Associations between prepulse inhibition and executive visual attention in children with the 22q11 deletion syndrome.

The 22q11 deletion syndrome (DS) results in the loss of approximately 30 gene copies and is associated with possible physical anomalies, varied learning disabilities, and a specific cluster of neurocognitive deficits, including primary impairment in working memory, executive visual attention, and sensorimotor processing. Retrospective studies have suggested that children with 22q11DS are at 25 times greater risk of developing schizophrenia, thus specification of early brain network vulnerabilities among children with 22q11DS is critical. Previously, we reported that children with 22q11DS as compared with sibling controls had selective deficits in visual executive attention, and subsequently found lowered prepulse inhibition (PPI) in these same children. Visual executive attention and PPI recruit the same brain pathways linking prefrontal cortex to basal ganglia structures. To test the specificity of brain pathway vulnerability among children with 22q11DS, we examined visual executive attention and PPI paradigm data collected during the same test session from 21 children with 22q11DS and 25 sibling controls. We predicted lower %PPI and less efficient executive attention scores, and a significant inverse correlation between measures. %PPI in children with 22q11DS as compared with sibling controls was 20% lower, and visual executive attention efficiency scores 40% worse. As predicted, %PPI was inversely correlated only with executive attention efficiency scores. The implications of these findings with regard to brain pathway vulnerability in children with 22q11DS are considered. These results suggest that children with 22q11DS have early functional abnormality in pathways linking the prefrontal cortex and basal ganglia.

Genome-wide scan in a large complex pedigree with predominantly male schizophrenics from the island of Kosrae: evidence for linkage to chromosome 2q.

It is widely accepted that founder populations hold promise for mapping loci for complex traits. However, the outcome of these mapping efforts will most likely depend on the individual demographic characteristics and historical circumstances surrounding the founding of a given genetic isolate. The 'ideal' features of a founder population are currently unknown. The Micronesian islandic population of Kosrae, one of the four islands comprising the Federated States of Micronesia (FSM), was founded by a small number of settlers and went through a secondary genetic 'bottleneck' in the mid-19th century. The potential for reduced etiological (genetic and environmental) heterogeneity, as well as the opportunity to ascertain extended and statistically powerful pedigrees makes the Kosraen population attractive for mapping schizophrenia susceptibility genes. Our exhaustive case ascertainment from this islandic population identified 32 patients who met DSM-IV criteria for schizophrenia or schizoaffective disorder. Three of these were siblings in one nuclear family, and 27 were from a single large and complex schizophrenia kindred that includes a total of 251 individuals. One of the most startling findings in our ascertained sample was the great difference in male and female disease rates. A genome-wide scan provided initial suggestive evidence for linkage to markers on chromosomes 1, 2, 3, 7, 13, 15, 19, and X. Follow-up multipoint analyses gave additional support for a region on 2q37 that includes a schizophrenia locus previously identified in another small genetic isolate, with a well-established recent genealogical history and a small number of founders, located on the eastern border of Finland. In addition to providing further support for a schizophrenia susceptibility locus at 2q37, our results highlight the analytic challenges associated with extremely large and complex pedigrees, as well as the limitations associated with genetic studies of complex traits in small islandic populations.

Early, non-psychotic deviant behavior in schizophrenia: a possible endophenotypic marker for genetic studies.

Early non-psychotic deviance occurs in some, but not all, pre-schizophrenic patients and has been linked to the later course of the disorder, suggesting its relationship with the schizophrenia syndrome. However, early deviance has rarely been explored as an endophenotypic marker in large samples of schizophrenic patients. We characterized the early childhood behavior and syndrome history of 205 adults with DSM-IV schizophrenia. Sixty percent of our sample had poor socialization, extreme fears/chronic sadness, and/or attention impairment/learning disabilities beginning before age 10. The remaining 40% were without behavioral difficulties until the onset of schizophrenia. Logistic regression analyses suggested that the risk of syndrome onset before age 17 was 2.5 times more likely among patients with poor socialization beginning before age 10. Schizoaffective disorder was 3.75 times greater among patients with extreme fears/chronic sadness in childhood, and schizophrenic patients with early attention impairment/learning disabilities were 2 times more likely to have a 1 degrees, 2 degrees or 3 degrees relative with schizophrenia. We concluded that early deviant behavior indicated a distinct subgroup of patients, and was linked to syndrome characteristics specifically relevant to genetic studies, in particular age at onset and family history of schizophrenia. Since early syndrome onset has been associated with specific genetic anomalies in other complex neuropathologic disorders, it may prove valuable to regard these early deviant behaviors as an indicator of early syndrome onset for future genetic studies of schizophrenia.

Phenotypic differences in early- and late-onset obsessive-compulsive disorder.

Early-onset forms of many medical diseases have been associated with specific genetic anomalies. To assess the potential marker value of onset age in obsessive-compulsive disorder (OCD), we examined and compared the phenotypic characteristics of patients with early and later onset. The study sample included 38 children with DSM-IV OCD and 129 adults 19 years of age or older, 77 of whom reported OCD onset prior to age 18 and 52 of whom reported OCD onset at 18 years of age or older. DSM-IV diagnoses were ascertained for all subjects using an amended version of the Diagnostic Interview for Genetic Studies (DIGS). An initial comparison of children and adults with childhood onset revealed several differences, including an earlier onset of clinically significant symptoms without impairment and earlier onset of DSM-IV OCD, a higher frequency of learning disabilities, and fewer obsessions and compulsions among our child patients. For this reason, subsequent analyses included only adult patients with early and later OCD onset. Nonimpairing symptom onset prior to puberty, a relatively aggressive course, and a greater number of obsessions and compulsions unrelated to the amount of time in illness characterized early-onset OCD. Later-onset OCD was characterized by nonimpairing symptom onset during puberty, a static course, and relatively few obsessions and compulsions that were variably related to the amount of time in illness. We conclude that children with OCD and adults with childhood onset differ in their report of clinical characteristics and should be analyzed separately in studies concerning the phenotypic characteristics of OCD. Early- and late-onset forms of OCD appear to be characterized by phenotypic features that have important neurobiologic and perhaps genetic implications.

Evidence of a schizotypy subtype in OCD.

OCD patients represent a heterogeneous mix of clinical phenotypes, likely reflecting a wide range of genetic vulnerabilities. In other medical illnesses, neurobiologically-based traits with a genetic component that are associated with the target disorder have been successfully used to detect patients with a specific genetic liability to disease. The overlap between symptoms of OCD and Schizophrenia suggested that schizotypal traits could have the potential to distinguish a relatively homogeneous subtype of OCD. We obtained schizotypy scores for 119 affected adult probands who met lifetime criteria for DSM-IV OCD. Five subscales from the Structured Interview of Schizotypy were used to assess ideas of reference, suspiciousness, magical thinking, illusions and psychotic-like thought. Selected for their obvious face validity with the cardinal signs of schizophrenia, Cronbach's alpha suggested that these subscales also provided a reliable measure of positive sign schizotypy (0.83). Fifty percent of our OCD sample had mild to severe positive schizotypy signs. t- and chi2 tests of significance suggested seven variables that distinguished OCD patients with schizotypy, including earlier age of onset, greater number of comorbid diagnoses and increased rates of learning disability, aggressive and somatic obsessions and counting and arranging compulsions. Three of these seven variables, including learning disabilities, counting compulsions and history of specific phobia, significantly increased the odds of schizotypy among patients with lifetime OCD. These findings enhanced the validity of the schizotypy construct in OCD. Whether this schizotypy subtype can distinguish a subgroup of patients with relatively homogeneous genetic characteristics waits further investigation.

Emotion in speech: the acoustic attributes of fear, anger, sadness, and joy.

Decoders can detect emotion in voice with much greater accuracy than can be achieved by objective acoustic analysis. Studies that have established this advantage, however, used methods that may have favored decoders and disadvantaged acoustic analysis. In this study, we applied several methodologic modifications for the analysis of the acoustic differentiation of fear, anger, sadness, and joy. Thirty-one female subjects between the ages of 18 and 35 (encoders) were audio-recorded during an emotion-induction procedure and produced a total of 620 emotion-laden sentences. Twelve female judges (decoders), three for each of the four emotions, were assigned to rate the intensity of one emotion each. Their combined ratings were used to select 38 prototype samples per emotion. Past acoustic findings were replicated, and increased acoustic differentiation among the emotions was achieved. Multiple regression analysis suggested that some, although not all, of the acoustic variables were associated with decoders' ratings. Signal detection analysis gave some insight into this disparity. However, the analysis of the classic constellation of acoustic variables may not completely capture the acoustic features that influence decoders' ratings. Future analyses would likely benefit from the parallel assessment of respiration, phonation, and articulation.

Phenotypic characteristics of Obsessive-Compulsive Disorder ascertained in adulthood.

Over the past decade, the increased awareness and knowledge of Obsessive-Compulsive Disorder (OCD) has allowed the in-depth study of its phenotypic characteristics. The largest studies to date have described the symptom and syndrome characteristics of treatment-seeking patients. While usefully homogeneous with regard to their current state, the clinical characteristics of patients seeking treatment may only partially represent the OCD population. We report findings from 100 self-selected volunteers at various stages of their OCD illness who were participating in a genetic study. Many similarities with past reports were found, including high rates of mood disorder, significantly more mood disorder in females as compared with males, and increased social impairment among males despite an equal amount of time in episodes of disorder. On the other hand, mean age of onset in this nontreatment seeking population was younger. Lifetime rates of obsessions and compulsions in this population were substantially higher than previous reports, suggesting that the content of obsessions and compulsions shifted over time, and evolved into a lifetime repertoire. Furthermore, a separate analysis of the age of clinically significant O-C symptom onset without impairment revealed that males and females did not differ, suggesting that previous reports of earlier onset age in males may actually reflect earlier onset of impairment. Future genetic studies may benefit from the analysis of both significant O-C symptom onset, as well as the onset of full-syndromal OCD. These findings may suggest phenotypic characteristics that define homogeneous subgroups of patients with OCD.

Family-based association studies support a sexually dimorphic effect of COMT and MAOA on genetic susceptibility to obsessive-compulsive disorder.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a common and severe psychiatric illness that affects 1-3% of the population and presents a well-established co-morbidity with major depressive disorder (MDD). Twin and family studies have suggested a genetic component in the etiology of OCD, although the mode of inheritance is unknown. Pharmacotherapy of the disease implicates both serotonergic and dopaminergic pathways. Previously, guided by the 22q11 microdeletion-related psychiatric phenotype, we provided evidence for a sexually dimorphic association between OCD and the gene for catechol-O-methyltransferase (COMT). In this report, we use 110 nuclear OCD families to analyze the inheritance of variants of COMT and monoamine oxidase-A (MAOA), another gene modulating monoamine metabolism. METHODS: A sample of 110 nuclear OCD families was collected, and lifetime diagnoses were ascertained using the Diagnostic Interview for Genetic Studies (DIGS). DNA was genotyped for functional variants of the COMT and MAO genes, and allele inheritance was examined using the Transmission Disequilibrium Test (TDT) and Haplotype-based Haplotype Relative Risk (HHRR) test. RESULTS: We provide evidence supporting the previously reported sexually dimorphic association between low COMT enzymatic activity and OCD. We also provide evidence for a similar sexually dimorphic association between OCD and an allele of the MAOA gene, previously linked to high MAO-A enzymatic activity. In agreement with the well-established action of MAO-A inhibitors as antidepressants, this association is particularly marked among male OCD probands with co-morbid MDD, who represent more than 50% of our male OCD sample. CONCLUSIONS: Our analysis indicates that variants of two genes modulating monoamine metabolism contribute significantly to OCD susceptibility. Most importantly, an unexpected sexually dimorphic pattern of genetic susceptibility to OCD is revealed and suggests the possibility that profound gender differences in genetic predisposition may exist not only for other OCD susceptibility genes, but for an array of other psychiatric disorders as well.

The motor agitation and retardation scale: a scale for the assessment of motor abnormalities in depressed patients.

Increasing recognition of the neurologic aspects of depressive disorder has aroused new interest in the potential neuropathologic significance of "psychomotor" symptoms in depression. Psychomotor symptoms have yet to be clearly defined, however. The Motor Agitation and Retardation Scale (MARS) was developed to provide a comprehensive and nonredundant measure of the motor abnormalities associated with agitation and retardation in depression. Forty-one depressed in patients and 20 normal control subjects were assessed. In this sample, the MARS provided a reliable and valid scale for the clinical assessment of 19 abnormal motor behaviors associated with agitation and retardation in depression. The MARS may be useful for investigation of the pathophysiologic significance of various manifestations of motor abnormalities in depression and, as part of a larger battery, for the investigation of the relative contribution of motor abnormalities to psychomotor impairment in depression.

Psychomotor symptoms of depression.

OBJECTIVE: The authors summarize current knowledge regarding the psychomotor symptoms of depression. METHOD: Findings from the objective quantification of psychomotor symptoms are reviewed, and methodological issues are considered. The contemporary empirical literature regarding the diagnostic, prognostic, and potential pathophysiologic significance of psychomotor symptoms is summarized. RESULTS: It has been repeatedly shown that depressed patients differ from normal and psychiatric comparison groups with regard to objectively quantified gross motor activity, body movements, speech, and motor reaction time. Course of illness, diurnal variation, medication status, sex, and age are associated with agitation and retardation and should be controlled when one is studying psychomotor symptoms. Psychomotor symptoms in depression may have unique significance. They have high discriminative validity, may be the only symptoms of depression that distinguish depression subtypes, and are predictive of good response to tricyclic antidepressants. Results of brain imaging and biochemical studies link depression and motor symptoms to abnormalities in the basal ganglia and basal ganglia/thalamo-cortical circuits. CONCLUSIONS: The investigation of psychomotor disturbance in depression is specifically consistent with neo-Kraepelinian standards for the study of psychiatric disorders. Our current knowledge of psychomotor symptoms is conceptually obscure, yet a large body of evidence specifies their manifestation and supports their significance. Identifying the incidence of abnormal motor behaviors in depressed patients and assessing the component processes that accompany and determine their manifestation may be important advances in the study of psychomotor symptoms in depression.

Who responds to electroconvulsive therapy? A comparison of effective and ineffective forms of treatment.

BACKGROUND: It has been reported that real ECT is more effective than simulated treatment among depressed patients with delusions and/or retardation, and that ECT is not effective among depressed patients who lack these features. METHOD: In two randomised, double-blind studies, 143 patients with major depression were subtyped regarding psychosis, retardation and agitation. In both studies, low dosage, right unilateral ECT was ineffective compared with other forms of ECT. This report examined whether the depressive subtypes differed in clinical response to the ineffective and effective forms of ECT. RESULTS: The therapeutic advantage of effective forms of ECT was similar across the depression subtypes. Patients who lacked both psychosis and retardation showed this pattern. CONCLUSIONS: The findings cast doubt on the utility of these depression subtypes in predicting ECT response. ECT is a viable treatment option for patients with major depression regardless of the presence or absence of psychosis, retardation and/or agitation.

Predictors of retrograde amnesia following ECT.

OBJECTIVE: Substantial progress has been made in identifying how the treatment parameters used in ECT impact on cognitive side effects. However, there is limited information regarding individual differences in vulnerability to these side effects. The authors examined patients' pretreatment global cognitive status and postictal orientation recovery time as potential predictors of the magnitude of retrograde amnesia for autobiographical memories after ECT. METHOD: Seventy-one inpatients with major depressive disorder were randomly assigned to four ECT conditions that varied in electrode placement (right unilateral versus bilateral) and stimulus dosage (low versus high intensity). Orientation recovery time was assessed at virtually every session during the course of ECT. Global cognitive status was assessed with the modified Mini-Mental State examination before treatment, during the week after termination of treatment, and 2 months after treatment ended. Retrograde amnesia was assessed at these same time points with the Autobiographical Memory Interview. RESULTS: Pre-ECT global cognitive status and the duration of postictal disorientation were strong predictors of the magnitude of retrograde amnesia in the week after the course of ECT and at 2-month follow-up. In general, these relationships were maintained regardless of technical parameters in the administration of the ECT. CONCLUSIONS: Patients who manifest global cognitive impairment before treatment and patients who experience prolonged disorientation in the acute postictal period may be the most vulnerable to persistent retrograde amnesia for autobiographical information.

Is the comorbidity between social phobia and panic disorder due to familial cotransmission or other factors?

BACKGROUND: We previously reported significantly elevated rates of social phobia in relatives of probands with panic disorder compared with relatives of other proband groups. This study further investigates the relationship between social phobia and panic disorder. METHOD: This sample is from a family study that included 193 probands from four mutually exclusive groups (patients with panic disorder, patients with panic disorder and major depression, patients with early-onset major depression, and normal controls) and 1047 of their adult first-degree relatives. Best-estimate diagnoses were completed using DSM-III-R criteria. RESULTS: Social phobia and agoraphobia aggregate in the families of probands with panic disorder without major depression. Social phobia frequently co-occurs with panic disorder in relatives, but the risk for comorbidity does not vary across proband groups. CONCLUSIONS: The familial aggregation of social phobia with panic disorder may be explained by the aggregation of panic disorder in relatives of probands with panic disorder combined with the tendency for panic disorder to occur comorbidly with social phobia in individuals.

Psychiatric disorders in relatives of probands with panic disorder and/or major depression.

BACKGROUND: Panic disorder and major depression (MDD) are both highly familial disorders that co-occur in individuals but do not cosegregate in families. Evidence concerning their familial aggregation with other psychiatric disorders, including phobias, substance abuse, and antisocial personality, has been contradictory. In part, the contradictory findings may be due to failure to account for the effects of proband comorbidity on risks in relatives. METHODS: A family study of 1047 adult first-degree relatives of 193 probands in four diagnostic groups (panic disorder without MDD, panic disorder plus MDD, early-onset MDD, and screened normal controls) was used to determine the range of psychiatric disorders associated with panic disorder and MDD and the effects of proband comorbidity on the rates of disorders in relatives. RESULTS: Compared to relatives of normal controls, relatives of probands with panic disorder or panic disorder and MDD showed significantly increased risks of panic disorder, but relatives of probands with early-onset MDD did not. After proband comorbidity was controlled for, relatives of probands with panic disorder were also at a significantly increased risk for social phobia but not for any other psychiatric disorders. Relatives of probands with early-onset MDD were at significantly increased risk for MDD, dysthymia, abuse of or dependence on alcohol and other drugs, and antisocial personality disorders but not for any other psychiatric disorders. CONCLUSIONS: We conclude that panic disorder is a specific familial entity that is not associated with a broad range of other anxiety or other psychiatric disorders, with the possible exception of social phobia. Dysthymia, substance abuse, and antisocial personality appear to be on the spectrum of early-onset MDD.