosis patients, Schizophr Res 2004;68:11–19; Krieger S, Executive function and cognitive subprocesses in first-episode, drug-naïve schizophrenia: an analysis of N-back performance, Am J Psychiatry 2005;162:1206–1208; Snitz BE et al., Lateral and medial hypofrontality in first-episode schizophrenia: functional activity in a medication-naïve state and effects of short-term atypical antipsychotic treatment, Am J Psychiatry 2005;162:2322–2329.
- 11 Censits DM et al., Neuropsychological evidence supporting a neurodevelopmental model of schizophrenia: a longitudinal study, Schizophr Res 1997;24:289–298; Mohamed S et al., Generalized cognitive deficits in schizophrenia: a study of first-episode patients, Arch Gen Psychiatry 1999;56:749–754; Riley EM et al., Neuropsychological functioning in first-episode psychosis—evidence of specific deficits, Schizophr Res 2000;42:47–55. There are recent studies that show that antipsychotic medications improve neuropsychological functioning; see, for example, Keefe RS et al., The effects of atypical antipsychotic drugs on neurocognitive impairment in schizophrenia: a review and meta-analysis, Schizophr Bull 1999;25:201–222; Meltzer HY, McGurk SR, The effects of clozapine, risperidone, and olanzapine on cognitive function in schizophrenia, Schizophr Bull 1999;25:233–255; Merlo MCG et al., Improvement of cognitive functions in acute first-episode psychosis treated with risperidone (abstract), Schizophr Res 2002;53:27.
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DO ANTIPSYCHOTIC DRUGS CHANGE BRAIN STRUCTURE?
SUMMARY: Antipsychotic drugs, used to treat schizophrenia and manic-depressive disorder (bipolar disorder), change some aspects of brain structure, as do drugs used to treat Parkinson’s disease, epilepsy, and other brain diseases. Some of the brain changes appear to be related to the efficacy of the antipsychotic drugs, while other changes are probably related to the side effects of the drugs. Studying the brain changes may eventually lead to a better understanding of how they work and the prediction of which individuals are most likely to respond to which drugs and which patients are most likely to develop side effects, include tardive dyskinesia.
The publication of a paper by Dr. Paul Harrison, “Review: The Neuropathological Effects of Antipsychotic Drugs”1 has focused attention on this area of current research. Some opponents of the use of antipsychotic medication have misunderstood such research and have argued that brain changes prove that antipsychotic drugs are dangerous and should not be used. On the contrary, this research is very important and may eventually lead to better and more effective medications. The Stanley Foundation/NAMI Research Institute not only provides ongoing support for Dr. Harrison (he is the Director of a Stanley International Research Center and acknowledges the Stanley Foundation in the above-cited paper) but also supports many of the researchers doing work in this field, including Dr. Natalya Uranova (supported by a Stanley International Research Center) and Drs. Francine Benes and Rosalind Roberts (both recipients of Stanley Research Awards).
The findings that antipsychotic drugs produce structural brain changes should not be a surprise. Schizophrenia and manic-depressive disorder are known to produce structural brain changes as part of the disease process, so it is reasonable to expect drugs that are effective in treating these diseases to do likewise. Furthermore, many drugs known to be effective in other brain disorders also produce structural brain changes. For example, levodopa, a mainstay of treatment for Parkinson’s disease, has been shown to produce some changes in the cellular mitochondria and neuronal degeneration2. Phenobarbital, widely used for many years to treat some forms of epilepsy, has been shown to produce “lasting effects on fine structure of cells” in the cerebellum3. And diphenylhydantoin, also commonly used to treat epilepsy, has been shown to produce “marked dystrophic changes in the Purkinje cell axons”4 and to interfere with the formation of neuronal processes5. Drugs used to treat diseases of other organs of the body (e.g., heart, joints) also may cause structural changes of those organs.
Structural Brain Changes Caused by Antipsychotic Drugs
The following are the structural brain changes that appear to be caused by antipsychotic drugs. There is considerable ongoing work in this research area. The majority of the work to date has been carried out in rats and needs to be replicated in humans, since there are substantial species variation in brain structure and function.
Increased size of the striatum: An increased size of the striatum (the striatum is composed of the caudate and putamen and is part of the basal ganglia) has been found in human MRI studies of individuals taking some antipsychotic drugs6 but not with clozapine. The increased size is thought to be due both to increased blood flow and to structural changes of the neurons. It is not known whether this increased blood flow has any relationship to either the efficacy of the drug or its side effects.
Increased density of glial cells in the prefrontal cortex: Glial proliferation and hypertrophy of the prefrontal cortex is reported to be “a common response to antipsychotic drugs” and may “play a regulatory role in adjusting neurotransmitter levels or metabolic processes”7.
Increased number of synapses (connections between neurons) and changes in the proportions and properties of the synapses: This includes changes in the distribution and subtypes of synapses. The changes have been found primarily in the caudate nucleus of the striatum, and there is some evidence that they may also occur in layer 6 of the prefrontal cortex but not elsewhere. The changes may be secondary to the effects of the antipsychotic drug on dopamine or glutamate neurotransmitters. It is not yet clear what these changes mean; they may be related to the efficacy of the drug or may possibly be a marker for side effects. If the latter, being able to identify such changes in living individuals could potentially provide an early marker for tardive dyskinesia and thus indicate which individuals should not take these drugs. Most of these studies have been carried out in rats, so it is not yet known how applicable the findings are to humans. Virtually all the studies have used haloperidol (Haldol), so it is not yet known whether clozapine or other newer antipsychotics may also produce them.
Research on other kinds of structural brain changes caused by antipsychotic drugs has been negative to date. There is no evidence, for example, that antipsychotic drugs cause any loss of neurons or neurofibrillary tangles such as are found in Alzheimer’s disease.
In summary, structural changes in the brain caused by antipsychotic drugs are of major research interest since they may explain more precisely how these drugs work and/or predict which individuals are more likely to experience side effects. The changes caused by antipsychotic drugs used to treat schizophrenia and manic-depressive disorder (bipolar disorder) are similar in kind to structural brain changes caused by drugs used to treat Parkinson’s disease, epilepsy, and other brain diseases. It is incorrect to characterize these brain changes as an indication that these drugs are dangerous or should not be used.
- 1Harrison P. Review: the neuropathological effects of antipsychotic drugs. Schizophrenia Research 40:87-99, 1999.
- 2Ogawa N, Edamatsu R, Mizukawa K, Asanuma M, Kohno M, Mori A. Degeneration of dopaminergic neurons and free radicals. Advances in Neurology 60:242–250, 1993.
- 3Fishman RHB, Ornoy A, Yanai J. Correlated ultrastructural damage between cerebellum cells after early anticonvulsant treatment in mice. International Journal of Developmental Neuroscience 7:15–26, 1989.
- 4Volk B, Kirchgässner N. Damage of Purkinje cell axons following chronic phenytoin administration: an animal model of distal axonopathy. Acta Neuropathologica 67:67–74, 1985.
- 5Bahn S, Ganter U, Bauer J, Otten U, Volk B. Influence of phenytoin on cytoskeletal organization and cell viability of immortalized mouse hippocampal neurons. Brain Research 615:160–169, 1993.
- 6Chakos MH, Lieberman JA, Bilder RM, Borenstein M, Lerner G, Bogerts B, Wu H, Kinon B, Ashtari M. Increase in caudate nuclei volumes of first-episode schizophrenic patients taking antipsychotic drugs. American Journal of Psychiatry 151:1430–1436, 1994.
- 7Selemon LD, Lidow MS, Goldman-Rakic PS. Increased volume and glial density in primate prefrontal cortex associated with chronic antipsychotic drug exposure. Biological Psychiatry 46:161–172, 1999.