Introduction to Current Controversies in Schizophrenia Research
Introduction to Current Controversies in Schizophrenia Research
This past year has seen several interesting patterns in the literature on schizophrenia research. Increasingly, the emphasis has been on early detection and treatment, but two social aspects of the illness, comorbid substance abuse and suicidal behavior have also been investigated, one having a tendency to lead to the other. Clues to the etiology from brain imaging studies are reviewed in this issue, as well as a revival of the 'estrogen hypotheses' and olfactory processing as an indication of cortical dysfunction. Genetic susceptibility from the results of new large genome-wide scans and some new candidate genes have also been reported and are reviewed by Levinson (pp. 157-170). Genetics (see Malhotra (pp. 171-174)) is also examined by how genomics can aid in the prediction of treatment response and to the occurrence of deleterious side effects.
The original observation that the duration of untreated illness was a determination of outcome led some investigators to consider that neuroleptics given early on in illness may be doing more to the brain then just suppressing positive symptoms. Could they also be exerting a neuroprotective effect, preventing the deterioration that is described above? This was refuted specifically by Hoff et al., who found no correlation between the duration of untreated illness and the size of cerebral ventricles or cognitive function at the onset of treatment. Nevertheless, a whole field of 'early psychosis' has emerged to try and define premorbid symptoms that justify early neuroleptic treatment. In this issue, Verdoux and Cougnard (pp. 175-179) review this controversy. In addition, Hoff and Kremen (pp. 149-155) review how cognitive deficits and neuropsychology have been used to gage treatment response, and to be used in itself as a treatment modality as well.
Whether substance abuse of any kind is related to the etiology of some forms of schizophrenia has been a controversial issue for years. Many have seen amphetamine, PCP, mescaline, LSD and miscellaneous other drug-induced psychoses. However, whether or not these substances actually induce the lifetime course of schizophrenia long after the cessation of the drug is unclear. There are now reported epidemics of ingestion of metamphetamine containing plants, particularly in African countries, that have induced what appears to be chronic schizophrenia, which has become a nationwide social problem. Continual use of drugs, besides causing earlier onset of schizophrenia in vulnerable individuals, leads to poor outcome Certainly, this is an issue that requires attention from a prevention and treatment perspective.
Probably the most serious consequence of mental illness is the tendency for suicidal behavior. However, is the ability for self-annihilation biological? There is no doubt that suicidal behavior is not only a consequence of depression, but it is also increased in cases of schizophrenia. We have not yet come close to being able to predict suicidal behavior biologically, although it has long been thought that malfunctioning of the serotonin system is somehow associated with such behavior. The results of a large treatment trial indicate that clozapine treatment substantially prevents suicidal behavior, while another atypical neuroleptic, olanzapine, does not appear to have any implications and is in need of close follow-up. I suspect, however, that the best preventive measure in the long term is adequate community support mechanisms. From my own experience with first-episode patients with schizophrenia who have committed suicide, I found them to be somehow lost to follow-up care.
Niznikiewicz and colleagues (pp. 123-147) review recent findings that show reduced temporal and frontal structural brain changes in schizophrenia and evidence for connectivity change. Much to my surprise, our original findings of longitudinal structural change after the onset of schizophrenia have recently been confirmed in several different studies examining other aspects of brain structure, despite the claims of supporters of a neurodevelopmental hypothesis that this could not be so. We still need to interpret these findings cautiously, however, because it is unclear how long active deterioration may occur in each individual and, more importantly, whether it is meaningful clinically or just an epiphenomenon of other physiological changes.
What has been clear for a long time, regardless of the mechanism, is that the brain changes seen in schizophrenia must be related to the genetic susceptibility for the disorder Although there seems to be acknowledgment of this in a new wave of family magnetic resonance imaging studies, the most prevalently used study design hampers interpretation of the results. Too often, unrelated persons with schizophrenia and unaffected relatives are compared with controls, because such data are so much more easily obtainable. However, when some unaffected relatives appear to have findings similar to the patients, this is not easily interpretable, despite the conclusions drawn in many manuscripts that the findings represent genetic vulnerability. Several years ago, Reider and Gershon set out rules for these types of biological marker studies, but unfortunately these have not received much attention. Once a 'marker' is shown to be significantly different between patients and controls, it must be shown to be heritable and then segregated with illness within families having multiple ill members. We showed this many years ago with ventricular size and more recently with reduced Sylvian fissure asymmetry, but not recently when temporal and frontal cortical structure was examined (unpublished observations).
Extensive neuroendocrine investigations can be found in the early literature, with many previous attempts to provide hormone therapy to patients with mental illness without effect. It is doubtful that hormones are primary causes of the disorder and thus perhaps renewed interest is unwarranted. Nevertheless, we await further evidence from long-term estrogen replacement trials in older women. It is tempting to assume that the sex differences in neuroleptic responsiveness, age of onset and outcome in patients with schizophrenia are hormonal effects; however, data exist to refute this hypothesis and may implicate a role for the sex chromosomes. Estrogens have recently been revived as the cure for almost everything, from Alzheimer's to cardiovascular disorders. However, since estrogens have also recently been shown to lead to elevated risk for breast and possibly other cancers, caution is needed in their use.
Could olfactory deficits provide clues to the etiology of schizophrenia? This certainly seems plausible. Perception deficits have long been known to be at the core of schizophrenia, auditory are by far the most frequent, but visual and olfactory deficits have also been characteristic of the disorder with hallucinatory and perceptual disturbances. How these different sensory modalities are connected to frontal and temporal cortex may be crucial and aberrant in schizophrenia, and it is interesting that specifically the lateralization of these perceptions are anomalous.
It has long been thought that there is a familial pattern to neuroleptic response. Now that the field of pharmacogenetics has come of age (tailoring treatment to one's relevant genotype), these pursuits are being applied in psychiatry. However, there is no consistent marker as yet for response to conventional or atypical neuroleptics, or for prediction of their side effects, although in a review of this new field, Malhotra (pp. 171-174) is hopeful that this will happen. He suggests that variants in the 5HT2A and some dopamine receptors are the most likely candidates, given the actions of these drugs in general. Whether this field will ultimately be helpful to clinical psychiatrists in prescribing appropriate pharmacotherapies remains to be seen.
In summary, progress in schizophrenia research continues, although there is still a long way to go in the search for the etiology and preventive measures. Probably the field to follow most closely over the next couple of years is 'Psychiatric Genetics'. No factor elevates one's risk for schizophrenia more than that of family history for illness. However, research findings implicating several genes in schizophrenia susceptibility continue to hit the news reports prematurely. Time will tell whether the optimism displayed for several candidate genes by Levinson in his review (pp. 157-170) holds up. What most hampers this research is not knowing what the clinical entity 'schizophrenia' really is, whether it extends etiologically to other psychoses as well, what the underlying biological phenotype is, and how many genetically distinct biological phenotypes there may be, if more than one exists. I remain confident, however, that 2002 has seen more steps taken forward within the field.
This past year has seen several interesting patterns in the literature on schizophrenia research. Increasingly, the emphasis has been on early detection and treatment, but two social aspects of the illness, comorbid substance abuse and suicidal behavior have also been investigated, one having a tendency to lead to the other. Clues to the etiology from brain imaging studies are reviewed in this issue, as well as a revival of the 'estrogen hypotheses' and olfactory processing as an indication of cortical dysfunction. Genetic susceptibility from the results of new large genome-wide scans and some new candidate genes have also been reported and are reviewed by Levinson (pp. 157-170). Genetics (see Malhotra (pp. 171-174)) is also examined by how genomics can aid in the prediction of treatment response and to the occurrence of deleterious side effects.
The original observation that the duration of untreated illness was a determination of outcome led some investigators to consider that neuroleptics given early on in illness may be doing more to the brain then just suppressing positive symptoms. Could they also be exerting a neuroprotective effect, preventing the deterioration that is described above? This was refuted specifically by Hoff et al., who found no correlation between the duration of untreated illness and the size of cerebral ventricles or cognitive function at the onset of treatment. Nevertheless, a whole field of 'early psychosis' has emerged to try and define premorbid symptoms that justify early neuroleptic treatment. In this issue, Verdoux and Cougnard (pp. 175-179) review this controversy. In addition, Hoff and Kremen (pp. 149-155) review how cognitive deficits and neuropsychology have been used to gage treatment response, and to be used in itself as a treatment modality as well.
Whether substance abuse of any kind is related to the etiology of some forms of schizophrenia has been a controversial issue for years. Many have seen amphetamine, PCP, mescaline, LSD and miscellaneous other drug-induced psychoses. However, whether or not these substances actually induce the lifetime course of schizophrenia long after the cessation of the drug is unclear. There are now reported epidemics of ingestion of metamphetamine containing plants, particularly in African countries, that have induced what appears to be chronic schizophrenia, which has become a nationwide social problem. Continual use of drugs, besides causing earlier onset of schizophrenia in vulnerable individuals, leads to poor outcome Certainly, this is an issue that requires attention from a prevention and treatment perspective.
Probably the most serious consequence of mental illness is the tendency for suicidal behavior. However, is the ability for self-annihilation biological? There is no doubt that suicidal behavior is not only a consequence of depression, but it is also increased in cases of schizophrenia. We have not yet come close to being able to predict suicidal behavior biologically, although it has long been thought that malfunctioning of the serotonin system is somehow associated with such behavior. The results of a large treatment trial indicate that clozapine treatment substantially prevents suicidal behavior, while another atypical neuroleptic, olanzapine, does not appear to have any implications and is in need of close follow-up. I suspect, however, that the best preventive measure in the long term is adequate community support mechanisms. From my own experience with first-episode patients with schizophrenia who have committed suicide, I found them to be somehow lost to follow-up care.
Niznikiewicz and colleagues (pp. 123-147) review recent findings that show reduced temporal and frontal structural brain changes in schizophrenia and evidence for connectivity change. Much to my surprise, our original findings of longitudinal structural change after the onset of schizophrenia have recently been confirmed in several different studies examining other aspects of brain structure, despite the claims of supporters of a neurodevelopmental hypothesis that this could not be so. We still need to interpret these findings cautiously, however, because it is unclear how long active deterioration may occur in each individual and, more importantly, whether it is meaningful clinically or just an epiphenomenon of other physiological changes.
What has been clear for a long time, regardless of the mechanism, is that the brain changes seen in schizophrenia must be related to the genetic susceptibility for the disorder Although there seems to be acknowledgment of this in a new wave of family magnetic resonance imaging studies, the most prevalently used study design hampers interpretation of the results. Too often, unrelated persons with schizophrenia and unaffected relatives are compared with controls, because such data are so much more easily obtainable. However, when some unaffected relatives appear to have findings similar to the patients, this is not easily interpretable, despite the conclusions drawn in many manuscripts that the findings represent genetic vulnerability. Several years ago, Reider and Gershon set out rules for these types of biological marker studies, but unfortunately these have not received much attention. Once a 'marker' is shown to be significantly different between patients and controls, it must be shown to be heritable and then segregated with illness within families having multiple ill members. We showed this many years ago with ventricular size and more recently with reduced Sylvian fissure asymmetry, but not recently when temporal and frontal cortical structure was examined (unpublished observations).
Extensive neuroendocrine investigations can be found in the early literature, with many previous attempts to provide hormone therapy to patients with mental illness without effect. It is doubtful that hormones are primary causes of the disorder and thus perhaps renewed interest is unwarranted. Nevertheless, we await further evidence from long-term estrogen replacement trials in older women. It is tempting to assume that the sex differences in neuroleptic responsiveness, age of onset and outcome in patients with schizophrenia are hormonal effects; however, data exist to refute this hypothesis and may implicate a role for the sex chromosomes. Estrogens have recently been revived as the cure for almost everything, from Alzheimer's to cardiovascular disorders. However, since estrogens have also recently been shown to lead to elevated risk for breast and possibly other cancers, caution is needed in their use.
Could olfactory deficits provide clues to the etiology of schizophrenia? This certainly seems plausible. Perception deficits have long been known to be at the core of schizophrenia, auditory are by far the most frequent, but visual and olfactory deficits have also been characteristic of the disorder with hallucinatory and perceptual disturbances. How these different sensory modalities are connected to frontal and temporal cortex may be crucial and aberrant in schizophrenia, and it is interesting that specifically the lateralization of these perceptions are anomalous.
It has long been thought that there is a familial pattern to neuroleptic response. Now that the field of pharmacogenetics has come of age (tailoring treatment to one's relevant genotype), these pursuits are being applied in psychiatry. However, there is no consistent marker as yet for response to conventional or atypical neuroleptics, or for prediction of their side effects, although in a review of this new field, Malhotra (pp. 171-174) is hopeful that this will happen. He suggests that variants in the 5HT2A and some dopamine receptors are the most likely candidates, given the actions of these drugs in general. Whether this field will ultimately be helpful to clinical psychiatrists in prescribing appropriate pharmacotherapies remains to be seen.
In summary, progress in schizophrenia research continues, although there is still a long way to go in the search for the etiology and preventive measures. Probably the field to follow most closely over the next couple of years is 'Psychiatric Genetics'. No factor elevates one's risk for schizophrenia more than that of family history for illness. However, research findings implicating several genes in schizophrenia susceptibility continue to hit the news reports prematurely. Time will tell whether the optimism displayed for several candidate genes by Levinson in his review (pp. 157-170) holds up. What most hampers this research is not knowing what the clinical entity 'schizophrenia' really is, whether it extends etiologically to other psychoses as well, what the underlying biological phenotype is, and how many genetically distinct biological phenotypes there may be, if more than one exists. I remain confident, however, that 2002 has seen more steps taken forward within the field.
Source...