Funding for this monograph has been provided through an unrestricted educational grant by Eli Lilly and Company.
An expert panel review of clinical challenges in psychiatry
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Statement of Need and Purpose:
Advances in psychiatric neuroscience have led to very early identification of individuals at risk for psychosis, even during the prodromal stage where the psychosis has not yet manifested clinically but pre-psychotic stigmata appear. Clinical and biological studies of early psychosis are increasing the understanding of the pathogenesis, pathophysiology, and neurobiology of early psychosis. In this activity, neuroimaging, cognitive, and psychopharmacologic data of early psychosis will be presented.
This activity is designed to meet the educational needs of psychiatrists, primary care physicians, pharmacists, nurses, psychologists, and case managers.
• Recognize early psychosis as the phase of illness when comprehensive and appropriate treatment may offer the best protection against the deterioration that typically occurs in schizophrenia.
• Describe the neurobiological abnormalities reported in individuals with schizophrenia.
• Discuss the emerging findings in neuroscience and neuroprotection.
Faculty Affiliations and Disclosures:
Dr. Lieberman is chairman of psychiatry at the Columbia University College of Physicians and Surgeons, director of the New York State Psychiatric Institute, director of the Lieber Center for Schizophrenia Research, and psychiatrist-in-chief at New York Presbyterian Hospital and Columbia University Medical Center in New York City. Dr. Lieberman is a consultant to AstraZeneca, Eli Lilly, GlaxoSmithKline, Merck, and Pfizer; and has received grant/research support from Bristol-Myers Squibb and GlaxoSmithKline. Dr. Lieberman’s presentation does not include unapproved/investigative use of commercial products/devices.
Dr. Malaspina is professor of clinical psychiatry at Columbia University College of Physicians and Surgeons, director of the Laboratory of Clinical Neurobiology, and research psychiatrist at New York State Psychiatric Institute in New York City. Dr. Malaspina is a consultant to, is on the speaker’s bureaus of, and receives grant/research support from Wyeth. Dr. Malaspina’s presentation does not include discussion of any unapproved/investigative use of commercial products/devices.
Dr. Jarskog is associate professor in the Department of Psychiatry at the University of North Carolina School of Medicine. Dr. Jarskog is a consultant to Eli Lilly; and receives grant/research support from AstraZeneca. Dr. Jarskog’s presentation does not include discussion of any unapproved/investigative use of commercial products/devices.
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To obtain credit, you should score 70% or better. Termination date: April 30, 2008. The estimated time to complete this activity is 1 hour.
In this monograph, Jeffrey L. Lieberman, MD, introduces the phases of schizophrenic illness in relation to the concepts of progression and deterioration. Next, Dolores Malaspina, MD, reviews the neurodevelopmental and neurodegenerative components of schizophrenia. Finally, L. Fredrik Jarskog, MD, focuses on the neuroprotective aspects of therapeutic interventions in schizophrenia.
Jeffrey A. Lieberman, MD—Moderator
Current State of Treatment
This monograph reviews an exciting topic that will outline a new strategy for utilizing pharmacotherapy in the treatment of schizophrenia. As recently demonstrated by the National Institute of Mental Health (NIMH) Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study,1 the efficacy of the current antipsychotics are limited when used in patients during the chronic phase of illness. However, when used appropriately at the beginning of the illness, these medications can be very beneficial in terms of both controlling symptoms and preventing the progression of the illness. This is a process that may occur as a result of a mechanism of neuroprotection.
As noted by Kraepelin in 1919,2 people who are left to suffer the ravages of schizophrenia without treatment are persistently symptomatic, functionally disabled, and eventually require ongoing supervision and custodial care in an asylum. Patients with chronic schizophrenia are known as people who are disorganized and dysfunctional. However, most patients prior to their illness are for the most part normal individuals; the severe disability and persistent symptoms are often a result of progression of the illness due to inappropriate treatment or lack of treatment.
Course of Illness
Based on longitudinal studies and extensive research on the neurobiology of schizophrenia, we know that the illness begins with a genetic diathesis. However, genes only produce the potential to develop the illness—not the illness itself. Schizophrenic illness lies mostly dormant during the premorbid phase and begins to express itself after puberty when people enter the high-risk period of adolescence and early adulthood (Slide 1). The illness usually expresses itself in the form of prodromal, or nonspecific, early warning signs. It is only when those symptoms progress to the syndromal level that the person is said to have had a first break or episode of schizophrenia.
Treatment during the first episode of schizophrenia is very effective and patients who are treated at this early stage have a good chance of symptomatic remission and recovery. However, virtually all patients go on to develop subsequent episodes in the form of psychotic relapses. Patients may not achieve the same level of response to treatment of these subsequent episodes, and they may not recover as well either. This process has been described as clinical deterioration, which was the hallmark of the illness that led Kraepelin2 to identify it as dementia praecox.
Clinical progression and deterioration is not unique to schizophrenia; rather, it occurs in many brain disorders, including Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. However, while in those diseases the deterioration progresses inexorably to death or complete disability, in schizophrenia it reaches a plateau and is only somewhat self-limiting. At that point, the patient is said to be in the chronic/residual phase of illness, which consists of persistent symptoms and functional impairment. That is the level of illness that most patients live with for the rest of their lives.
We may now have the ability to prevent patients with schizophrenia from progressing and experiencing clinical deterioration. However, once they have arrived at the chronic stage of illness, we cannot necessarily restore them to their prior functioning.
Dolores Malaspina, MD, MSPH
Is Schizophrenia a Neurodevelopmental or Neurodegenerative Disorder?
There have been many recent advances in identifying important risk factors for schizophrenia, including susceptibility genes, prenatal exposures, and advanced paternal age. However, we have not yet discovered how to prevent or cure schizophrenia, which remains a very costly component of the global burden of disease.
In the early 1900s, Kraepelin1 proposed that schizophrenia is a degenerative disease after observing that deterioration, which is the core pathology of the disease, begins after an apparently normal childhood. In more recent years, a consensus developed that schizophrenia could be explained by brain developmental abnormalities. This model, which has become the more popular one, is based on observations that many patients with schizophrenia are shown in retrospective studies to have subtle abnormalities in development milestones, speech, and social function from the earliest stages of life. They also have many minor physical anomalies, including abnormalities of the arched palate and craniofacial structures that suggest abnormality in the development of the brain (Slide 2).
While the developmental and degenerative models are two different ways of explaining the disease, abnormal neuronal development and later neural degeneration are not exclusive processes. They may predominate at different illness stages and in different subtypes of illness. If neuronal degeneration plays an important role in the pathophysiology of schizophrenia, and the evidence suggests that it does, then there may be treatment opportunities through neural protection.
Our best clue about the genetic risk for schizophrenia also came from Kraepelin, who observed that the relatives of patients with schizophrenia had abnormalities in thought and functioning.2 Since then, decades of family, twin, and adoption studies have demonstrated recurrence of schizophrenia in relatives of patients with the illness (Slide 3). The risk of developing illness is 50% for an identical twin of an affected person, 10% among siblings, and 2% among cousins. The rapid decrease in risk based on degree of relationship indicates that no single gene explains the disease. It is thought that each individual has several susceptibility alleles that differ between family members.
The genes alone, do not predict the patient’s course of illness. One affected relative might have only 6 months of psychosis followed by resolution and no further symptoms, while another may require lifelong care. The course of illness can even differ markedly among identical twins.
Early genetic studies expected to link dopamine genes to the risk for schizophrenia, based on the hypothesis that excess dopamine function caused psychosis. While a few putative susceptibility genes are involved with dopamine, many more of them appear to be related to glutamate neurotransmission. Furthermore, many of the genes are not specific to schizophrenia, and have also been linked to bipolar disorders. We know that the risk for schizophrenia is not wholly explained by heredity. The same twin recurrence data that provide strong evidence for the importance of genes, also demonstrate the importance of non-genetic factors. While identical twins have an increased risk for schizophrenia, half of them stay well. This suggests that it is not genes alone, but an interaction of a person’s genes and the exposures that they have during the course of their life, that makes them more susceptible to expressing schizophrenia. These exposures can be intra-uterine, such as prenatal stress, preeclampsia, infection, or malnutrition; obstetrics events; or life exposures, such as cannabis abuse, stressors, or traumatic brain injury.3-6
Some epigenetic changes are rapid, but other lifelong epigenetic patterns are determined based on exposures that occur at key developmental periods, such as during fetal development.
Humans and other mammals do not develop from a DNA blueprint, but from maternal-placental-fetal interactions. The fetal environment provides information about the health of the mother and the kind of environment into which the offspring may be born. For example, offspring exposed to severe maternal stress during pregnancy have increased rates of stress sensitivity and perhaps of vigilance.7
The Human Genome Project has estimated that there are ~23,000 human genes. Half of these are expressed in the brain; however, each individual cell expresses only about 20% of the genes. While our view of heredity has been the DNA code, it is known that heritable changes in gene expression can occur without a change in the DNA sequence. Environmental exposures, even stress and medication treatments, can change gene expression. For example, a fetus does not develop from a genetic “blueprint.” There is interplay between the fetal genes and the maternal environment that can influence lifelong gene expression. Thus, there is another level of gene regulation that is separate from the sequence of nucleotides. This concept, which considers the effects of both genes and environment on gene expression, is called epigenetics.
Epigenetics involves such mechanisms as the placement of methyl groups in promoter regions of genes (typically preventing those genes from being transcribed), and the wrapping of DNA around histone proteins. Some of these changes in gene expression happen minute to minute, while a person is sitting, speaking, or responding to a stressor. Some medications actually shift gene expression. However, there are critical periods of life when lifelong gene expression may be established, and that may influence a person’s illness susceptibility. One of those time periods is during fetal life. The fetus receives signals about the health and environment of the mother through the placental circulation, including nutritional status, infection, and even stress. These exposures can determine the lifelong gene expression of the fetus, through a process called fetal programming. These effects of fetal exposures on adult-onset chronic disorders are becoming very well-known. Many adult-onset chronic diseases, such as hypertension, cardiovascular disease, obesity, diabetes, and some cancers, can be influenced by exposure to fetal adversity. These diseases remain latent until adulthood, when they present clinically and can progress.
The genotype of an individual may determine the developmental consequences of any fetal exposures or obstetric complications. For some genes, expression is also influenced by a process called parental imprinting (Slide 4). These genes are not expressed through a mendelian pattern, but based on inheritance from either the male or the female parent. For some genes the maternal copy is expressed and the paternal copy is silenced, and for others the converse is true. Many are related to development, growth, and behavior. We suspect that abnormalities in paternal imprinting may explain the strong association of advanced paternal age and the risk for schizophrenia, which may underlie a quarter of all schizophrenia cases.8
Degenerative and Developmental Components of Schizophrenia
There is strong evidence for neuronal degeneration that commences around the time of onset of psychosis. Postmortem data demonstrate altered cell structure in the hippocampal formation and in the prefrontal cortex. Neuroimaging data demonstrate neuronal changes over the course of illness, particularly loss of gray matter in early illness. Clinical deterioration after onset is evident in declining function, worsening symptoms, and decline in cognitive ability and intelligence test scores.
There is evidence for both a degeneration process as well as a developmental process of schizophrenia. The two are not necessarily exclusive hypotheses, although they may be predominant at different stages of illness and have separate risk factors. Some have claimed that the lack of increased incidence of Alzheimer’s disease in schizophrenia indicates that degeneration does not occur. However, this is a simplistic view as degeneration refers to changes in the integrity and circuitry of the brain system, which do not necessarily have to lead to an Alzheimer’s type of pathology to impact greatly on functioning of the brain.
One way to conceptualize both the neurodevelopmental and neurogenerative concepts in one model, is that a person’s vulnerability genes may influence the development of a prodromal condition. Other exposures (eg, stress, substance abuse, or traumatic brain injury) may further trigger the onset of psychosis, which may lead to deterioration (Slide 5). However, there is also a possibility for a more parsimonious model, where both the neurodevelopmental and neurodegenerative risk is laid down during fetal development. The risk for developmental abnormalities in childhood may be caused by direct effects on the development of the fetal tissues. Later on, fetal programming effects may constrain the health of neural functioning by influencing the expression of growth factor genes.
Disease Progression and Treatment Goals
Schizophrenia represents a disease with prenatal origins, in which there is the potential for secondary fetal effects on brain growth factors to become evident in later life and cause deterioration. Similarly, in many cases of cardiovascular disease, the roots of the illness lie in fetal development and symptoms first present in midlife. Physicians readily accept that diabetes, obesity, and cardiovascular disease, if not treated, will progress and cause morbidity and damage. The same is true about schizophrenia. Psychosis may be considered the tip of the iceberg of an underlying pathogenic process that is damaging the brain. Similar to stopping chest pain before it damages the heart muscle, psychosis needs to be treated promptly to prevent degeneration and deterioration.
Although it is important to identify the prodrome and provide early treatments to prevent psychosis, it is also important to treat early psychosis thoroughly. The symptoms of emerging and persistent psychosis may mark an underlying neurodegenerative process. Those patients who develop a deteriorating course may have been more symptomatic before their illness was recognized, showing a greater decline in functioning in their late adolescent premorbid period (Slide 6).9
Even after psychosis onset, untreated symptoms may signify ongoing neural damage. A study by Goetz and colleagues10 demonstrated that residual positive symptoms were significantly related to a deteriorating course, even when patients were on stable medication (Slide 7).
Clinicians should be encouraged to treat early to reduce the duration of untreated psychosis, particularly delusions.11 The emergence of psychosis is a very important time to intervene, and even subtle symptoms could herald future deterioration. The goal is to treat effectively, aiming for full remission of psychotic symptoms. In doing so, clinicians should offer their patients a full armamentarium of interventions to improve their long-term outcome and fu
nctioning. This includes combining medication with cognitive-behavioral or other therapies to minimize stress and optimize psychosocial outcome; and using job coaching, cognitive remediation, or other strategies to achieve and retain a full functional recovery (Slide 8).
L. Fredrik Jarskog, MD
Neuroprotection and Neurobiological Consequences of Treatment
Clinically, neuroprotection refers to treatment that helps to maintain the functional integrity of the central nervous system (CNS) in response to neurobiological stress.1 Neuroprotection is a rapidly advancing concept in the treatment of acute and chronic neurological disorders but has received little attention in the treatment of psychiatric disorders. Recent developments in our understanding of the pathophysiology and treatment of schizophrenia suggest an important role for neuroprotective strategies for this devastating illness. Neuroprotective strategies are potentially useful both as therapeutic interventions to improve actual loss of function, and as prophylactic interventions to minimize anticipated loss of function. Although prophylactic interventions hold promise for providing tremendous benefits, we currently lack predictive specificity for who is going to develop schizophrenia. This review will focus on the neuroprotective aspects of therapeutic interventions in schizophrenia.
It is well established that a functional deterioration follows the formal onset of psychosis in most patients.2 A key observation that has encouraged the search for neuroprotective treatments in schizophrenia is evidence that progressive brain changes accompany the functional decline early in the course of illness (Slide 9). Both longitudinal neuroimaging studies and postmortem neuropathological studies will be reviewed to support the view that schizophrenia is a limited neuroprogressive disorder that can benefit from neuroprotection.
Studies Demonstrating Neurobiological Changes Associated with Psychosis
Pantellis and colleagues3 recruited patients with prodromal symptoms who were judged to be at high risk for conversion to psychosis. Patients were scanned by magnetic resonance imaging (MRI) at study entry and then at regular intervals. Only those patients who actually went on to convert to psychosis demonstrated a significant loss of cortical gray matter in specific regions of the cortex, such as the orbito-frontal, medial and inferior temporal lobe, cingulate gyri, and the cerebellar cortex. This demonstrates that there are progressive brain changes even at the very earliest stages of schizophrenia (Slide 10).3
Similarly, Thompson and colleagues4 studied a cohort of patients with childhood-onset schizophrenia and found regionally specific progressive loss of cortical gray matter, especially in the prefrontal cortex, the parietal cortex, and the temporal lobe. The annual rate of loss was between 1% and 4% of cortical gray matter in these regions, and there was also a gender specificity regarding this loss (Slide 11).4
These two studies3,4 demonstrate that both in prodromal psychosis and in childhood-onset psychosis, there is progressive loss of gray matter in early stages of the illness. These data are also consistent with studies of young adults with first-episode schizophrenia.5,6 Taken together, the studies demonstrate that progressive neurostructural changes accompany the functional decline seen in the early course of schizophrenia. These observations have lead to the hopeful conclusion that if the rate of progressive decline can be slowed, both in gray matter loss and in overall level of function, then patients can have better long-term outcomes.
Potential Underlying Mechanisms for Loss of Gray Matter
There are several potential underlying mechanisms that could contribute to the loss of gray matter (Slide 12). One of the more favored hypotheses concerns glutamate excitotoxicity. It has been thought that hypofunction of the N-methyl-D-aspartate glutamatergic receptor may paradoxically lead to glutamatergic disinhibition associated with excess release of glutamate, resulting in excitotoxicity.7 This is a theoretically appealing hypothesis since it could potentially account for both clinical synptomatology and neuropathological deficits. However, to date it has been difficult to demonstrate evidence of glutamatergic excitotoxicity in schizophrenia, possibly because any excitoxic damage may be relatively transient and the resulting lesions may be subtle.
Other potential mechanisms that could impact on gray matter loss include oxidative stress, based on evidence of altered antioxidant levels, changes in the phospholipase A2 system, and glucocorticoid toxicity8; mitochondrial dysfunction, based on evidence of reduced mitochondrial numbers and volume and evidence of altered mitochondrial gene expression9; and reduced neurotrophic factor support, in which there is decreased brain-derived neurotrophic factor,10 possibly stemming from reduced glial cells numbers in the prefrontal cortex.11
One of the most recent mechanisms implicated in the pathophysiology of schizophrenia is apoptosis, a form of programmed cell death. Apoptosis can be activated by a number of triggers including each of the aforementioned mechanisms associated with schizophrenia. While apoptosis has normally been associated with neuronal death, its impact can also be sublethal, potentially accounting for neuronal atrophy and synaptic loss without large-scale cell loss. Several postmortem studies have demonstrated that apoptotic vulnerability may be increased in the brains of patients with chronic schizophrenia, even though active cell death is not occurring.12,13
Evidence for Reduced Neuronal Density in Schizophrenia
While postmortem studies do not allow us to track the longitudinal changes in terms of the progressive loss of gray matter, they do allow us to determine whether the neuropathology is consistent with reduced gray matter.
Rajkowska and colleagues14 demonstrated that in comparison to control subjects, prefrontal cortex in schizophrenia showed reduced size of neuronal cell bodies and increased neuronal density, while there was an absence of gliosis or neuronal loss. These investigators determined that a reduction in neuropil (consisting of synapses, dendrites, and axons) contributed to increased neuronal density. This is in contrast to the reduction in neuronal density found in the cortex of patients with Huntington’s disease (Slide 13). Importantly, these data distinguish the neuropathology of schizophrenia from classic neurodegeneration. However, the subtle pathology seen in schizophrenia is consistent with a more limited progressive disorder primarily affecting synaptic connectivity.
Further evidence to support altered connectivity has been demonstrated by Glantz and Lewis,15 who found that in patients with schizophrenia, there is a significant reduction in the density of dendritic spines on pyramidal neurons in prefrontal cortex (Slide 14). This reduction of synaptic content is consistent with the loss of cortical gray matter observed in neuroimaging studies.
Potential for Neuroprotection
Given the evidence of progressive gray matter loss, researchers have begun to address whether the progressive deterioration in schizophrenia can be slowed. A recently completed study examined whether the choice of antipsychotic medication influenced the rate of gray matter loss in the early stages of psychosis and whether this correlated with CNS function.
In a 2-year double-blind, randomized study, Lieberman and colleagues16 compared conventional and atypical antipsychotics on the clinical, cognitive, and neurostructural outcomes in first-episode psychosis. All participants met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,17 criteria for first-episode psychotic disorder, including schizophrenia, schizophreniform disorder, or schizoaffective disorder. All patients had been psychotic for <60 months, and had <16 weeks of cumulative prior antipsychotic treatment.
Almost 300 patients participated, and were randomized to olanzapine 5–20 mg/day or haloperidol 2–20 mg/day, doses adjusted as clinically indicated. Average doses were relatively low, at 10 mg/day for olanzapine and 4 mg/day for haloperidol. (In many previous studies that have compared conventional and atypical antipsychotics, haloperidol was used at considerably higher doses which increased the likelihood of side-effects that could bias against haloperidol. The current strategy assured a more meaningful comparison.) Cognitive and MRI assessments were performed at baseline and at 3 months, 6 months, 1 year, and 2 years. The expectation was that the study would demonstrate differential advantage for olanzapine over haloperidol on clinical, cognitive, and neurostructural measures.
The olanzapine-treated patients showed no significant change in whole brain gray volume over the course of the 2-year study. In comparison, the haloperidol patients showed a significant loss in whole brain gray volume starting at the 12-week mark and continuing over the course of the 2-year period (P<.05) (Slide 15). Significance was lost only at the 2-year mark, likely because of considerable patient attrition by that time.18
This is the first randomized study demonstrating that the choice of antipsychotic treatment determines whether progressive loss of gray matter occurs in first-episode psychosis. The total volume of gray matter is about 700 cc’s, and the average loss was 10–12 cc’s. Thus, while the effect was small, it may have a significant impact on cognitive and functional recovery.18
Cortical subregions, particularly the frontal cortex, showed similar patterns of gray matter volume changes (Slide 16).
Olanzapine-treated patients showed no significant loss in frontal cortical gray matter over the course of the 2 years, whereas haloperidol-treated patients showed significant loss at each time interval. Interestingly, in the temporal lobe there was a slightly different pattern, where the haloperidol-treated patients did not have a significant loss of gray matter, but the olanzapine-treated patients exhibited a small but significant increase in volume (Slide 17).18
Finally, neurocognitive composite scores indicated that for haloperidol-treated patients, less improvement in neurocognitive function was associated with greater decrease in gray-matter volume. This was seen for whole brain gray (P=.01), frontal gray (P=.001), and parietal gray (P=.003). Clinically, neurocognitive function has been identified as the most important measure determining functional outcome. Therefore, these findings suggest that treatment really does affect neurocognitive function and functional outcome and that these clinical measures appear to have important neurostructural correlates.18
What is the Basis of MRI-Observed Effects?
When considering the possible basis for the observed effects on MRI variables in the abovementioned study, two primary considerations emerge (Slide 18).18 One possibility is that the the loss of gray matter was a consequence of haloperidol-induced neurotoxicity and unrelated to the pathophysiology of schizophrenia. Preclinical studies have demonstrated haloperidol-induced neurotoxicity in animal models19 and tissue culture,20 providing some support for this interpretation. Alternatively, one could postulate that the underlying pathophysiology of schizophrenia involves progressive gray matter loss and that olanzapine exerted a neuroprotective effect against this measure of disease progression. Support for this interpretation comes from preclinical studies demonstrating neuroprotective qualities of atypical antipsychotics, including olanzapine,21 quetiapine,22 and risperidone,23 in response to neurotoxic stressors. While the basis for the observed changes in gray matter may represent a combination of pathophysiology and treatment effects, the current study could not distinguish between these two possibilities due to the absence of a placebo arm, which could not ethically have been included.
It is intriguing that there was the appearance of increased temporal lobe gray matter in the olanzapine-treated group, suggesting a potential neurotrophic effect of olanzapine. Again, certain preclinical data support this possibility; however, the effect in the current study was quite small and will need replication. If it turns out that certain medications can have a regenerative property, this could also prove very important for the more chronic stages of the illness.
Another possible basis for the observed effects is the differential effect of treatment on brain development. There is ongoing synaptic pruning during late adolescence and early adulthood,24 as well as cortical myelination that proceeds well into the twenties.25 Therefore, it is possible that differential effects on normal developmental processes contributed to the observed effects.
Finally, it is possible that the findings represented an artifact of the imaging process, although the authors could not identify any evidence to support this interpretation.
Beyond the use of antipsychotics, it will be of interest to examine whether agents that demonstrate neuroprotective properties in neurological disorders may prove to have neuroprotective effects in schizophrenia. Examples of such approaches include the free-radical-trapping agent NXY-059 that can enhance outcome in ischemic stroke,26 and the apoptosis inhibitor minocyclin that can potently protect in animal models against ischemia and several classic neurodegenerative disorders.27 Furthermore, nootropic agents such as the acetylcholinesterase inhibitor donepezil have been examined for cognitive and negative symptom improvement in schizophrenia with modest effects.28 It may be of interest to examine whether nootropics could also exert neuroprotective properties.
Schizophrenia is a neurodevelopmental disorder that also appears to encompass limited neuroprogressive features. Strategies aimed at reducing gray matter loss hold promise for improving functional dimensions of the illness. While underlying mechanisms remain uncertain, evidence of improved outcomes suggests that neuroprotection in schizophrenia is possible. Choice of treatment may impact the rate of decline and the downward trajectory of loss of function associated with schizophrenia, as demonstrated in the reduced loss of cortical gray matter and improved neurocognitive function observed with atypical antipsychotics.
Q: If you have a first-episode patient who is treated and gets better, how long should the patient keep taking the medication?
Dr. Lieberman: I think it is fair to say that there is no one-size-fits-all answer to this question yet, but it is probably safe to say that even if somebody chooses to stop medication, that does not mean they should stop treatment. They have to stay in touch and stay involved.
Dr. Malaspina: Absolutely. Active management of someone who has had a psychotic episode is very important.
Q: Should neuroprotection of medications be considered when selecting medications for children?
Q: People who have a family history of type 2 diabetes can influence their likelihood of developing diabetes by their eating and exercise habits. Does this kind of phenomenon exist with schizophrenia?
Q: Is it really possible that certain medications can have a regenerative property which may ultimately help during the more chronic stages of the illness?
Dr. Lieberman: That idea would have been completely preposterous several years ago. However, in the ensuing time there have been studies with antidepressants and mood stabilizers which suggest that those psychotropic drugs are able to stimulate brain growth.
Q: Minor physical anomalies and subtle social and cognitive impairments appear to be a signal of a genetically mediated effect on brain development. Being that these deficits do not occur in all patients before they develop schizophrenia, and are not outside the distribution of the normal population range, how are these findings applicable?
Dr. Malaspina: It is important to realize that we cannot predict who will go on to develop schizophrenia. Patients can indeed become ill quite suddenly without any previous abnormalities, and even when these abnormalities are found, they do not usually interfere with function and are apparently normal as children and adolescents. Findings of genetic effects on brain development are only of interest in epidemiology studies because they hint to us that some patients have stigmata of an unfolding abnormal brain development from very earliest life.
Q: The process of gene expression at conception and gestation is much more dynamic than previously thought. There is both heredity and environment involved, and there is a lot of potential for variability. Is this the basis for discordant monozygotic twins?
Dr. Malaspina: While identical twins share all of their genes, they may differ in the expression of those genes because of epigenetic differences. These epigenetic differences can arise because of different exposures, either in utero or during their lifetimes. Over evolution, this influence of the fetal environment on later health has likely been adaptive. For example, a fetus that is exposed to severe malnutrition will be more likely to be obese as an adult because of changes in the physiology of metabolism that favor the storage of fat reserves.
Q: The study by Thompson and colleagues2 reported volume reductions in gray matter of 1% to 4% annually in child-onset schizophrenia. How does this compare to the rate of decline in Alzheimer’s disease?
Dr. Jarskog: In Alzheimer’s disease, the rate of decline or loss is probably even greater, maybe on the order of 5% or more annually. However, in Alzheimer’s disease there is an inexorable continuation of loss ultimately until death. With schizophrenia, we would still expect that after a period of progression the annual loss in gray matter in childhood-onset schizophrenia would attenuate.
Dr. Lieberman: Yes. So there are two important differences. The disease is much less aggressive in schizophrenia than in Alzheimer’s disease and it is self-limiting, as opposed to just a disease that inexorably progresses to the point of complete devastation or death.
Dr. Jarskog: That is exactly right.
Q: It seems that because there has been so much emphasis on neurodevelopmental theories of schizophrenia, we have good models of how the illness evolves in children. However, we do not have well-developed models of what occurs after the onset of illness. Is that the case?
Dr. Malaspina: That is very true. The neurodevelopmental model would say that as the brain is forming, a latent lesion is wired in, which is only unmasked late in development due to maturational changes in the brain, and then presents as psychosis. But what we see is that there continues to be a progression of illness and a clinical deterioration after the psychosis occurs. Thus, the model is not sufficient to explain what we are seeing.
Q: A number of the genes that have been found either involve glutamate metabolism or synthesis, or are involved in synaptic transmission, including glutamate. Is it likely that glulatame exerts excitotoxic effects?
Dr. Malaspina: This is certainly a possibility. Glutamate may exert its effects by influencing higher cortical functioning or, perhaps, through a neurotoxicity mechanism.
Dr. Jarskog: The involvement of glutamate clearly can be both toxic and potentially therapeutic, depending on how it is modulated.
Q: Huntington’s disease has similar neuropathology to other neurodegenerative diseases while schizophrenia does not. It this why schizophrenia has been called the “graveyard of neuropathology”?
Dr. Jarskog: I think that the subtlety of the neuropathology really represents the challenge with schizophrenia. We are making headway in defining the many discrete deficits in schizophrenia; unfortunately, progress is quite slow. I think that with the advanced techniques that are available we are going to be able to ultimately dissect and define a more pathomnemonic neuropathology.
Dr. Lieberman: Let us hope so, but this is basically the search for the proverbial smoking gun. We are trying to find the root cause, the cellular basis, the fingerprint of schizophrenia. And although we have some clues, I think it is probably fair to say that we have not found it yet.
Dr. Jarskog: That is right.
Q: The olanzapine-haloperidol study1 mentioned suggests that a patient is much better off with an atypical in terms of gray matter preservation. However, I have patients who have been on low-dose haloperidol and patients who have been on atypicals, and I am not seeing tremendous improvements in their cognitive function even after prolonged treatment.
Dr. Lieberman: If you are beginning to treat them when they are 5, 10, 15, or 20 years into their illness, that may be too late for these differential effects to actually present. It is like you are trying to close the barn door after the horses have left. I think that the natural history of cognitive effects of schizophrenia are really less well-known as to whether it is a linear progressive process or not. At this point it looks like the greatest changes in terms of deterioration and loss of cognitive capacity appears to occur in the early phase of the illness. It is not clear if it progresses that much more after 5 or 10 years.
Q: In the neuroprotection study1 comparing haloperidol and olanzapine, the magnetic resonance imaging outcomes demonstrated that less improvement in neurocognitive function was associated with greater decrease in gray matter volume. What is the most significant aspect of this analysis?
Dr. Lieberman: I think it is an important analysis because previously there was awareness that schizophrenia patients tended to deteriorate over time, and there was the emerging body of evidence that there was a slight loss of gray matter volume, but the clinical course and the volume reduction had not been clearly associated. Doing a clinical trial with imaging as an outcome measure allowed for a determination of whether these were actually statistically associated, and it appears that they were.
Q: In the olanzapine versus haloperidol study,1 brain volumes did not appear to be reduced in olanzapine-treated patients. Is this due to a reversal of neurotoxicity? That is, might olanzapine have some inherent N-methyl-d-aspartate (NMDA) activity?
Dr. Jarskog: In animal studies, it appears that atypical antipsychotics, such as olanzapine and clozapine, have very different interactions with cortical and subcortical NMDA function when compared with haloperidol. This may indeed be an interesting avenue for understanding the beneficial role of olanzapine and other atypical medications.
Dr. Lieberman: It is interesting that the drugs do not have any affinity for glutamate or NMDA receptors, but they seem to act on these in some way. You may be correct about what the possible mechanism for these drugs reversing this progressive effect might be.
Q: It would have been unethical to have a non-treated group in the olanzapine versus haloperidol study.1 However, what would you expect to find had there been such a group?
Dr. Lieberman: If we would have been able to have a placebo-control group, the expectation would have been that that group would have done worse and would have had a greater loss of gray matter than either the haloperidol or the olanzapine group.
Dr. Jarskog: That is probably true. However, this continues to represent a critical issue in understanding the pathophysiology of schizophrenia and we will need to try to figure out new ways to answer this question.
Q: People with schizophrenia have reduced dendritic spines in the prefrontal cortex. Do they lose some of those spines from toxicity, or are they just not capable of growing them?
Dr. Jarskog: The neurodevelopmental hypothesis might posit that the reduction in spines represents an agenesis from early in development. Alternatively, a pure neurodegenerative hypothesis would propose toxicity from a defined pathophysiological process. Most likely, the real cause represents some combination of factors that may even include treatment-related factors as suggested by the first-episode psychosis study comparing olanzapine and haloperidol.
— Lieberman —
1. Lieberman JA, Stroup TS, McEvoy JP, et al. Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353(12):1209-1223.
2. Kraepelin E. Dementia Praecox. Barclay E, Barclay S, trans. New York, NY: Churchill Livingstone Inc; 1919/1971.
3. Lieberman JA, Perkins D, Belger A, et al. The early stages of schizophrenia: speculations on pathogenesis, pathophysiology, and therapeutic approaches. Biol Psychiatry. 2001;50(11):884-897. Erratum in: Biol Psychiatry. 2002;51(4):346.
— Malaspina —
1. Kraepelin E. Dementia Praecox. Barclay E, Barclay S, trans. New York, NY: Churchill Livingstone Inc; 1919/1971.
2. Gottesman II, Shields J. Schizophrenia: The Epigenetic Puzzle. Cambridge, UK: Cambridge University Press; 1982.
3. Krabbendam L, van Os J. Schizophrenia and urbanicity: a major environmental influence–conditional on genetic risk. Schizophr Bull. 2005;31(4):795-799.
4. Henquet C, Murray R, Linszen D, van Os J. The environment and schizophrenia: the role of cannabis use. Schizophr Bull. 2005;31(3):608-612.
5. Caspi A, Moffitt TE, Cannon M, et al. Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: longitudinal evidence of a gene X environment interaction. Biol Psychiatry. 2005;57(10):1117-1127.
6. Malaspina D, Goetz RR, Friedman JH, et al. Traumatic brain injury and schizophrenia in members of schizophrenia and bipolar disorder pedigrees. Am J Psychiatry. 2001;158(3):440-446.
7. Kofman O. The role of prenatal stress in the etiology of developmental behavioural disorders. Neurosci Biobehav Rev. 2002;26(4):457-470.
8. Malaspina D. Paternal factors and schizophrenia risk: de novo mutations and imprinting. Schizophr Bull. 2001;27(3):379-393.
9. Harkavy-Friedman J, Kimhy D, Goetz R, Malaspina D. Course of illness in schizophrenia: is there a relationship with premorbid social adjustment? Schizophr Bull. 2005;31:201.
10. Goetz D, Goetz R, Yale S, et al. Comparing early and chronic psychosis clinical characteristics. Schizophr Res. 2004;70:120.
11. Gunduz-Bruce H, McMeniman M, Robinson DG, et al. Duration of untreated psychosis and time to treatment response for delusions and hallucinations. Am J Psychiatry. 2005;162(10):1966-1969.
— Jarskog —
1. Ehrenreich H, Siren AL. Neuroprotection – what does it mean? – what means do we have? Eur Arch Psychiatry Clin Neurosci. 2001;251:149-151.
2. Lieberman JA. Is schizophrenia a neurodegenerative disorder? A clinical and neurobiological perspective. Biol Psychiatry. 1999;46:729-739.
3. Pantelis C, Velakoulis D, McGorry PD, et al. Neuroanatomical abnormalities before and after onset of psychosis: a cross-sectional and longitudinal MRI comparison. Lancet. 2003;361:281-288.
4. Thompson PM, Vidal C, Giedd JN, et al. Mapping adolescent brain change reveals dynamic wave of accelerated gray matter loss in very early-onset schizophrenia. Proc Natl Acad Sci U S A. 2001;98(20):11650-11655.
5. Kasai K, Shenton ME, Salisbury DF, et al. Progressive decrease of left superior temporal gyrus gray matter volume in patients with first-episode schizophrenia. Am J Psychiatry. 2003;160:156-164.
6. Cahn W, Pol HE, Lems EB, et al. Brain volume changes in first-episode schizophrenia: a 1-year follow-up study. Arch Gen Psychiatry. 2002;59:1002-1010.
7. Olney JW, Farber NB. Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry. 1995;52(12):998-1007.
8. Mahadik SP, Evans D, Lal H. Oxidative stress and role of antioxidant and omega-3 essential fatty acid supplementation in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2001;25:463-493.
9. Middleton FA, Mirnics K, Pierri JN, Lewis DA, Levitt P. Gene expression profiling reveals alterations of specific metabolic pathways in schizophrenia. J Neurosci. 2002;22(7):2718-2729.
10. Hashimoto T, Bergen SE, Nguyen QL, et al. Relationship of brain-derived neurotrophic factor and its receptor TrkB to altered inhibitory prefrontal circuitry in schizophrenia. J Neurosci. 2005;25:372-383.
11. Stark AK, Uylings HB, Sanz-Arigita E, Pakkenberg B. Glial cell loss in the anterior cingulate cortex, a subregion of the prefrontal cortex, in subjects with schizophrenia. Am J Psychiatry. 2004;161:882-888.
12. Jarskog LF, Gilmore JH, Selinger ES, Lieberman JA. Cortical bcl-2 protein expression and apoptotic regulation in schizophrenia. Biol Psychiatry. 2000;48(7):641-650.
13. Jarskog LF, Selinger ES, Lieberman JA, Gilmore JH. Apoptotic proteins in the temporal cortex in schizophrenia: high Bax/Bcl-2 ratio without caspase-3 activation. Am J Psychiatry. 2004;161(1):109-115.
14. Rajkowska G, Selemon LD, Goldman-Rakic PS. Neuronal and glial somal size in the prefrontal cortex: a postmortem morphometric study of schizophrenia and Huntington disease. Arch Gen Psychiatry. 1998;55(3):215-224.
15. Glantz LA, Lewis DA. Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Arch Gen Psychiatry. 2000;57(1):65-73.
16. Lieberman JA, Tollefson G, Tohen M, et al. Comparative efficacy and safety of atypical and conventional antipsychotic drugs in first-episode psychosis: a randomized, double-blind trial of olanzapine versus haloperidol. Am J Psychiatry. 2003;160(8):1396-1404.
17. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
18. Lieberman JA, Tollefson GD, Charles C, et al. Antipsychotic drug effects on brain morphology in first-episode psychosis. Arch Gen Psychiatry. 2005;62(4):361-370.
19. Mitchell IJ, Cooper AC, Griffiths MR, Cooper AJ. Acute administration of haloperidol induces apoptosis of neurones in the striatum and substantia nigra in the rat. Neuroscience. 2002;109:89-99.
20. Lezoualc’h F, Rupprecht R, Holsboer F, Behl C. Bcl-2 prevents hippocampal cell death induced by the neuroleptic drug haloperidol. Brain Res. 1996;738:176-179.
21. Wei Z, Bai O, Richardson JS, Mousseau DD, Li XM. Olanzapine protects PC12 cells from oxidative stress induced by hydrogen peroxide. J Neurosci Res. 2003;73:364-368.
22. Xu H, Qing H, Lu W, et al. Quetiapine attenuates the immobilization stress-induced decrease of brain-derived neurotrophic factor expression in rat hippocampus. Neurosci Lett. 2002;321:65-68.
23. Ukai W, Ozawa H, Tateno M, Hashimoto E, Saito T. Neurotoxic potential of haloperidol in comparison with risperidone: implication of Akt-mediated signal changes by haloperidol. J Neural Transm. 2004;111:667-681.
24. Huttenlocher PR, Dabholkar AS. Reginal differences in synaptogenesis in human cerebral cortex. J Comp Neurol. 1997;387:167-178.
25. Bartzokis G, Beckson M, Lu PH, Nuechterlein KH, Edwards N, Mintz J. Age-related changes in frontal and temporal lobe volumes in men. Arch Gen Psychiatry. 2001;58:461-465.
26. Lees KR, Zivin JA, Ashwood T, et al. Stroke-Acute Ischemic NXY Treatment (SAINT I) Trial Investigators. NXY-059 for acute ischemic stroke. N Engl J Med. 2006;354:588-600.
27. Zhu s, Stavrovskaya IG, Drozda M, et al. Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis. Nature. 2002;417:74-78.
28. Buchanan RW, Summerfelt A, Tek C, Gold J. An open-labeled trial of adjunctive donepezil for cognitive impairments in patients with schizophrenia. Schizophr Res. 2003;59:29-33.
— Question-and-Answer session —
1. Lieberman JA, Tollefson GD, Charles C, et al. Antipsychotic drug effects on brain morphology in first-episode psychosis. Arch Gen Psychiatry. 2005;62(4):361-370.
2. Thompson PM, Vidal C, Giedd JN, et al. Mapping adolescent brain change reveals dynamic wave of accelerated gray matter loss in very early-onset schizophrenia. Proc Natl Acad Sci U S A. 2001;98(20):11650-11655.
This roundtable monograph supplement is based on an i3 DLN broadcast presentation held December 20, 2005, in New York City. Funding for this monograph has been provided through an unrestricted educational grant by Eli Lilly. The content and views presented in this educational activity are those of the faculty and do not necessarily reflect those of Eli Lilly and Company, i3 DLN, or MBL Communications, Inc. The speakers have disclosed if any unlabeled use of products is mentioned in the material. Before prescribing any medicine, primary references and full prescribing information should be consulted.
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