They wander in like lost Buddhas,
awake when they wish to sleep.
Before their rest I bind them tight
to measure the strain of every breath,
anoint them with sensors
on scalp and chin.
Five rooms bear five seekers
who begin their journey never
   knowing
angels mistook Adam for immortal
before they saw him sleep.
Through the one-way mirror 
I watch their eyes
grow calm as summer lakes, 
surfaces shimmering in a breeze 
   of dreams
blown by varieties of waking.
Reverie glows in green lines
on my monitors, like threads
between underworld and paradise.
All night, patterns repeat
with the trance of prayers
until dawn startles the horizon
and I hum for shadows
to rejoin their bodies.
It is said that in heaven there is
   no sleep
and when I rouse my subjects
all swear they never slept.


Articles

Sleep Lab Meditation

Many people who have family members afflicted by psychiatric disorders wonder if mental illness is inherited. In fact, over the last several decades, research has provided clinicians with information and empirical risk estimates for some psychiatric disorders. Despite the large body of work, clinical implications of psychiatric genetic data have only recently become apparent. This reflects both increased media attention to genetics, as well as the growing sophistication of patients and their families.

In this article we will address two clinical applications of genetic information. First, we will discuss genetic counseling, which provides general principles to help clinicians communicate genetic risks to patients and family members. Genetic counseling is a well-established medical subspeciality, typically applicable to many rare non-psychiatric medical disorders. Second, we will discuss the potential adverse consequences and the ethical implications raised by the availability of genetic testing. We will illustrate ethical issues using lessons learned from genetic testing in classical Mendelian diseases and discuss established guidelines that may apply to psychiatric disorders.

There has been explosive growth in the number of disease genes identified over the past several years, giving clinicians more information about the heritability of many diseases. However, new knowledge can-and often does-create confusion. There are still several misconceptions concerning human genetics and psychiatric illness. The primary purpose of genetic counseling, therefore, is to correct misunderstandings about the heritability of psychiatric disorders, such as:

 If a disorder is genetic, it inevitably occurs in those who carry the harmful gene(s).

 The influence of genetic factors in psychiatric disorders is highly variable. More commonly, environmental and genetic interactions influence most psychiatric conditions. Furthermore, genetic and environmental influences are likely to differ between individuals and have variable impacts on each individual. Thus, the expression of a single disorder is not necessarily the same in each affected individual. It is also possible that an individual who carries the susceptible gene will not develop the disorder.

If a disorder is genetic, it is untreatable.

 Although many genetic conditions are currently untreatable (for example, Huntington's disease), most psychiatric disorders respond to some form of treatment. Similarly, while the underlying genetics cannot yet be changed, the expression of those genes can be treated. Individuals with identified psychiatric genetic disorders may mitigate the effects of the disorder through medical treatment, psychotherapeutic intervention and lifestyle changes. In addition, much scientific effort has been invested in gene therapy, with the eventual goal of reversing the effects of the deleterious gene. While this may sound like science fiction, gene therapy may become a reality in the future.3.) 

Genetic counseling is associated with eugenics and genocide. 

In fact, contemporary genetic counseling is non-directive, with an emphasis on individual autonomy and informed decision-making. The goal of genetic counseling is to disseminate current scientific knowledge concerning the disorder at hand and to aid the consultand (the person seeking genetic counseling) in making the best possible decision.As with other medical conditions, some psychiatric disorders are inherited while others are not. Genetic counseling serves to educate consultands and provide them with information concerning the disorder of interest. The Table* outlines the seven stages of genetic counseling. Multiple visits may be necessary to complete all stages. Genetic counseling should be tailored to the specific needs of the individual and their family. Interested readers are referred to the chapter entitled "Clinical Applications of Psychiatric Genetics" in Genetics in Mental Disorders: A Guide for Students, Clinicians, and Researchers (1999; Guilford Press) for additional details.

DNA-based tests are the newest technique in testing for genetic disorders. These techniques require direct examination of the DNA molecule (e.g., determination of the number of repeated DNA sequences in the Huntington's disease gene). Other genetic tests include those that detect gene products (e.g., biochemical tests, such as one that screens for phenylketonuria) and those that detect chromosomal changes by microscopic examination of fluorescent chromosomes (e.g., fluorescent in-situ hybridization techniques to screen for velocardiofacial syndrome). Genetic tests are currently used in a variety of situations, including:

presymptomatic testing for prediction of adult-onset disorders;

presymptomatic testing for estimating the risk of developing adult-onset diseases;

diagnostic testing for symptomatic individuals; 

>, genetic tests are currently available for over 700 diseases. For many at-risk individuals, the availability of genetic tests gives them the opportunity to relieve uncertainty and to appropriately plan for their future.

For treatable disorders, a positive test can result in a higher level of surveillance as well as intervention to reduce risk. Unfortunately, only a few genetic tests are definitive (e.g., the test for Huntington's disease, which is 99% predictive). In other single-gene disorders, although the presence of a mutation is highly predictive of the disorder (as in some forms of familial early-onset Alzheimer's disease [AD], in which age of onset is consistently before the age of 60), genetic testing is more complicated. Testing for mutations in one of the three known causative genes (presenilin 1) is clinically available. Testing is recommended only in individuals with age of onset of AD younger than 60 and who have another affected family member with early-onset AD. Although apparent sporadic cases of early-onset AD exist, there is still the possibility of false paternity or early death of an asymptomatic parent who carried the mutation. Testing is not recommended for people with late-onset AD, both sporadic and familial.

When testing at-risk individuals, an affected family member should be tested first to confirm the molecular diagnosis of the family. In the absence of this information, a negative test could simply indicate that the family has another genetic form of dementia. Testing for mutations in the two other genes (amyloid precursor protein and presenilin 2) is only available on a research basis. Testing for mutations causative for AD is not useful in predicting the age of onset, severity or type of clinical symptoms, or rate of progression of the disease.

The apolipoprotein E4 (APO E4) should not be used in presymptomatic testing. Although 35% to 60% of AD cases have an E4 allele, its presence is not highly diagnostic of AD. Furthermore, epidemiologic data in presymptomatic individuals with longitudinal follow-up are not well-established. In addition, there is consensus that children at risk for adult-onset disorders should not be tested in the absence of clinical symptoms. Additional information on testing guidelines for AD and other genetic disorders is available on GeneClinics' Web site <

In more common diseases, such as adult-onset cancers and coronary artery disease, only age-adjusted risk estimates can be provided. Likewise, most psychiatric disorders are presumed to be multifactorial (e.g., due to multiple genes and gene-environmental interactions). Many uncertainties regarding future presymptomatic testing in psychiatric disorders remain. Testing guidelines for individual disorders depends on who is at risk for specific disorders, the accuracy of risk prediction, the best age to provide test results and how the genetic test results are to be used to improve the lives of those tested.

Informed consent is the guiding principle behind the ethics of clinical practice and genetics research and testing. Consultands who choose to undergo genetic testing for clinical reasons should be thoroughly informed about the risks and benefits of the procedure and should always have the option to terminate the process. The counselor should discuss the potential social consequences of genetic testing with consultands. Unlike other laboratory tests, genetic tests may also reveal information about other family members, who, in turn, may or may not want access to this information. Part of the consent process should routinely describe the confidentiality of the data, although clinicians must inform the consultand that the genetic information is part of their medical records. Since stigmatization may occur as a consequence of test results, consultands should review their life and disability insurance prior to testing, as insurance companies have argued that they should have access to presymptomatic genetic testing results.

To compute the costs of health and life insurance, actuaries take into account many factors known to predict disease and death. Few people can argue with the rationale that smokers should pay higher health insurance premiums than non-smokers. Does a parallel argument justify the use of genetic information? Theoretically, insurance companies should have access to genetic profiles of individuals who apply for insurance. Should those who are at risk for untreatable or chronically debilitating disorders pay higher insurance premiums? Should insurance companies have the right to deny coverage to those individuals?

In the same vein, employers may want access to employee records regarding medical information including risk factors for genetic disorders since potential at-risk employees could eventually become less productive, and they may increase health care costs. Understandably, there is reason for concern that discrimination based on genetic testing could occur. Proponents have argued that employers should have access to genetic test results for disorders that may impair judgment and job performance in occupations involving the safety of the general public (e.g., commercial airline pilots and physicians).

The implications of the Human Genome Project have not escaped the attention of legislators. In the United States, several states have already enacted genetic privacy laws. In general, these laws limit the use of genetic data by insurance companies. However, the idea that genetic data should be treated differently from other clinical data has been hotly debated. Society can anticipate additional ethical and legal debates. Indeed, such debates are likely to intensify as the ability to predict behavioral and personality traits becomes a reality. Society will then have to decide the ethical, legal and social implications of this new knowledge. Much work is ongoing as part of the Ethical, Legal, and Social Implications Program of the Human Genome Project. (For additional information, please visit <

The Human Genome Project will undoubtedly provide an abundance of data to assist researchers in identifying the genes that contribute to human behavioral disorders. With the working draft of the human genome in hand, identification of genes relevant to human behavior continues. The implications of genetic data for diagnosing and treating psychiatric disorders remain speculative. Clinical applications often arise during the mature phases of a scientific discipline. As psychiatric genetics enters into the gene identification era, more clinical applications will be discovered. Although the future of psychiatric genetics will answer many scientific and clinical questions, it will also raise many questions about the legal, ethical and social implications of these answers. Medical and scientific advances may bring many gifts to society in the form of new knowledge; as clinicians and scientists, we should approach this new knowledge with caution, as one of these gifts could be a Pandora's box.

The Human Genome project has provided an abundance of genetic information, including identification of many disease-causing genes. Clinical applications, genetic counseling and the potential ethical issues raised by the availability of genetic testing are all areas of concern in gene research. Will genetic counseling in classical genetic diseases help to provide guidelines for behavioral disorders?

Clinical Uses and Ethical Implications of Psychiatric Genetic Counseling

(This is the first installment in a series of articles on the 2001 meeting of the New Clinical Drug Evaluation Unit [NCDEU]-Ed.)

Risperidone (Risperdal) and olanzapine (Zyprexa) were directly compared for several populations in studies reported at the 41st annual NCDEU Meeting of the National Institute of Mental Health in Phoenix, May 28-31.

In a double-blind study sponsored by risperidone manufacturer Janssen Pharmaceutica, 377 patients with schizophrenia or schizoaffective disorder were randomly assigned to receive eight weeks of treatment with either risperidone 2 mg to 6 mg daily (mean dose 4.8 mg) or 5 mg to 20 mg of olanzapine (mean dose 12.4 mg). The groups were similar in the number of patients who dropped from the study and in the number experiencing extrapyramidal side effects (EPS), as well as in the severity of their EPS. The researchers reported greater improvement with risperidone on the Positive and Negative Syndrome Scale (PANSS) anxiety/depression cluster and the depression and grandiosity items, but they found no significant differences between groups on individual factors.

In another Janssen-sponsored study, 176 elderly patients with schizophrenia were treated with either 1 mg to 3 mg of risperidone daily (mean 2 mg) or 5 mg to 20 mg olanzapine (mean 10 mg). While there was greater reduction in PANSS scores with risperidone at study midpoint, there were no significant between-group differences at eight weeks on this or the secondary efficacy measures, and the groups had a similar incidence of common adverse events.

In an assessment of the level of functioning of 30 patients with schizophrenia receiving eight weeks of treatment with either risperidone or olanzapine, researchers at University of California, San Diego, reported comparable improvement, measured with the Scale of Functioning (SOF). The SOF total scores increased 4.7% for 15 patients on risperidone and 6.5% for those on olanzapine, although the final analysis did not significantly differentiate the groups.

Both olanzapine and risperidone, as well as haloperidol (Haldol), appeared less effective than clozapine (Clozaril) in specifically reducing hostility symptoms in 157 treatment-resistant patients, in a study conducted by researchers at the Nathan Kline Institute at New York University and others. Patients were randomly assigned to 14 weeks of treatment with one of the four agents. The researchers reported that patients receiving clozapine evidenced greater improvement on the PANSS hostility item and that this difference was independent of antipsychotic effect. Neither risperidone nor olanzapine showed superiority over haloperidol on this measure.

An additional comparison of olanzapine and risperidone with a traditional neuroleptic was conducted in a naturalistic setting by University of Pittsburgh researchers. They commented that although the efficacy of atypical antipsychotics has been well-established, "the comparative effectiveness between agents is less clear. We set out to evaluate treatment effectiveness of olanzapine, risperidone and the conventional agent, perphenazine [Etrafon, Triavil, Trilafon]."

The researchers conducted a retrospective review of 386 patients discharged on one of these agents between January 1997 and June 1998. They found no statistical differences in one-year readmission rates between the groups nor in time to first admission. Other measures of drug effectiveness such as functioning were not applied nor were measures of how the drugs were tolerated.

Olanzapine was also compared to ziprasidone (Geodon) in a study sponsored by ziprasidone manufacturer Pfizer Inc. In the six-week assessment, 268 patients were randomized to receive either 5 mg to 15 mg olanzapine daily or 40 mg to 80 mg ziprasidone twice daily. The groups demonstrated comparable improvement on efficacy measures, as well as on movement disorder ratings. Although there were no significant differences on these measures, the researchers noted differences favoring ziprasidone on "health parameters" of weight gain and cholesterol level increase.

Addressing the issue of weight gain, Eli Lilly and Company researchers reported administering the histamine H

 blocker nizatidine (Axiol), a putative appetite suppressant, in combination with olanzapine in an effort to mitigate associated weight gain. In comparison to an olanzapine and placebo combination, there was significantly less weight gain in patients receiving 300 mg nizatidine twice daily, but not in those receiving 150 mg. In the 16-week treatment period, olanzapine with placebo was associated with an average body weight increase of 12.15 lbs; patients receiving nizatidine 150 mg twice daily with olanzapine gained an average of 9.72 lbs, and those receiving 300 mg twice daily with olanzapine gained 6.08 lbs.

Most antidepressant comparisons pitted a selective serotonin reuptake inhibitor antidepressant against a non-SSRI. In one comparative study sponsored by Wyeth-Ayerst, the rate of remission from depression in patients receiving its antidepressant, venlafaxine (Effexor), was compared to that in patients treated with the SSRI paroxetine (Paxil). In another Wyeth-sponsored study, the emergence of suicidal ideation was assessed in patients treated with either venlafaxine or one of several SSRIs.

In the first investigation, pooled original data from studies involving 1,108 patients with depression treated for eight weeks with venlafaxine, paroxetine or placebo were analyzed for achievement of remission, defined as a Hamilton Rating Scale for Depression (HAM-D-17) score of less than 7. The researchers reported a significantly greater remission rate at weeks 6 and 8 with venlafaxine (45%) than paroxetine (38%) and a significantly greater number of patients with an absence of symptoms (HAM-D-17 score of 0). They noted, however, that no significant treatment differences were discerned with the Montgomery-Asberg Depression Rating Scale (MADRS).

In the second study, emergence of suicidal ideation was defined as a change in HAM-D suicide item score at baseline from 0 or 1 to a score of 2 or more. Suicidal ideation was then found in 6%, 9.5% and 13.7%, respectively, of patients receiving venlafaxine, an SSRI or placebo. The differences on both the HAM-D and MADRS suicide items between venlafaxine and the SSRIs, and between venlafaxine and placebo, were significant, as were the differences between SSRIs and placebo.

Mirtazapine (Remeron) was compared with the SSRI sertraline (Zoloft) in patients who had not improved with another SSRI. In this study, which was sponsored by Organon, 119 patients were treated for eight weeks with mirtazapine (mean dose 30.4 mg) and 124 patients with sertraline (mean dose of 120.2 mg). The discontinuation rate due to adverse events was twice as high with mirtaza-pine (18.5%) as sertraline (9.5%). Antidepressant response on day 28, defined as a 50% reduction from baseline of HAM-D score, was demonstrated by 40.3% of patients receiving mirtazapine, compared to 27.4% of those on sertraline. Remission rates, however, were approximately 50% in both groups by day 56. Although this population had previously demonstrated resistance to an SSRI, these results were offered as evidence of earlier onset of action with mirtazapine.

In a retrospective analysis of pooled data from two eight-week trials, the effectiveness of bupropion sustained release (Wellbutrin SR) was compared to that of sertraline for alleviating anxiety symptoms in patients with depression. This GlaxoSmithKline-sponsored assessment determined that the antidepressants were similar in their antidepressant and anxiolytic effects. The researchers concluded, "Selection between these agents cannot be based on anticipation of differential anxiolytic effects."

With reversible monoamine oxidase-A inhibitor antidepressants such as moclobemide not yet available in the United States, there is interest in the selective monoamine oxidase-B inhibitor approved for Parkinson's disease, selegiline (Eldepryl), as a possible alternative for depression with less liability than the monoamine oxidase inhibitor antidepressants for hypertensive drug interactions. A transdermal delivery system for selegiline was investigated by manufacturer Somerset Pharmaceuticals to ascertain whether circumventing the "first-pass" hepatic metabolism of oral administration and delivering higher selegiline levels to the central nervous system also reduced potential for adverse interaction with co-administered pressor drugs or with dietary tyramine.

In the first safety study, 10 healthy volunteers received the selegiline transdermal system (STS) with 20 mg/20 cm

 alone and with pseudoephedrine (Sudafed) in increasing dosage over two weeks. Tolerance of the combination was ascertained through monitoring of vital signs, electrocardiograms (EKGs), physical examinations and clinical laboratory results. Administration of the STS alone had little effect on blood pressure or heart rate, while pseudoephedrine alone raised both. Addition of pseudoephedrine to steady-state administration of STS, however, caused minimal changes in the pressor response indicators; and there were no clinically meaningful changes in other monitored parameters.

In another manufacturer-sponsored safety study, 301 patients with major depression were randomized to receive either the STS or topical placebo over an eight-week period without dietary tyramine restrictions. Safety monitoring revealed adverse effects, most of mild to moderate intensity, in 82.6% of patients with the STS and 77.6% of those with placebo; a statistically insignificant difference. There were no statistically significant differences between the groups in vital signs, physical examination, laboratory or EKG. 

A separately reported kinetics study indicated that the STS provided higher and more sustained selegiline blood levels than oral administration, with significantly less metabolite formation. The researchers concluded that the transdermal administration of selegiline is safe for adults with major depression, and they anticipate future trials of efficacy.

The administration of rapid transcranial magnetic stimulation (rTMS) as a possible adjunct or alternative to electroconvulsive therapy (ECT) for major depression has been investigated in a number of open-label and sham-controlled trials. In a study sponsored by the Pritzker Foundation, the treatment was provided to 24 patients with treatment-resistant depression who had failed at least two adequate antidepressant trials and exhibited a HAM-D-17 total score of at least 18.

In the 21 patients completing the trial, involving a total of 120 stimulations over a two-week period, there was a 26% mean improvement in HAM-D total scores and a 37% mean improvement in the Beck Depression Inventory (BDI). In addition, 10 of the 21 patients rated themselves as much or very much improved on the Clinical Global Impression scale (CGI). Response was particularly prominent in women, with 53% having greater than 50% reduction in HAM-D or BDI, while no males achieved this level of response.

Vagus nerve stimulation (VNS), a procedure now indicated for treating severe epileptic seizures, also appeared safe and effective for patients with treatment-resistant depression in a study sponsored by the device manufacturer, Cyberonics. In 60 patients receiving the VNS implant device who completed eight weeks of the procedure while continuing antidepressant medication, 31% demonstrated a 50% reduction on the 28-item HAM-D. Twenty-seven percent had a 25% to 49% reduction, and 15% of patients met criteria for remission at the end of the study. There was congruence between the HAM-D-28 and the MADRS results.

The patients with most severe treatment resistance, indicated by failure to respond in seven or more adequate trials of antidepressant treatment, had a response rate of 6% with VNS, compared to 40% of patients who had failed two to six antidepressant trials. The researchers concluded, "VNS seems to be an effective treatment in patients with moderate treatment resistance and was well-tolerated by a majority of the patients."

This novel procedure, referred to as a "pacemaker for the brain" in some press coverage at the earlier American Psychiatric Association meeting in May, was approved for treatment of resistant depression in Canada in April and in Europe several weeks earlier. The first controlled study of VNS for depression (with implanted but inactivated devices in half of the 210 patients) is being conducted at 21 sites in the United States and Canada and is anticipated to be completed by mid-2002. 

In the first of this series of articles, some of the innovative research and technologies presented at the 41st annual New Clinical Drug Evaluation Unit meeting in Phoenix in May are discussed.

Leading Agents Compared; Innovations Assessed at NCDEU

The term neurosteroid refers to steroids formed in the brain. It was created in 1981 by Dr. Etienne-Emile Baulieu and colleagues, following the remarkable discovery that the brain appeared to have the capacity to synthesize its own steroids in situ. In a set of rodent experiments, these researchers determined that the steroid dehydroepiandrosterone sulfate (DHEAS) was present in adult rat brains at concentrations up to 20-fold greater than plasma (Corpechot et al., 1981). Moreover, brain DHEAS concentrations persisted unchanged for over two weeks following adrenalectomy and gonadectomy in these animals, demonstrating that central nervous system DHEAS levels were likely independent of peripheral DHEAS formation in the adrenals or gonads. Hence, the brain itself appeared to be a potential site of steroidogenesis, and subsequent efforts confirmed this possibility. These molecules became known as neurosteroids, since they can be synthesized de novo in the brain from cholesterol or from peripheral steroid precursors that cross the blood-brain barrier readily. 

, includes steroids formed in the brain and periphery that exhibit rapid actions on neuronal excitability. Unlike classical steroid mechanisms that involve the binding of intracellular receptors and the regulation of gene transcription, neuroactive steroids have nongenomic actions (Paul and Purdy, 1992). Specifically, neuroactive steroids bind to membrane-bound ligand-gated ion channel receptors. As a result, their actions occur very rapidly (over the course of seconds to minutes), in contrast to steroid genomic actions that require hours to days. Interestingly, certain neuroactive steroids with rapid nongenomic effects, such as progesterone, also exhibit traditional genomic steroid actions. Progesterone is considered to be a neurosteroid if  it is synthesized in the brain, hence, the terms neurosteroid and neuroactive steroid are often used interchangeably. 

Neurosteroids can therefore alter neuronal excitability very rapidly by binding to receptors for inhibitory or excitatory neurotransmitters at the cell membrane. Neurosteroid actions at inhibitory 

-amino-butyric acid type A (GABAA) receptors are the most extensively characterized to date, but neurosteroid activity has also been demonstrated at excitatory glutamatergic (N-methyl-D-aspartate [NMDA], 

-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid [AMPA], kainate), 5-HT

, glycine, sigma type 1 and nicotinic acetylcholine receptors (Rupprecht and Holsboer, 1999). Neurosteroid actions at GABA

 receptors can occur at low nanomolar physiologic concentrations, while neurosteroid activity at other receptor types frequently requires higher concentrations of 1.0 x 10

 M or greater. In addition to the characterization of neurosteroid actions at membrane-bound ligand-gated ion channel receptors, in the last decade it has also been established with certainty that enzymes leading to neurosteroid biosynthesis are present in glia and neurons in the brain (Compagnone and Mellon, 2000). In other words, the enzymatic biosynthetic machinery facilitating steroid formation from cholesterol in peripheral endocrine organs (such as the adrenals, ovaries and testes) is also present in the brain. 

Currently, there are relatively few neurosteroid clinical studies, however, converging evidence suggests that these molecules may be relevant to the pathophysiology and pharmacological treatment of psychiatric disorders such as depression and schizophrenia. Specifically, neurosteroids are differentially regulated in males and females and may, therefore, modulate the neurobiology of gender differences observed in a variety of psychiatric illnesses. Neurosteroids are important in neurodevelopment and regulate neuronal cytoarchitecture (Compagnone and Mellon, 1998), suggesting a potential role for these molecules in the pathophysiology of psychiatric disorders demonstrating a neurodevelopmental component and neuronal cytoarchitectural alterations such as schizophrenia. Finally, neurosteroids modulate GABAergic neurotransmission, are linked to antidepressant and antipsychotic drug action, act as neuroprotective agents, modulate the hypothalamic-pituitary-adrenal (HPA) axis, and represent potential targets for pharmacological intervention. These latter neurosteroid properties are discussed below. 

Certain neurosteroids bind with very high affinity to GABA

 receptors. For example, the neurosteroid 3

-pregnan-20-one (allopregnanolone) is synthesized by the reduction of progesterone via the enzymes 

-HSD). Astonishingly, allopregnanolone potentiates GABAergic neurotransmission with 20-fold higher potency than benzodiazepines and 200-fold higher potency than barbiturates (Morrow et al., 1990, 1987). Indeed, the neurosteroid progesterone metabolites allopregnanolone, its stereoisomer 3

-hydroxy-5ß-pregnan-20-one (pregnanolone) and the deoxycorticosterone metabolite 3

-pregnan-20-one (THDOC) are the most potent known modulators of GABA

   receptors. Many of the physiologic functions of these endogenous molecules in the human brain remain to be determined, but it is likely that allopregnanolone and other neurosteroids with GABA

 receptor activity might play an important role in the regulation of GABA, the major inhibitory neurotransmitter in the mammalian central nervous system.

 receptors are not completely understood. The GABA

 receptor is a pentameric complex with at least 21 subunit types involved in receptor assembly: 

 (Bonnert et al., 1999; Bormann, 2000; Penschuck et al., 1999). As a result, more than 500,000 different GABA

 receptor subunit combinations are theoretically possible (Lambert et al., 1996). Adding yet another level of molecular complexity, subunit composition appears to determine the pharmacological profile of GABA

 receptors. For example, benzodiazepines bind to GABA

 receptors but require the presence of a 

 subunit to potentiate GABAergic neurotransmission (Pritchett et al., 1989), suggesting that benzodiazepine activity may be limited to a specific subset of GABA

 receptors. In contrast, the neurosteroid allopregnanolone acts at a wide variety of GABA

 receptor subtypes with similar potency and efficacy and does not exhibit stringent GABA

 subunit specificity, possibly reflecting a broad spectrum of action in the central nervous system (Puia et al., 1990).

Recent efforts have linked neurosteroids to selective serotonin reuptake inhibitors. In a clinical study of 15 patients with major depression, cerebrospinal fluid (CSF) levels of the GABAergic neurosteroid allopregnanolone were decreased at baseline compared to control subject levels (Uzunova et al., 1998). Following treatment with fluoxetine (Prozac) or fluvoxamine (Luvox), CSF allopregnanolone levels increased in subjects with depression and correlated strongly with improvements in depressive symptoms. The authors hypothesized that SSRI-induced increases in allopregnanolone may represent a novel mechanism contributing to SSRI efficacy. 

Enzyme kinetic studies subsequently demonstrated that fluoxetine, paroxetine (Paxil) and sertraline (Zoloft) increase the efficiency of the enzyme 3

-HSD, which catalyzes allopregnanolone biosynthesis from its immediate precursor 5

-dihydroprogesterone (Griffin and Mellon, 1999), resulting in dramatically enhanced allopregnanolone formation. In addition, allopregnanolone is known to exhibit marked anxiolytic effects in rodents (Crawley et al., 1986; Wieland et al., 1991), consistent with its GABA

 receptor actions. These studies support the possibility that SSRI-induced allopregnanolone biosynthesis may be relevant to SSRI therapeutic actions in depression and anxiety. 

Neurosteroids have also been linked to antipsychotic drug action in recent rodent investigations. For example, the antipsychotic olanzapine (Zyprexa) dose-dependently increases the potent GABAergic neurosteroid allopregnanolone in rat cerebral cortex (Marx et al., 2000a), and preliminary evidence indicates that clozapine (Clozaril) has similar effects (Marx et al., 2001). Since GABAergic neurotransmission appears to be altered in schizophrenia (Lewis, 2000), antipsychotic-induced elevations in allopregnanolone may be relevant to this component of schizophrenia pathophysiology. If olanzapine also induces elevation in allopregnanolone in humans, it is possible that allopregnanolone may contribute to the efficacy of this antipsychotic. Olanzapine also has anxiolytic-like effects in animals (Arnt and Skarsfeldt, 1998), and, therefore, olanzapine-induced elevations in the anxiolytic neurosteroid allopregnanolone may represent a mechanism contributing to these actions. Finally, olanzapine has marked effects on rodent serum progesterone levels, a steroid that appears to have non-reproductive functions in addition to its well-established reproductive actions. For example, recent evidence suggests that progesterone plays an important role in myelination (Baulieu and Schumacher, 2000), a finding that may be relevant to schizophrenia, since recent evidence suggests a dysregulation in myelin-related genes in the disorder (Hakak et al., 2001). Future investigations will be required to determine the potential clinical significance of antipsychotic-induced neurosteroid alterations for schizophrenia pathophysiology and treatment.

Many lines of investigation demonstrate that neurosteroids have neuroprotective properties. For example, the GABAergic neurosteroid allopregnanolone demonstrates anticonvulsant effects in a variety of animal seizure models (Belelli et al., 1989; Devaud et al., 1995). A synthetic homologue of the inhibitory neurosteroid pregnanolone sulfate inhibits NMDA-induced current and cell death in rat hippocampal neuronal cultures and significantly reduces cortical and subcortical infarct size in rats (Weaver et al., 1997). The neurosteroid DHEA and its sulfated derivative DHEAS protect rodent embryonic cerebral cortical neurons from anoxia (Marx et al., 2000b), a neurodevelopmental stressor associated with increased schizophrenia risk. DHEA also protects neurons against glutamate and amyloid ß-protein toxicity (Cardounel et al., 1999), glucocorticoid toxicity (Kimonides et al., 1999), and numerous other insults resulting in oxidative stress. 

Interestingly, DHEA and DHEAS levels decrease markedly with age in humans, and levels in elderly populations are reduced to 20% to 30% of peak levels in young adulthood (Labrie et al., 1997; Orentreich et al., 1992), but the clinical relevance of this finding has not yet been established. Since DHEA has memory-enhancing effects in animals (Flood et al., 1992; Roberts et al., 1987), it has been hypothesized that DHEA has neuroprotective effects on cognition and that its age-related decline may be related to declining cognitive function with age in the elderly. Since a number of neurosteroids demonstrate prominent neuroprotective effects in a variety of rodent experimental systems, these molecules may function to modulate neuronal insults leading to psychiatric morbidity and merit further exploration in the clinical realm.

Several neurosteroids, including allopregnanolone and THDOC, have pronounced effects on the HPA axis. Allopregnanolone decreases corticotropin-releasing factor release from the hypothalamus (Patchev et al., 1994) and also dampens adrenocorticotropin hormone (Patchev et al., 1996) and corticosterone release (Guo et al., 1995; Patchev et al., 1996) in rats. Allopregnanolone is known to increase with stress (Purdy et al., 1991), and, therefore, stress-induced elevations in this neurosteroid would ultimately suppress the HPA axis. It has been hypothesized that stress-induced allopregnanolone induction may therefore represent an endogenous autoregulatory mechanism to restore homeostasis following a stressful event (Morrow et al., 1995). 

The GABAergic neurosteroid THDOC also appears to demonstrate HPA axis modulation. Specifically, THDOC appears to be protective against early adverse events in neonatal rats subjected to intermittent maternal deprivation (Patchev et al., 1997). Rats treated with THDOC and exposed to this stressor were protected against HPA axis dysregulation. Since many psychiatric disorders are stress-sensitive and illnesses such as depression demonstrate a dysregulation in stress hormones (including cortisol), neurosteroid modulation of the HPA axis may have important clinical ramifications.

Given accumulating evidence suggesting that neurosteroids may be important in psychiatric disorders and treatment strategies, the possibility that neurosteroids (or the enzymes leading to neurosteroid biosynthesis) may serve as targets for pharmacological intervention has received increasing attention. Limiting factors in drug development have included the rapid metabolism and poor water-solubility of neurosteroids, but efforts are currently underway to address these difficulties. For example, the synthetic neurosteroid ganaxolone is a 3ß-methylated analogue of allopregnanolone with more favorable pharmacokinetic properties (Gasior et al., 1999). Similar to allopregnanolone, it demonstrates anticonvulsant efficacy. At this time, it appears likely that neurosteroid drug development initiatives will yield a number of promising compounds to be utilized in the treatment of neuropsychiatric disorders in future years.

Neurosteroids are fascinating molecules with potential relevance to the pathophysiology and treatment of psychiatric disorders. Although future research will be required to characterize the precise roles of neurosteroids in psychiatric illness, current evidence is compelling and justifies further investigations into the actions of these unique compounds in the central nervous system.

The author thanks A. Leslie Morrow, Ph.D., and Jeffrey A. Lieberman, M.D., at University of North Carolina for their generous assistance.

Arnt J, Skarsfeldt T (1998), Do novel antipsychotics have similar pharmacological characteristics? A review of the evidence. Neuropsychopharmacology 18(2):63-101.
 

Baulieu EE, Schumacher M (2000), Progesterone as a neuroactive neurosteroid, with special reference to the effect of progesterone on myelination. Hum Reprod 15(suppl 1):1-13.
 

Belelli D, Bolger MB, Gee KW (1989), Anticonvulsant profile of the progesterone metabolite 5

-ol-20-one. Eur J Pharmacol 166(2):325-329.
 

Bonnert TP, McKernan RM, Farrar S et al. (1999), q, a novel 

-aminobutyric acid type A receptor subunit. Proc Natl Acad Sci U S A 96(17):9891-9896.
 

Bormann J (2000), The 'ABC' of GABA receptors. Trends Pharmacol Sci 21(1):16-19.
 

Cardounel A, Regelson W, Kalimi M (1999), Dehydroepiandrosterone protects hippocampal neurons against neurotoxin-induced cell death: mechanism of action. Proc Soc Exp Biol Med 222(2):145-149.
 

Compagnone NA, Mellon SH (1998), Dehydroepiandrosterone: a potential signalling molecule for neocortical organization during development. Proc Natl Acad Sci U S A 95(8):4678-4683.
 

Compagnone NA, Mellon SH (2000), Neurosteroids: biosynthesis and function of these novel neuromodulators. Front Neuroendocrinol 21(1):1-56.
 

Corpechot C, Robel P, Axelson M et al. (1981), Characterization and measurement of dehydroepiandrosterone sulfate in rat brain. Proc Natl Acad Sci U S A 78(8):4704-4707.
 

Crawley JN, Glowa JR, Majewska MD, Paul SM (1986), Anxiolytic activity of an endogenous adrenal steroid. Brain Res 398(2):382-385.
 

Devaud LL, Purdy RH, Morrow AL (1995), The neurosteroid, 3

-pregnan-20-one, protects against bicuculline-induced seizures during ethanol withdrawal in rats. Alcohol Clin Exp Res 19(2):350-355.
 

Although many of the physiological functions of neurosteroids are currently unknown, evidence suggests that these endogenous molecules may play a role in the pathophysiology of psychiatric disorders and treatment strategies. Neurosteroids have been linked to SSRI action and may be relevant to antipsychotic drug effects. Do neurosteroids have neuroprotective properties or HPA axis effects?

Neurosteroids and Psychiatric Disorders

For almost a century, researchers have suggested that schizophrenia is the result of brain-based abnormalities (Kraepelin, 1919). The first structural neuroanatomic studies conducted in patients with schizophrenia were undertaken in the 1930s and 1940s using pneumoencephalography -- a radiologic technique wherein cerebrospinal fluid (CSF) is replaced by air, thereby facilitating X-ray imaging of the brain ventricular system. These early investigations demonstrated lateral ventricle enlargement in some patients with schizophrenia (Haug, 1962). A few investigators found evidence of progression of ventricular enlargement in severely ill patients; however, technical factors involved in image acquisition limited the veracity of the results.

The first computed tomography (CT) scan study in patients with schizophrenia was published in 1976 by Johnstone et al. The researchers found that, in chronically ill patients, ventricle enlargement was common and most pronounced in those patients who were most ill (i.e., had the most negative symptoms). Since that time, dozens of studies have replicated the finding of ventricular enlargement in schizophrenia (as well as findings of cerebral cortical atrophy) (Shelton and Weinberger, 1986), some found evidence for progression (Illowsky et al., 1988; Nasrallah et al., 1986), while others did not (Kemali et al., 1989; Woods et al., 1990). The discrepancy in results is very likely the result of methodologic differences between studies.

Magnetic resonance imaging studies in schizophrenia began to appear in the psychiatric literature in 1984 (Smith et al., 1984). Since then, this powerful imaging technology has allowed researchers to demonstrate a number of neuroanatomic findings, in addition to confirming findings from CT studies. These include reduction in the size of the hippocampus and amygdala (Hirayasu et al., 1998), superior temporal gyrus (Pearlson, 1997), and frontal and temporal lobes (Woodruff et al., 1997), as well as changes in corpus callosum size (Jacobsen et al., 1997) in patients with schizophrenia. Magnetic resonance imaging offers many advantages over CT scans, such as greater spatial resolution, the ability to separately measure gray and white matter volume, and the ability to image the brain in any plane. Advances in MRI technology, accompanied by the availability of increasingly powerful computerized image analysis technology, have allowed highly detailed and reliable measurements of various brain structures, both cross-sectionally and over time. As with CT studies, longitudinal MRI studies conducted in patients with schizophrenia have yielded mixed results in terms of evidence for progressive neuro-anatomic changes (DeLisi, 1999).

Several recent structural imaging studies have demonstrated progressive neuroanatomic changes in some patients with schizophrenia. These studies have methodologic advantages over prior work, such as more homogenous patient populations, larger study populations, and/or use of sophisticated image analysis techniques. The result of these improvements is greater sensitivity to detect subtle changes in neuroanatomy over time.

Giedd and colleagues (1999) studied 42 patients with childhood-onset schizophrenia (COS) and compared them to 74 control subjects drawn from a neuroimaging database used to study normal brain development. Due to its severity, COS -- a particularly virulent form of schizophrenia with multiple similarities to adult-onset schizophrenia -- may be a particularly fruitful setting in which to conduct studies investigating brain changes related to the illness. Patients and controls were carefully screened and underwent MRI imaging at study entry and at approximately two-year intervals for one to three follow-up timepoints. The MRI scans were used to quantify total volume of the cerebrum, lateral ventricles, hippocampus and amygdala. The volume of these structures and a measure of their left-right laterality in patients and controls were compared at each scan time. The severity of patients' illnesses was quantified by rating global psychopathology (Brief Psychiatric Rating Scale [BPRS]), positive symptoms (Scale for the Assessment of Positive Symptoms [SAPS]) and negative symptoms (Scale for the Assessment of Negative Symptoms [SANS]) at baseline and at the time of each follow-up scan. Statistical comparisons were conducted both with and without controlling for total cerebral volume.

At study entry, patients and controls were similar in age, gender, handedness and height; patients' weights were significantly greater than controls. At initial scan, patients had significantly smaller total cerebral volume and larger lateral ventricle volume than control subjects. Volumes of the hippocampus and amygdala did not differ between groups. In the patients with COS, but not in the controls, there was a significant decrease in total cerebral and hippocampal volume and an increase in lateral ventricle volume during follow-up. Amygdala volume did not change with time. In the control group, none of the structures assessed changed significantly with time. There were no group differences in laterality for any structure. The volume-by-time curves for cerebral, hippocampus and lateral ventricle volumes were significantly nonlinear, tending to asymptote during adolescence. Change in negative symptom severity correlated positively with change in ventricle volume, and positive symptom change correlated inversely with change in hippocampal volume. In other words, patients with greater decline in hippocampal volume experienced less improvement in positive symptoms over time, whereas greater increases in lateral ventricle volume were associated with greater improvement in negative symptoms during the course of the study. This finding may stem from the curvilinear relationship between change in ventricle volume and time or other statistical anomaly.

The authors pointed out that the rate of change of cerebral, lateral ventricle and hippocampus volume could not continue in a linear fashion without producing gross neurologic abnormalities. The fact that the volume-by-time curves appear to level off during late adolescence point to this developmental period as potentially important in the pathophysiology of schizophrenia. During this time, synaptic pruning is intense and important metabolic changes occur, highlighting the importance of this accelerated developmental epoch. These investigators also pointed out that their finding of progressive neuroanatomic changes during the course of illness is not inconsistent with neurodevelopmental theories of schizophrenia.

In contrast to the relatively young, early-onset patients (Giedd et al., 1999), Mathalon and colleagues (2001) examined brain changes occurring over time in patients with schizophrenia. The 24 patients with schizophrenia and the 25 controls were matched on handedness, age and inter-scan interval. Baseline MRI scan data were compared with data obtained from follow-up scans conducted a mean of 3.6 years after initial scans in patients and after a mean of 4.2 years in controls. Patients were drawn from inpatient units in a U.S. Department of Veterans Affairs hospital associated with Stanford University. Control individuals were community volunteers involved in clinical and normal-aging neuroimaging studies, during which they were rescanned at various intervals over time. Both groups were systematically screened utilizing structured diagnostic interviews. 

Patients were initially treated in the VA system, and many received follow-up care there as well. However, patients were not followed systematically in terms of documenting symptom severity or treatment variables as part of the study. Patients' symptom severity (assessed via the BPRS) and other clinical data (e.g., number of hospitalizations) were obtained by the investigators near the time of each scan. The mean of the baseline and follow-up BPRS scores was used as an index of illness severity during the inter-scan interval.

Magnetic resonance imaging scans were obtained at both time points utilizing identical scan acquisition protocols. The images were used to quantify region of interest (ROI) volumes representing intracranial contents; lateral ventricles; pre-frontal, frontal, temporal, parietal and occipital lobes; and the superior temporal gyrus. Change in ROI volume over time was quantified by determining the rate of change (slope) of each ROI volume over time. These slopes were compared between patients and controls to assess differences in rates of structural change with time, controlling for group differences in premorbid IQ and age.

The authors found that left lateral ventricle and right frontal sulcal (CSF) volume increased and gray matter volume decreased faster in patients with schizophrenia than in control subjects. Additionally, in patients with schizophrenia there were more rapid bilateral increases in the volume of prefrontal and posterior superior temporal sulci (CSF) and more decreases in posterior superior temporal gray matter volume than there were in controls. In 14 of 18 ROIs examined, patients with schizophrenia demonstrated faster progression than controls, although not all comparisons were statistically significant. Furthermore, these results remained the same whether or not the analysis statistically controlled for baseline ROI volume.Comparing symptom severity at baseline and follow-up scan times, patients were significantly less ill at follow-up. Higher BPRS total scores were significantly correlated with greater frontal sulcal expansion and anterior temporal gray matter decline. Higher positive symptom scores correlated with more rapid frontal sulcal expansion and faster decline in left frontal gray matter volume. Negative symptom severity correlated with faster decline of prefrontal gray matter volume and expansion of right prefrontal sulci.

The authors also noted that their results are similar to previously published works on several fronts. Their findings support the theory of progressive degenerative neuroanatomic changes, involving several brain regions, in patients with schizophrenia during the course of the illness. Furthermore, because greater brain changes over time were associated with greater symptom severity and poorer clinical course, neuroanatomic changes may reflect the neurotoxic effects of psychotic illness. The pathophysiologic mechanism(s) underlying psychosis-related neurotoxicity include abnormal regulation of excitatory amino acid and/or neuroprotective systems. The authors further noted that their findings suggested that neurodevelopmental theories do not account for all neuroanatomic abnormalities seen in the brains of patients suffering from schizophrenia. Due to the fact that they had only two data points, they could not fully describe the pattern and rate of change of neuroanatomic structures in schizophrenia over time. Other limitations included using only male subjects, geometrically defined (as opposed to anatomically defined) ROIs, and lack of detailed follow-up data related to symptoms, resource use and medication compliance.

The two previously described studies looked at brain changes over time involving volume (size) of various brain structures. Gharaibeh and colleagues (2000) studied the change in brain shape independent of the size of the structures examined. This investigation utilized shape analysis techniques, developed by Fred Bookstein, Ph.D., at University of Michigan, that involved averaging the shape of a set of neuroanatomic landmarks on MRI scans of both patients and controls. The analysis mathematically eliminates the effects of size and rotation on the landmark set and statistically tests differences in landmark shape between groups under study. It can also be used to produce averaged MRI images that pictorially display group differences.

In the study, 55 patients with a first episode of non-affective psychosis (the majority were diagnosed with schizophrenia when reassessed over time) and 22 controls (matched with patients on age, gender and socioeconomic status) were examined. All subjects were carefully screened for medical, neurological and psychiatric exclusion criteria. Magnetic resonance imaging scans were obtained at baseline and after a period of time ranging from 33 to 64 months using identical image acquisition protocols at both time points. Only the mid-sagittal image was used in the analysis. A set of landmarks clearly and reliably identified on this image focused the analysis primarily on sub-cortical structures, including cerebellum, corpus callosum and pons. The statistical analyses controlled for age, gender, diagnosis and number of comparisons in assessing landmark shape changes over time.

These investigators found no statistically significant landmark shape differences between patients and controls at baseline or follow-up, although the between-group shape differences were very similar to those seen in previous studies. At baseline and follow-up there were significant gender differences in shape across groups; these shape differences tended to be less pronounced in the schizophrenia sample. However, the splenium was thicker and farther from the cerebellum in women than in men, regardless of diagnostic group. The change in shape over time was significantly different between patients and controls. For example, the analysis found a relative increase in the distance between the superior colliculus and the splenium of the corpus collosum in patients. Controls' landmark shape changed little over time. The authors suggested that their findings are consistent with differential shape changes over time between patients with schizophrenia and controls. These shape changes seem to be tied to onset of symptoms and may be neurodegenerative in nature. The mechanism underlying the differential shape changes may be related to abnormalities in neuroplasticity in schizophrenia that may be impacted in a positive way by treatment with antipsychotic medication. They also pointed out, similar to Giedd et al. (1999) and Mathalon et al. (2001), that their results are not inconsistent with a neurodevelopmental hypothesis of schizophrenia.

The results of these three studies that examined very different patient populations and/or utilized different quantification and analysis techniques produced a similar conclusion: There are progressive neuroanatomic changes in the brains of patients with schizophrenia. This limited review of recent research is not meant to suggest that all longitudinal neuroimaging studies have found evidence for progressive brain changes, because there are negative studies in the literature. Research findings suggesting progression of neuroanatomic abnormalities in schizophrenia have important implications for theories of the pathophysiology of psychosis and do not preclude neurodevelopmental theories of the illness. Indeed, the neuropathophysiologic processes that are at work prior to the onset of illness may continue after the onset of frank psychotic symptoms, perhaps muted by consistent treatment with antipsychotic medication.

The studies by Giedd et al. (1999) and Mathalon et al. (2001) both found a relationship between symptom severity and clinical course and change in brain structure over time in patients with schizophrenia. These results, coupled with research findings suggesting the possibility of normalization of neuroanatomic abnormalities in schizophrenia over time, suggest that early and consistent treatment with atypical antipsychotic medication may not only improve symptom severity and overall functioning, but it may also limit neurodegeneration and chronicity. Future prospective, longitudinal neuroimaging studies, carefully documenting symptom severity, medication treatment and resource utilization, will be required to clarify these relationships.

DeLisi LE (1999), Defining the course of brain structural change and plasticity in schizophrenia. Psychiatry Res 92(1):1-9.
 

Gharaibeh WS, Rohlf FJ, Slice DE, DeLisi LE (2000), A geometric morphometric assessment of change in midline brain structural shape following a first episode of schizophrenia. Biol Psychiatry 48(5):398-405.
 

Giedd JN, Jeffries NO, Blumenthal J et al. (1999), Childhood-onset schizophrenia: progressive brain changes during adolescence. Biol Psychiatry 46(7):892-898 [see comment pp869-870].
 

Haug JO (1962), Pneumoencephalographic studies in mental disease. Acta Psychiatrica Scandinavica 38(suppl 165):1-114.
 

Hirayasu Y, Shenton ME, Salisbury DF et al. (1998), Lower left temporal lobe MRI volumes in patients with first-episode schizophrenia compared with psychotic patients with first-episode affective disorder and normal subjects. Am J Psychiatry 155(10):1384-1391.
 

Illowsky BP, Juliano DM, Bigelow LB, Weinberger DR (1988), Stability of CT scan findings in schizophrenia: results of an 8 year follow-up study. J Neurol Neurosurg Psychiatry 51(2):209-213.
 

Jacobsen LK, Giedd JN, Rajapakse JC et al. (1997), Quantitative magnetic resonance imaging of corpus callosum in childhood onset schizophrenia. Psychiatry Res 68(2-3):77-86.
 

Johnstone EC, Crow TJ, Frith CD et al. (1976), Cerebral ventricular size and cognitive impairment in chronic schizophrenia. Lancet 2(7992):924-926.
 

Kemali D, Maj M, Galderisi S et al. (1989), Ventricle-to-brain ratio in schizophrenia: a controlled follow-up study. Biol Psychiatry 26(7):756-759.
 

Kraepelin E (1919), Dementia Praecox and Paraphrenia. Edinburgh, Scotland: E & S Livingstone.
 

Mathalon DH, Sullivan EV, Lim KO, Pfefferbaum A (2001), Progressive brain volume changes and the clinical course of schizophrenia in men: a longitudinal magnetic resonance imaging study. Arch Gen Psychiatry 58(2):148-157.
 

Nasrallah HA, Olson SC, McCalley-Whitters M et al. (1986), Cerebral ventricular enlargement in schizophrenia. A preliminary follow-up study. Arch Gen Psychiatry 43(2):157-159.
 

Pearlson GD (1997), Superior temporal gyrus and planum temporale in schizophrenia: a selective review. Prog Neuropsychopharmacol Biol Psychiatry 21(8):1203-1229.
 

Shelton RC, Weinberger DR (1986), X-ray computerized tomography studies in schizophrenia: a review and synthesis. In: Handbook of Schizophrenia, Vol. 1: The Neurology of Schizophrenia, Nasrallah HA, Weinberger DR, eds. Amsterdam, Netherlands: Elsevier Medical Publishing, pp207-250.
 

Smith RC, Calderon M, Ravichandran GK et al. (1984), Nuclear magnetic resonance in schizophrenia: a preliminary study. Psychiatry Res 12(2):137-147.
 

Woodruff PW, Wright IC, Shuriquie N et al. (1997), Structural brain abnormalities in male schizophrenics reflect fronto-temporal dissociation. Psychol Med 27(6):1257-1266.
 

Woods BT, Yurgelun-Todd D, Benes FM et al. (1990), Progressive ventricular enlargement in schizophrenia: comparison to bipolar affective disorder and correlation with clinical course. Biol Psychiatry 27(3):341-352.

The first magnetic resonance imaging studies in schizophrenia began to appear in the literature in 1984. These studies confirmed earlier theories and also contributed new findings such as changes in size of the hippocampus, amygdala, corpus callosum and so on in patients with schizophrenia. What other neuroimaging techniques are being used? What do recent studies show regarding the neuroanatomic abnormalities found in patients with schizophrenia?

Neuroanatomic Abnormalities

Research conducted over the past 30 years leads to the conclusion that 

 does influence viewers' attitudes, values and behavior (Hearold, 1986; Murray, 2000, 1994, 1973; Paik and Comstock, 1994; Surgeon General's Scientific Advisory Committee on Television and Social Behavior, 1972). Although the social effect of viewing televised violence is a controversial topic of research and discussion, the body of research is extensive and fairly coherent in demonstrating systematic patterns of influence. In general, there seem to be three main classes of effects:

 Viewing televised violence can lead to increases in aggressive behavior and/or changes in attitudes and values favoring the use of aggression to solve conflicts (Huston et al., 1992).

 Extensive violence viewing may lead to decreased sensitivity to violence and a greater willingness to tolerate increasing levels of violence in society (Drabman and Thomas, 1974; Thomas et al., 1977).

 Extensive exposure to television violence may produce the "mean world syndrome," in which viewers overestimate their risk of victimization (Gerbner, 1970; Gerbner et al., 1994).

Although we know that viewing televised violence can lead to increases in 

 or fearfulness and to changed attitudes and values about the role of violence in society, we need to know more about how these changes occur in viewers-the neurological processes that lead to changes in social behavior.

Within the context of social learning theory, we know that changes in behavior and thoughts can result from observing models in the world around us, such as parents, 

 or the mass media. The processes involved in modeling or imitating overt behavior were addressed in social learning theories from the 1960s (Bandura, 1969, 1965, 1962; Berkowitz, 1965, 1962), but we must expand our research approaches if we are to understand the neurological processes that might govern the translation of the observed models into thoughts and actions.

Both Bandura (1994) and Berkowitz (1984) have provided some theoretical foundations for the translation of communication events into thoughts and actions. Bandura's social-cognitive approach and Berkowitz's cognitive-neoassociation analysis posit a role for emotional arousal as an "affective tag" that may facilitate lasting influences. With regard to aggression, we know that viewing televised violence can be emotionally arousing (e.g., Cline et al., 1973; Osborn and Endsley, 1971; Zillmann, 1982, 1971), but we lack direct measures of cortical arousal or neuroanatomical patterns in relation to viewing violence.

The pursuit of neurological patterns in viewing violence would likely start with the amygdala, because it has a well-established role in controlling physiological responses to emotionally arousing or threatening stimuli (Damasio, 1999, 1994; LeDoux, 1996; Ornstein, 1997). Indeed, a National Research Council report (Reiss and Roth, 1993) concluded:

, is the outcome of complex processes in the brain. Violent behaviors may result from relatively permanent conditions or from temporary states...Biological research on aggressive and violent behavior has given particular attention to functioning of steroid hormones such as testosterone and glucocorticoids, especially their action on steroid receptors in the brain;...neurophysiological (i.e., brain wave) abnormalities, particularly in the temporal lobe of the brain; brain dysfunctions that interfere with language processing or cognition.

Thus, one suggestion for further research on the impact of viewing media violence is to assess some of its neurological correlates. In particular, the use of videotaped violent scenes can serve as the ideal stimulus for assessing activation patterns in response to violence.

It is very likely that the amygdala is involved in processing violence, but the projections to the cortex are not clear. However, developing hypotheses about viewing violence and brain activation needs to start with research on physiological arousal (e.g., Osborn and Endsley, 1971; Zillmann, 1982; Zillmann and Bryant, 1994) and then link this to cortical arousal. In this regard, the work of Paul Ekman, Ph.D., and Richard Davidson, Ph.D., using electroencephalogram recordings while subjects viewed gruesome films indicated asymmetries in activation patterns in the anterior regions of the left and right hemispheres (Davidson et al., 1990; Ekman and Davidson, 1993; Ekman et al., 1990). In particular, positive affect (indexed by facial expression) was associated with left-sided anterior activation, while negative affect was associated with right-sided activation (Davidson et al., 1990).

Our preliminary research (Liotti et al., in press; Murray et al., 2001) has focused on the amygdala and related structures in an effort to identify the neurological correlates of viewing televised violence. In this instance, we used functional magnetic resonance imaging (fMRI) to map the brains of eight children (five boys, three girls; aged 8 to 13 years) while they watched violent and nonviolent videotapes. The violent video segments consisted of two, three-minute clips of boxing from "Rocky IV." The nonviolent video segments were two, three-minute clips of a National Geographic program on animals at play and "Ghostwriter," a children's literacy program set in a mystery context. In addition, we presented two, three-minute control, rest/fixation clips of an "X" on a blue screen.

We conducted whole-brain (18 to 22 slices) echoplanar fMRI throughout the 18 minutes of viewing. Following the viewing, structural or anatomical (aMRI) images were acquired. Both the fMRI and aMRI images were normalized to Talairach space, and statistical analyses were conducted with task-induced blood oxygenation-level dependent (BOLD) changes detected using a conventional statistical parametric mapping method of voxel-wise independent paired t-tests.

In this study, we found that both violent and nonviolent viewing activated regions implicated in aspects of visual and auditory processing. In contrast, however, viewing violence selectively recruited right precuneus, right posterior cingulate, right amygdala, bilateral hippocampus and parahippocampus, bilateral pulvinar, right inferior parietal and prefrontal, and right premotor cortex. Thus, viewing televised violence appears to activate brain areas involved in arousal/attention, detection of threat, episodic memory encoding and retrieval, and motor programming. These findings are displayed in the Figure, which provides the significant contrasts between the violence-viewing and nonviolence-viewing sessions. The regions of interest in the composite activations of the eight children included the amygdala, hippocampus and posterior cingulate. These areas of the brain are likely indicators of threat-perception and possible long-term memory storage of the threat-event (particularly, these patterns are similar to the memory storage of traumatic events in posttraumatic stress disorder) (Brannan et al., 1997; Liotti et al., 2000). These activation patterns are important because they demonstrate that viewing video violence selectively activates right hemisphere and some bilateral areas that collectively suggest significant emotional processing of video violence.

Of course, this is a preliminary study with a small sample of children, and we must conduct further studies with larger samples of young viewers. However, this preliminary research leads us to conclude that there are important, theoretically predictable patterns of neurological response to viewing media violence. In our next series of studies, we will explore these neuroanatomical correlates of viewing violence in children who have had differing experiences with violence in their lives in order to better understand the processes of sensitization and desensitization.

In this instance, we will assess the responses of children who have experienced violence as victims of abuse, in contrast to youngsters who are more aggressive. We also expect to see differences in response to viewing violence among the abused, high-aggression and low-aggression children. We expect to see increased responsiveness to threat in the abused children and decreased responsiveness to threat in the high-aggression children.

Furthermore we anticipate differences in media preferences and viewing patterns to correlate with the level of aggression in these children. This constellation of findings will begin to address the patterns of response to aggression and the learning of aggression from media models. The issues of desensitization and enhanced aggression may be related to the patterns of brain activation observed in these children. The social significance of brain mapping and violence viewing is the contribution these studies make to our understanding of the learning and cognitive/affective processing of aggression in children and youth.

Bandura A (1962), Social learning through imitation. In: Nebraska Symposium on Motivation, Jones MR, ed. Lincoln, Neb.: University of Nebraska Press.

Bandura A (1965), Vicarious processes: a case of no-trial learning. In: Advances in Experimental Social Psychology, Vol. II, Berkowitz L, ed. New York: Academic Press.

Bandura A (1969), Social learning theory of identificatory processes. In: Handbook of Socialization Theory and Research, Goslin DA, ed. Chicago: Rand-McNally, pp213-262. 

Bandura A (1994), Social cognitive theory of mass communication. In: Media Effects: Advances in Theory and Research, Bryant J, Zillmann D, eds. Hillsdale, N.J.: Lawrence Erlbaum Associates Inc., pp61-90.

Berkowitz L (1962), Aggression: A Social Psychological Analysis. New York: McGraw-Hill.

Berkowitz L (1965), Some aspects of observed aggression. J Pers Soc Psychol 12:359-369. 

Berkowitz L (1984), Some effects of thoughts on anti- and prosocial influences of media events: a cognitive-neoassociation analysis. Psychol Bull 95(3):410-427. 

Brannan SK, Mayberg HS, Liotti M et al. (1997), Neural correlates of fear provocation in normals and PTSD patients. Abstract 228. Presented at the 27th Annual Meeting of the Society for Neuroscience. New Orleans; Oct. 25-30.

Cline VB, Croft RG, Courrier S (1973), Desensitization of children to television violence. J Pers Soc Psychol 27(3):360-365.

Damasio AR (1994), Descartes' Error: Emotion, Reason, and the Human Brain. New York: Putnam.

Damasio AR (1999), The Feeling of What Happens: Body and Emotion in the Making of Conscious-ness. New York: Harcourt Brace.

Davidson RJ, Ekman P, Saron CD et al. (1990), Approach-withdrawal and cerebral asymmetry: emotional expression and brain physiology. I. J Pers Soc Psychol 58(2):330-341.

Drabman RS, Thomas MH (1974), Does media violence increase children's toleration of real-life aggression? Dev Psychol 10(3):418-421. 

Ekman P, Davidson R (1993), Voluntary smiling changes regional brain activity. Psychol Sci 4(5):342-345. 

Ekman P, Davidson RJ, Friesen WV (1990), The Duchenne smile: emotional expression and brain physiology. II. J Pers Soc Psychol 58(2):342-353. 

Gerbner G (1970), Cultural indicators: the case of violence in television drama. The Annals of the American Academy of Political and Social Science 388:69-81. 

Gerbner G, Gross L, Morgan M, Signorielli N (1994), Growing up with television: the cultivation perspective. In: Media Effects: Advances in Theory and Research, Bryant J, Zillmann D, eds. Hillsdale, N.J.: Lawrence Erlbaum Associates Inc., pp17-42. 

Hearold S (1986), A synthesis of 1043 effects of television on social behavior. In: Public Communication and Behavior, Vol. I, Comstock GA, ed. San Diego: Academic Press. 

Huston AC, Donnerstein E, Fairchild H et al. (1992), Big World, Small Screen: The Role of Television in American Society. Lincoln, Neb.: University of Nebraska Press. 

LeDoux J (1996), The Emotional Brain: The Mysterious Underpinnings of Emotional Life. New York: Simon & Schuster. 

Liotti M, Murray JP, Ingmundson P et al. (in press), Children's brain activations while viewing televised violence revealed by fMRI. Hum Brain Map.

Liotti M, Mayberg HS, Brannan SK et al. (2000), Differential limbic-cortical correlates of sadness and anxiety in healthy subjects: implications for affective disorders. Biol Psychiatry 48(1):30-42.

Murray JP (1973), Television and violence. Implications of the Surgeon General's research program. Am Psychol 28(6):472-478. 

Murray JP (1994), The impact of televised violence. Hofstra Law Review 22:809-825.

Murray JP (2000), Media effects. In: Encyclopedia of Psychology, Vol. 5, Kazdin AE, ed. New York: Oxford University Press, pp153-155.

Murray JP, Liotti M, Ingmundson P et al. (2001), Children's brain response to TV violence: functional magnetic resonance imaging (fMRI) of video viewing in 8-13 year-old boys and girls. Presented at the 2001 Biennial Meeting of the Society for Research in Child Development. Minneapolis; April 20.

Ornstein R (1997), The Right Mind: Making Sense of the Hemispheres. New York: Harcourt Brace.

Osborn DK, Endsley RC (1971), Emotional reactions of young children to TV violence. Child Dev 42(1):321-331. 

Paik H, Comstock G (1994), The effects of television violence on antisocial behavior: a meta-analysis. Communication Research 21(4):516-546.

Reiss AJ, Roth JA, eds. (1993), Understanding and preventing violence, volume 1. National Research Council. Washington, D.C.: National Academy Press. 

Surgeon General's Scientific Advisory Committee on Television and Social Behavior (1972), Television and Growing Up: The Impact of Televised Violence. Washington, D.C.: U.S. Government Printing Office.

Thomas MH, Horton RW, Lippincott EC, Drabman RS (1977), Desensitization to portrayals of real-life aggression as a function of exposure to television violence. J Pers Soc Psychol 35(6):450-458. 

Zillmann D (1971), Excitation transfer in communication-mediated aggressive behavior. Journal of Experimental Social Psychology 7(4):419-434. 

Research conducted over the past 30 years leads to the conclusion that televised violence does influence viewers' attitudes, values and behavior.

Psychiatric Times Vol 18 No 10

Sleep Lab Meditation

Clinical Uses and Ethical Implications of Psychiatric Genetic Counseling

Leading Agents Compared; Innovations Assessed at NCDEU

Neurosteroids and Psychiatric Disorders

Neuroanatomic Abnormalities

TV Violence and Brainmapping in Children

Tobacco Madness