Substance Use Does Not Prolong Bipolar Depression Impact of Substance Use Disorders on Recovery From Episodes of Depression in Bipolar Disorder Patients: Prospective Data From the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Ostacher MJ, Perlis RH, et al: Am J Psychiatry 2010; 167 (March): 289-297

Substance use disorders do not prolong bipolar depression, but they do predict higher rates of mood switching.

Background: Substance use disorders frequently co-occur with bipolar disorder and are believed to be associated with a worse prognosis. Objective: The authors hypothesized that patients with bipolar depression and comorbid substance use disorder (past or present) would take longer to recover than those without this comorbidity. Participants/Methods: Patients in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) trial were followed prospectively and monitored for response after onset of a major depressive episode. The percentage of patients switching to mania, hypomania, or a mixed mood state was also compared in those with and without alcohol and substance use disorders. Results: 2234 subjects developed a major depressive episode during the STEP-BD trial; 56% had no history of an alcohol use disorder, 32.2% had a past alcohol use disorder, and 11.8% had a current alcohol use disorder. The majority (70.9%) had no history of an illicit drug use disorder, 21.7% had a past history of an illicit drug use disorder, and only 7.3% had a current drug use disorder. There was no difference in median recovery time in patients with or without substance use disorders. Recovery time averaged 6 to 7 months regardless of past or present alcohol or drug use disorders. Slightly >21% (21.2%) of patients switched from a depressed state to a mixed, manic, or hypomanic state prior to recovery. Patients with past or present alcohol or drug use disorder were more likely to switch than patients with no substance abuse history. Past or present comorbid alcohol use disorders, but not drug use disorders, were associated with rapid cycling. Rapid cycling did not confound the rate of switching associated with substance use disorders. Conclusions: Current or past substance use disorders did not lengthen recovery time in bipolar depression. They did, however, increase the likelihood of switching to another mood state. This difference was not accounted for by rapid cycling alone in patients with alcohol use disorders. The authors postulate that bipolar disorder comorbid with substance use disorders may be inherently different than that not associated with substance abuse, based on the finding that the timing of substance abuse had no bearing on rates of switching in the study. Based on these results, the authors suggest that comorbid substance use disorders should not be a reason not to treat patients with bipolar disorder, arguing instead to focus interventions on treatment compliance, anxiety, or therapy. Reviewer's Comments: The authors were not able to discern the severity of substance abuse or dependence in this study. They were also not able to determine which substances were abused other than alcohol. Therefore, it is difficult to generalize the results for illicit substances. The rate of past or present drug misuse was relatively low and may reflect a higher level of functioning among study participants than in many patients with bipolar disorder. (Reviewer-Charlotte O. Ladd, MD, PhD). © 2010, Oakstone Medical Publishing Keywords: Substance Use, Bipolar Disorder Print Tag: Refer to original journal article

Benzodiazepine Use May Portend Worse Prognosis in Bipolar Disorder Benzodiazepine Use and Risk of Recurrence in Bipolar Disorder: A STEP-BD Report. Perlis RH, Ostacher MJ, et al: J Clin Psychiatry 2010; 71 (February): 194-200

Benzodiazepine use is associated with a higher recurrence risk in bipolar disorder.

Background: Patients with bipolar disorder are often prescribed benzodiazepines for management of anxiety, mania, or anxious depression. The risks of long-term benzodiazepine use include dependence, cognitive impairment, and disruption of sleep architecture. Few long-term studies have examined the impact of benzodiazepine use on long-term outcomes in bipolar disorder. Objective: To investigate the recurrence risk of recurrence with and without benzodiazepine use in patients with bipolar I or II disorder in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) trial. Participants/Methods: STEP-BD patients who were in a manic, mixed, or depressive episode at study entry and later recovered (30% are more likely to have inflated figures. (Reviewer-John G. Koutras, MD). © 2010, Oakstone Medical Publishing Keywords: Childhood Adversity, Adult Psychiatric Disorders, Child Abuse, Mood Disorders Print Tag: Refer to original journal article

More Is Not Necessarily Better for Depression Treatment Combination of Antidepressant Medications From Treatment Initiation for Major Depressive Disorder: A Double-Blind Randomized Study. Blier P, Ward HE, et al: Am J Psychiatry 2010; 167 (March): 281-288

The jury is still out on whether combined antidepressant treatment leads to faster remission of depression.

Background: The current pharmacotherapy algorithm for major depressive disorder (MDD) involves sequential medication trials or the addition of a second agent if remission is not reached with an adequate trial of an initial antidepressant. This process can take 2 to 3 months, with only approximately one-third of patients achieving remission with a single agent. Objective: The authors were interested in the speed of recovery and remission using a more aggressive pharmacologic approach consisting of 2 antidepressants initiated simultaneously. They hypothesized that combining mirtazapine with venlafaxine, fluoxetine, or bupropion would synergistically lower time to response and remission compared with fluoxetine monotherapy. They also investigated whether removal of the second agent after 6 weeks would increase relapse rates in the subsequent 6 months. Participants/Methods: 105 participants with MDD were recruited from newspaper advertisements in Florida and Ontario and randomized into 4 treatment groups: 20 mg fluoxetine + placebo; 20 mg fluoxetine + 30 mg mirtazapine; 225 mg venlafaxine + 30 mg mirtazapine; or 150 mg bupropion + 30 mg mirtazapine. Hamilton Depression Rate Scale (HAM-D) scores and Montgomery-Asberg Depression Rating Scale (MADRS) scores were monitored frequently. At the end of 6 weeks, the second "agent" was discontinued and participants were followed for an additional 6 months on either fluoxetine or mirtazapine monotherapy. Response (>50% decrease in HAM-D score), remission (HAM-D 12 for 2 consecutive visits) rates were analyzed using a 2-way ANOVA. Results: Ham-D scores dropped significantly by days 4 to 7, suggesting a substantial placebo response. The number of participants responding to treatment did not vary between groups (mean time to response was 14 to 22 days). However, the proportion of patients achieving remission was greater in the fluoxetine + mirtazapine group (52%) and the mirtazapine + venlafaxine group (58%), but not in the mirtazapine + bupropion group (46%) compared to the fluoxetine monotherapy group (25%). Mean time to remission was 22 to 23 days in each group. There were no group differences in MADRS scores at the end of 6 weeks. All groups receiving mirtazapine gained weight (2.2 to 3.1 kg), while the fluoxetine monotherapy group did not. Conclusions: The authors concluded that combination antidepressant treatment led to greater remission rates. However, this conclusion seems biased by industry support and poor study design. Reviewer's Comments: The study was sponsored by Organon, maker of mirtazapine, and the study design reflects favoritism toward combination treatments, all of which included mirtazapine instead of fluoxetine. Both fluoxetine and bupropion were given in suboptimal doses, making the results difficult to interpret. Patients in all 3 combination groups gained weight with mirtazapine, which may have unblinded them and their treating physicians, potentially skewing results. Finally, there was no placebo group. Given these limitations, it is premature to conclude that more is better in the initial pharmacologic treatment of depression. (ReviewerCharlotte O. Ladd, MD, PhD). © 2010, Oakstone Medical Publishing Keywords: Combination Antidepressant Treatment Print Tag: Refer to original journal article

Are the Criteria for MDD Just Too Long? A Simpler Definition of Major Depressive Disorder. Zimmerman M, Galione JN, et al: Psychological Med 2010; 40 (March): 451-457

A briefer set of major depression criteria focusing on 5 symptoms may be adequate to capture this syndrome.

Background: Major depressive disorder (MDD) criteria have been essentially unchanged for 35 years. That seems too long for the authors of this study who point out a few things. Numerous studies show that large percentages of multiple provider types, from psychiatrists, to general practitioners, to medical students, to residents, simply do not recall or do not use the full range of criteria in coming to a diagnosis. In one study, only 50% of psychiatry residents could name as much as 5 of the 9 criteria. Experienced psychiatrists who were surveyed report that they do not see if the criteria are met in diagnosing the disorder. And, as these authors argue, perhaps that is just as well. The inclusion of physical symptoms such as appetite and sleep disturbance has always had a controversial place in terms of their interpretation in light of common medical comorbidities of patients. The authors build upon work with other samples in which they looked at the comparative diagnostic value of using a full structured diagnostic DSM-IV interview and a truncated list of criteria that is comprised solely of the mood and cognitive symptoms: low mood; loss of interest/pleasure; guilt/worthlessness; impaired concentration/indecision; and suicidal thoughts. An initial derivation sample found high correlation between simplified and original criteria. Objective: This study repeated this comparison to a large sample of psychiatric outpatients as well as more niche-populations, ie those presenting for treatment of pathological gambling and for evaluation prior to bariatric services. Methods: 1100 general outpatients, 210 gambling patients, and 1200 bariatric surgery candidates were interviewed using a structured clinical interview for DSM-IV (SCID) interview. As the SCID only prompts to query all of the criteria symptoms of depressed mood or loss of interest, in this study, the SCID was performed to cover all of the depression symptom criteria whether or not they were prompted to do so. In this way, symptom reporting patterns and their comparative ability to predict meeting the full syndrome were able to be reliably ascertained. Results: In the general outpatient group, the agreement between the simplified and the full DSM-IV criteria was 91.8%. For gamblers, it was 94.3% and for bariatric surgery candidates, it was 99.1%. Across all 2510 patients, the level of agreement was 95.5%. Conclusions: A simplified definition of depression using only mood and cognitive criteria had substantial overlap in identifying someone with the disorder as did structured use of the full criteria across a range of patient populations. Reviewer's Comments: The authors argue that evidence to date supports changing the criteria for depression in DSM-V based on a longstanding conceptual problem around somatic symptoms and the fact that a simpler method appears to have substantial overlap in identifying cases, demonstrated now in multiple, large, samples. (Reviewer-Gary S. Belkin, MD, PhD, MPH). © 2010, Oakstone Medical Publishing Keywords: Major Depression, Criteria,DSM-IV Print Tag: Refer to original journal article

Significance of the Significance Criteria for Major Depression Does the DSM-IV Clinical Significance Criterion for Major Depression Reduce False Positives? Evidence From the National Comorbidity Survey Replication. Wakefield JC, Schmitz MF, Baer JC: Am J Psychiatry 2010; 167 (March): 298

The clinical significance criterion does not substantially improve the identification of persons with impairing major depressive illness.

Background: Most sets of criteria for disorders in DSM-IV specify that people who meet the symptom or behavior criteria for a disorder also have "…clinically significant distress or impairment in...functioning…" caused by those symptoms. The field testing for DSM-IV apparently assumed, but did not test, the degree such significance criterion reduced the likelihood of false positives (people with criteria, but not really impaired). The need to do so, at least for a disorder like major depression, is that other criteria already presumably ensure impairment or distress potentially making the significance criterion redundant. Also, in practice, it is unclear the degree the criterion is indeed specifically examined, and other major diagnostic methods, such as the use of International Classification of Diseases (ICD) categories, do not include such a criterion. Objective: The authors used data from the National Comorbidity Survey Replication (NCS-R) to examine the effect of the criterion in estimates of prevalence of depression. Methods: The NCS-R is a community-based epidemiological survey. The data here focused on 6707 responders aged 18 to 54 years. The study used structured interviewing to assess criteria for DSM-IV disorders. All subjects were asked to rate, on a numerical scale, levels of distress if they experienced persistent sadness, as well as questions as to areas of functional impairment if they satisfied the major depression duration criteria. Results: Of 2071 individuals who reported persistent sadness for ≥2 weeks, 97.2% also satisfied criteria for rated distress. Of those who met major depression symptom-duration criteria, 96.2% met thresholds for measured excess impairment. Conclusions: Distress appears redundant with DSM-IV symptoms of persistent sadness, and impairment appears similarly almost always concurrently present, and thus implied in major-depression-level symptoms. Reviewer's Comments: In the discussion of this paper, the authors respond to the fact that their conclusion (that the significance criterion does not reduce false positives since distress appears always present when the other criteria are met) is a different conclusion than was drawn by the leader of NCS-R, Ronald Kessler, in prior publications. Part of that difference of opinion lies in how or whether to consider the risk that reported dysphoria and anhedonia potentially generate false-positive answers. In some ways, the 2 groups may be talking past each other, but suffice it to say, it opens up the question of whether a proposal to no longer include the significance criterion will have enough behind it to prompt revisions in DSM-V. (Reviewer-Gary S. Belkin, MD, PhD, MPH). © 2010, Oakstone Medical Publishing Keywords:DSM-IV, Depression Criteria, Clinical Significance Print Tag: Refer to original journal article

Visualizing Cannabis in the Brain Neuroimaging in Cannabis Use: A Systematic Review of the Literature. Martín-Santos R, Fagundo AB, et al: Psychol Med 2010; 40 (March): 383-398

Structural neuroimaging shows minimal cannabis effects, but functional imaging shows changes in brain regions that would be consistent with demonstrated impairments in working memory, inhibition, and decision making.

Background: Cannabinoids act as agonists at specific endogenous cannabinoid receptors, CB1 and CB2. The CB1 receptor is largely expressed in the central nervous system, with the highest concentration in the basal ganglia, prefrontal cortex, anterior cingulated cortex (ACC), and hippocampus. CB2 receptors are present mainly in immune cells and peripheral tissue. Design/Objective: This systematic review was conducted to assess the evidence for specific effects of cannabis on brain structure and function, focusing on the cognitive changes associated with chronic or acute cannabis use. Methods: Extensive PsycLIT and PubMed searches were conducted. Forty-one studies were included: 15 involving THC (tetrahydrocannabinol), 3 involving CBD (cannabidiol, another active component of marijuana), 8 structural imaging studies evaluating the chronic effects of THC, and 17 functioning imaging studies on chronic THC effects. The reviewed articles included 655 cannabis users and 402 healthy controls. The heterogeneity in the study designs and methods used made it impractical to perform a meta-analysis. Results: Functional imaging studies suggest that resting global, prefrontal, and ACC blood flow is lower in cannabis users than in controls. Impairments in time estimation, attention, working memory, cognitive flexibility, and psychomotor speed in chronic cannabis users are, at least partly, mediated by these cortical regions. Evidence of effects of THC regions is also consistent with the relatively high concentration of CB 1 receptors in the prefrontal and cingulated cortex. Cannabis users make use of similar brain areas for control while performing some cognitive tasks, although to a lesser degree. Moderately greater task-related activation in these areas may reflect impaired efficiency of processing after cannabis use, such that more activation is required to maintain normal performance. The recruitment of different regions, such as the prefrontal cortex and hippocampus, also differentiates users from controls during cognitive performance. Despite these differences in brain activity, the level of performance of the cannabis users was equivalent to that of controls. Conclusions: Functional imaging appears to demonstrate that the brain is capable of some degree of functional reorganization, activating brain regions not engaged in non-cannabis users to, at times, achieve the tested cognitive demand. Reviewer's Comments: Structural neuroimaging provides minimal evidence of major cannabis effects on brain structure, both in regional gray matter and in white matter tracts. With functional neuroimaging, there needs to be larger, prospective studies, after cessation of use, to replicate findings and further investigate the reversibility of changes with abstinence. (Reviewer-John G. Koutras, MD). © 2010, Oakstone Medical Publishing Keywords: Cannabis, Functional Neuroimaging, Structural Neuroimaging Print Tag: Refer to original journal article

Where Re-Experiencing Traumatic Memories May Lie in the Brain Magnetic Resonance Imaging of Hippocampal Subfields in Posttraumatic Stress Disorder. Wang Z, Nylan TC, et al: Arch Gen Psychiatry 2010; 67 (March): 296-303

PTSD, once again, is associated with a smaller hippocampus and, in this study specifically, in a certain hippocampal subfield, CA3/DG.

Background: The National Comorbidity Survey estimates that the lifetime prevalence of posttraumatic stress disorder (PTSD) is 8% in the general population and 24% in persons exposed to trauma. Most neuroimaging studies of PTSD have focused on the hippocampus, due to its role with memory processing and communication with the amygdala, thereby creating a circuit for the persistent re-experiencing symptoms of trauma. Several MRI studies have found smaller hippocampal volumes in patients with PTSD. The hippocampus is composed of several subfields with distinctive histological characteristics and specialized functions such as the subiculum, the cornu ammonis sectors (CA1-CA3), and the dentate gyrus (DG). Objective: To investigate the volumes of these different subfields in relation to PTSD. Methods: 17 participants with PTSD and 19 without PTSD underwent MRI. All subjects with PTSD had traumatic exposure related to combat. Results: First, PTSD was related to reduced volumes of the CA3/DG, regardless of age, while other subfields were spared. Second, age was associated with reduced volumes of the CA1 and CA1/2 transition, consistent with previous subfield MRI studies in aging. Third, both PTSD and age contributed to the total hippocampal volume reduction. These findings suggest that PTSD is associated selectively with volume loss of the CA3/DG subfield. The main processes that are thought to be involved in stress-related remodeling, such as of the CA3/DG subfield, include suppression of neurogenesis, reduced dendritic branching, and reduced synaptic and neuronal plasticity. Stress-induced mice studies have found reduced brain-derived neurotrophic factor (BDNF); a lower level would inhibit neurogenesis because BDNF is associated with the growth and differentiation of stem cells into neurons in the hippocampus. Also, the hippocampus is especially vulnerable to elevated levels of glucocorticoids. Prolonged high levels of glucocorticoids may have direct and indirect neurotoxic effects in the CA3 region. Conclusions: PTSD is associated with a selective reduction of the CA3/DG subfield in the human hippocampus, regardless of age-related effects. Reviewer's Comments: The smaller volume of the hippocampus in patients with PTSD has become an area of research focus, primarily due to consistency of the finding (which is a relative rarity in neuroimaging studies). However, as is generally true of neuroimaging studies, it is difficult to determine cause and effect. As the authors noted, it is also possible that a smaller hippocampus poses a risk factor for the development of stressrelated psychopathology. (Reviewer-John G. Koutras, MD). © 2010, Oakstone Medical Publishing Keywords: PTSD, Hippocampus, Re-Experiencing Print Tag: Refer to original journal article

Smaller Hippocampal Volume in Daughters Exposed to Maternal Depression Decreased Hippocampal Volume in Healthy Girls at Risk of Depression. Chen MC, Hamilton JP, Gotlib IH: Arch Gen Psychiatry 2010; 67 (March): 270-276

Maternal depression is associated with decreased hippocampal volume in healthy daughters aged 9 to 15 years.

Background: Maternal depression is often cited as the greatest risk factor for the development of depression in offspring. In adults, depression is often associated with smaller hippocampal volumes, especially when recurrent or chronic in nature. Smaller hippocampal volume may lead to or result from dysregulation of the hypothalamic-pituitary adrenal (HPA) axis, also observed in depression, particularly when accompanied by early childhood trauma. It is not known whether smaller hippocampi are a state or trait marker for depression. The authors investigated this by examining hippocampal volumes in middle school-age girls whose mothers had at least 2 episodes of depression since their birth. Objective: They hypothesized that daughters of women with a history of depression would exhibit smaller hippocampi than daughters of women with no psychiatric history. Participants/Methods: 55 girls aged 9 to 15 years were recruited for the study, 23 of whom had mothers with a history of depression. Both mothers and daughters completed structured interviews. Children were excluded if they had ever been depressed or if their mothers had an active Axis I diagnosis. Mothers of girls in the lowrisk group had never met criteria for an Axis I diagnosis. Mothers of girls in the high-risk group had at least 2 past episodes of major depression during their daughter's lifetime. All girls completed the Children's Depression Inventory and had a brain MRI to determine hippocampal volume, which was measured using both voxel-based morphometry analyses and manual tracing. Results: Girls in the high-risk group had significantly smaller bilateral hippocampi than those in the low-risk group using voxel-based morphometry analyses and smaller left hippocampi using manual tracing. Conclusions: Smaller hippocampal volume may reflect an underlying vulnerability to depression rather than a depressed state per se. The authors postulate that this difference may be concurrent with changes in the HPA axis, as has been found in preclinical research studies. Reviewer's Comments: This is a good preliminary study linking maternal depression to smaller hippocampal volumes in female offspring. However, there are several limitations in the study's conclusions. Given the absence of any psychiatric history in the low-risk group, it is possible that these girls had larger hippocampi than would be observed in a normal control population with some psychopathology, however remote. We do not have any information on paternal mental health. We also do not know whether the mothers were depressed in pregnancy or early postpartum, during which their daughters may have been exposed to increased cortisol through the placenta or breast milk. Furthermore, the authors collected only rudimentary information on life events, which can also have a profound effect on hippocampal volume. Further studies are needed to clarify these potential confounds. (Reviewer-Charlotte O. Ladd, MD, PhD). © 2010, Oakstone Medical Publishing Keywords: Maternal Depression, Hippocampal Volume Print Tag: Refer to original journal article

Meeting Standards of Care for Children in Child Welfare System A Preliminary Analysis of the Receipt of Mental Health Services Consistent With National Standards Among Children in the Child Welfare System. Raghavan R, Inoue M, et al: Am J Public Health 2010; 100 (April): 742-749

Despite formal standards as to basic expectations of mental health care and screening for children in the child welfare system, these expectations are very infrequently met.

Background/Objective: It has been estimated that 40% to 60% of children in the child welfare systems in this country have a psychiatric diagnosis. The point prevalence of psychotropic use has been estimated at 13.5%, twice as high as that seen in Medicaid-enrolled children overall. Over the last 10 to 20 years, several national professional organizations have established somewhat similar national guidelines for frequency and types of assessments, access to care, coordination of care, etc. However, one survey of state and county mental health agencies, for example, found that only one third were aware of such standards. In fact, little is known about the degree that such children receive recommended evaluation and care. Methods: The National Survey of Child and Adolescent Well-Being (NSCAW) is the first national, longitudinal study of children that has contact with child welfare agencies. The authors of this study looked at results from NSCAW surveys in 1999-2001, 2000-2002, 2001-2002, and 2002-2004. This probability sample of such children included the Child Behavioral Checklist and gathered information on service use in order to identify rates of screening, assessment, and referral to mental health services—the kinds of practices covered by national standards. Results: Data were collected on the experience of 3802 subjects. Only half of the surveyed children received care consistent with any one national standard, with less than one-tenth receiving care with all standards. Apparently, more disruptive children, those with higher measured externalizing behaviors, and those placed in foster care were more likely to meet standards. Conclusions: Few children in the child welfare system, receive nationally recommended standards for access to mental health evaluation and services despite being a high-risk and high-morbidity population. Reviewer's Comments: Compounding this state of affairs of limited entrenched habits with respect to predictable and active attention to the mental health needs of these children, Medicaid regulatory changes have weakened entitlements to screening and assessment, which the authors fear may only aggravate these disparities. (Reviewer-Gary S. Belkin, MD, PhD, MPH). © 2010, Oakstone Medical Publishing Keywords: Child Welfare, Standards, Treatment Gap Print Tag: Refer to original journal article

Prenatal Infections and Schizophrenia -- An Update Prenatal Infections and Schizophrenia: A Review of Epidemiologic and Translational Studies. Brown AS, Derkits EJ: Am J Psychiatry 2010; 167 (March): 261-280

An infectious agent timed at a vulnerable time of fetal neurodevelopment for that agent, creates an immune response, and either the agent or the immune response or both, interacts with certain genes, thereby increasing the risk for schizophrenia.

Background: Rubella, herpes simplex virus (HSV), cytomegalovirus, toxoplasmosis, and other infections are potent disrupters of fetal neurodevelopment leading to abnormalities of brain and behavior (including mental retardation, learning disabilities, and hypoplasia of several brain regions). Objective: To review the major ecologic and birth cohort studies of prenatal exposure to infection and schizophrenia. Methods: Extensive PubMed searches were conducted. Results: For influenza infection in the first trimester, there is a 7-fold risk of developing schizophrenia. Exposure in the overall first half of gestation resulted in a 3-fold elevation of risk, and there was no significant elevation of risk for exposure in the second half of the pregnancy. For Toxoplasma gondii, the risk of schizophrenia among individuals who were exposed in utero to T. gondii IgG antibodies was more than twice that of comparison subjects. For HSV type 2, maternal-offspring transmission generally occurs during passage through the birth canal. For exposed offspring, there is a significant 1.8-fold elevated risk of schizophrenic psychosis. The elevated risk was confined to offspring of seropositive mothers who did not regularly use contraception and had frequent intercourse. Other studies measured cytokine levels in maternal serum. In one birth cohort, a nearly 2-fold elevation in maternal levels of interleukin-8 was observed during the second trimester and the early third trimester, giving rise to offspring with schizophrenia. In a different study, levels of tumor necrosis factor-α, a proinflammatory cytokine at the time of birth, were significantly increased among mothers of offspring with psychosis. Conclusions: There appears to be a complex interplay between actual infectious pathogens and proinflammatory responses, occurring at developmental windows of vulnerability at gestation or at birth, that are specific to the type of pathogen and that result in the later development of psychosis and schizophrenia. Reviewer's Comments: One theory is that the pathogens themselves influence the risk of schizophrenia by unique effects. An alternative model is that the infections act through common pathways, such as cytokines, to alter fetal brain development and increase vulnerability to schizophrenia. Either way, the resulting interplay would probably be through a gene-infection interaction. Evidence is emerging that 2 prominent putative schizophrenia susceptibility genes—DISC1 and neuregulin—appear to play critical roles in brain development. Mutations in these genes have resulted in brain and behavioral anomalies similar to those observed in the maternal immune activation model. One final thought that the authors leave us with is that schizophrenia was shown to be related to elevated maternal T. gondii IgG levels, and not the presence of the parasite itself, which suggests that most infections were acquired before pregnancy. (Reviewer-John G. Koutras, MD). © 2010, Oakstone Medical Publishing Keywords: Schizophrenia, Infectious Agents, Inflammatory Response Print Tag: Refer to original journal article

Coming of Age, Genetically Heritability of Anxious-Depressive and Withdrawn Behavior: Age-Related Changes During Adolescence. Lamb DJ, Middeldorp CM, et al: J Am Acad Child Adolesc Psychiatry 2010; 49 (March): 248-255

It appears that genetic influence plays a larger role as a child matures into adolescence in the development of anxious and depressive symptoms.

Background: Between the ages of 5 and 17 years, approximately 8% of children experience some type of anxiety disorder. Longitudinal studies have demonstrated that anxiety disorders during childhood are moderately stable and are predictive of other mental health problems, especially depression, in later life. Comorbidity within anxiety disorders, and with depression, is frequent in both children and adults. Most studies have found that familial resemblance is due to genetic and shared environmental factors in childhood, whereas in adolescence genetic factors are important but shared environmental factors are not. Objective: To study the course of genetic and environmental influences on anxiety and depression at 12, 14, and 16 years of age in monozygotic and dizygotic twins. Methods: Parents and teachers completed questionnaires concerning the twins' behavior up to age 12 years. The twins then completed the Youth Self Report (YSR) at age 12, 14, and 16. The study team inferred, a priori, that if dizygotic correlations are higher than half the monozygotic correlation, then shared environmental effects shared by members of the same family are present. In general, girls scored higher than boys on the anxious depression (AD) and the withdrawn behavior (WB) subscales of the YSR, and scores tended to increase with age. Results: At age 12, familial clustering of AD and WB was due to genetic and shared environmental risk factors, whereas at age 14 and 16 years, familial clustering was due only to genetic factors. One possible explanation for this finding is that the onset of puberty and hormonal changes lead to changes in gene expression influencing the risk for anxiety and depression. An alternative explanation is that the influence of shared environment decreases because of a gradual attenuation of the level of parental control and time spent at home and together with the co-twin. Conclusions: Genetic influences appear to play a larger role than environment in the development of anxious and depressive behavior as children enter into adolescence. Reviewer's Comments: I chose this article as an example of the influence of ongoing twin studies in creating a better understanding of possible more genetic effects and possible more environmental effects. Adoption studies help in this regard as well. Adoption twin studies offer even better opportunities but are becoming even rarer. (Reviewer-John G. Koutras, MD). © 2010, Oakstone Medical Publishing Keywords: Depression Anxiety Gene, Environment Print Tag: Refer to original journal article