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Molecular analysis of velo-cardio-facial syndrome patients with psychiatric disorders.

Velo-cardio-facial syndrome (VCFS) is characterized by conotruncal cardiac defects, cleft palate, learning disabilities, and characteristic facial appearance and is associated with hemizygous deletions within 22q11. A newly recognized clinical feature is the presence of psychiatric illness in children and adults with VCFS. To ascertain the relationship between psychiatric illness, VCFS, and chromosome 22 deletions, we evaluated 26 VCFS patients by clinical and molecular biological methods. The VCFS children and adolescents were found to share a set of psychiatric disorders, including bipolar spectrum disorders and attention-deficit disorder with hyperactivity. The adult patients, >18 years of age, were affected with bipolar spectrum disorders. Four of six adult patients had psychotic symptoms manifested as paranoid and grandiose delusions. Loss-of-heterozygosity analysis of all 26 patients revealed that all but 3 had a large 3-Mb common deletion. One patient had a nested distal deletion and two did not have a detectable deletion. Somatic cell hybrids were developed from the two patients who did not have a detectable deletion within 22q11 and were analyzed with a large number of sequence tagged sites. A deletion was not detected among the two patients at a resolution of 21 kb. There was no correlation between the phenotype and the presence of the deletion within 22q11. The remarkably high prevalence of bipolar spectrum disorders, in association with the congenital anomalies of VCFS and its occurrence among nondeleted VCFS patients, suggest a common genetic etiology.

Abnormalities, Multiple↗

The persecutory ideation questionnaire.

We report the development and evaluation of a brief questionnaire measure of persecutory ideation, the Persecutory Ideation Questionnaire (PIQ). Our approach was theoretically driven in that the PIQ was constructed in accordance with comprehensive definitional considerations and criteria set out by . Sixty-six more general paranoia-related items were accumulated, and 10 independent raters sorted the items into two sets, "persecutory ideation" and "other." An 80% agreement criterion was set, resulting in 10 persecutory ideation items. The PIQ was evaluated with a nonclinical and a clinical sample. In both samples, it was shown to have excellent reliability (internal consistency) and excellent convergent validity as a measure of certain aspects of general paranoid ideation. Finally, the PIQ shared unique variance with severity of persecutory delusions in the clinical group, providing good criterion validity for the PIQ as a measure of specifically persecutory ideation, rather than paranoia in general.

Adolescent↗

The social anxiety spectrum.

Social anxiety disorder is well suited to the spectrum concept because it has trait-like qualities of early onset, chronicity, and no empirically derived threshold that demarcates normal from clinically significant trait social anxiety. Social anxiety disorder has been shown to respond to relatively specific pharmacologic and cognitive-behavioral therapies, which makes identification of other conditions that may lie on the social anxiety disorder spectrum important because of possible treatment implications. Biologic markers associated with social anxiety disorder also may be shared by similar but nonidentical traits, such as behavioral inhibition and detachment. Clarification of the trait spectrums associated with specific biologic systems offers an opportunity for improving the understanding of the origin of these conditions. Strong evidence exists that at least some forms of shyness, avoidant personality disorder, and selective mutism lie on a social anxiety disorder spectrum. For several other disorders that share a prominent focus on social comparison, significant subgroups of patients seem to have features of social anxiety disorder. These disorders include major depression (especially the atypical subtype), body dysmorphic disorder, and eating disorders. Several other disorders marked by social dysfunction or inhibition, including substance use disorders (especially alcoholism), paranoid disorder, bipolar disorder, autism, and Asperger's disorder, also may show some overlap with social anxiety disorder features (e.g., social anxiety as a cause or complication of substance abuse, social avoidance in paranoid disorder, social disinhibiton in bipolar disorder, and social communication deficits in autism and Asperger's disorder). Social anxiety disorder also is associated with other anxiety disorders in general and other phobias in particular. In respect to traits, a growing body of evidence links behavioral inhibition to the unfamiliar to a social anxiety disorder spectrum with some specificity. Biologic measures of dopamine system hypoactivity have been linked to social anxiety disorder, trait detachment, and general deficits in reward and incentive function. It remains to be clarified, however, whether this brain system function is best characterized by a social anxiety disorder spectrum or some variant that incorporates social reward deficits or social avoidance behavior. Social anxiety disorder, shyness, and behavioral inhibition all seem to have a genetic component, but more research is needed to attempt to identify a more specifically heritable temperament associated with these conditions. Finally, the emergent concept of a social anxiety spectrum needs maturation. Although the notion of a single social anxiety disorder spectrum currently has some clinical use, the authors believe that exclusive focus on the notion of a single continuum with two extremes--from social disinhibition in mania to the most severe form of social anxiety, avoidant personality disorder--is premature and limiting in respect to etiologic research. An alternative approach is to conceptualize multiple, probably overlapping spectra in this area of social psychopathology. Individual dimensions might be based on various core phenomenologic, cognitive, or biologic characteristics. A bottom-up biologic approach holds promise for identifying spectra with a common etiology that might respond to specific treatments. Taking a pluralistic view of the concept of spectrum at this stage may help accelerate our understanding of social anxiety and related disorders.

Brain↗

Neuropsychological performance and spectrum personality traits in the relatives of patients with schizophrenia and affective psychosis.

Neuropsychological deficits are found in both schizophrenic patients and their relatives, and some studies have shown similar, but less severe, deficits in affective psychotic patients and their relatives. We set out to establish: (a) whether schizophrenia spectrum personality traits are more common in the relatives of schizophrenic patients than, in the relatives of affective psychotic patients; and (b) what the relation is between spectrum personality traits and neuropsychological deficits in these relatives. Relatives were interviewed using the International Personality Disorder Examination (IPDE), and also completed the National Adult Reading Test (NART), the Trail Making Test (TMT; Parts A and B) and Thurstone's Verbal Fluency Test (TVFT). Spectrum personality traits were equally common in 129 relatives of schizophrenic patients and 106 relatives of affective psychotic patients, but the performance of the former group was inferior to that of the latter on the NART and the TVFT. Relatives with high paranoid traits had lower NART scores than relatives without such personality traits; similarly, those with high schizoid traits took longer to complete the TMT, part B, than those without such traits; and relatives with high schizotypal traits generated significantly fewer words on the TVFT than those without such traits. We conclude that relatives of schizophrenic and affective psychotic patients share a propensity to schizophrenia spectrum traits, but relatives of the former have poorer neuropsychological performance. Furthermore, there exists an association between neuropsychological deficits and spectrum traits in both groups of relatives; in particular those with high paranoid traits have lower IQ scores than their less paranoid counterparts.

Adult↗

A twin study of personality disorders.

No twin study has previously investigated the whole range of personality disorders (PDs) recorded by interviews. Based on twin and patient registries, 92 monozygotic (MZ) and 129 dizygotic (DZ) twin pairs were interviewed with the Structured Clinical Interview for DSM-III-R Personality Disorders (SCID-II). Observed prevalence rates from a normal population study of more than 2,000 individuals were used in combination with data from the present study to generate statistics assumed to be valid for a normal twin population, and these statistics were used for structural equation modeling. The best-fitting models had a heritability of .60 for PDs generally, .37 for the eccentric (A) cluster, .60 for the emotional (B) cluster, and .62 for the fearful (C) cluster. Among the specific PDs, the heritability appeared to be .79 for narcissistic, .78 for obsessive-compulsive, .69 for borderline, .67 for histrionic, .61 for schizotypal, .57 for dependent, .54 for self-defeating, .29 for schizoid, .28 for paranoid, and .28 for avoidant PDs. The best-fitting models never included shared-in-families environmental effects. However, a model with only shared familial and unique environmental effects could not be ruled out for dependent PD. Shared familial environmental effects may also influence the development of any PD and borderline PD. Passive-aggressive PD did not seem to be affected by genes or family environment at all. The low occurrence of antisocial PD in the twin sample precluded any model for this disorder. PDs seem to be more strongly influenced by genetic effects than almost any axis I disorder, and more than most broad personality dimensions. However, we observed a large variation in heritability among the different PDs, probably partly because of a moderate sample size and low prevalence of the specific disorders.

Adult↗

Clinician ratings of the five-factor model of personality and the DSM-IV personality disorders.

This study explored the associations among the domains of the five-factor model (FFM) of personality (neuroticism, extraversion, openness, agreeableness, and conscientiousness) and the DSM-IV personality disorders (PDs). Clinician ratings were obtained for both the DSM-IV PDs and the FFM on a sample of 100 PD patients. The correlational data showed that the DSM PDs were most strongly associated with the FFM domains of neuroticism, extraversion, and agreeableness. Factor analysis revealed four underlying factors that provided insights into qualities shared by subgroups of the DSM-IV PDs. The domain of neuroticism was associated with the borderline, avoidant, and dependent PDs (factor 1). The paranoid, avoidant, schizoid, and schizotypal PDs were negatively associated with the domain of agreeableness (factor 2). The domain of extraversion was positively associated with the narcissistic and histrionic PDs and negatively with schizoid PD (factor 3). The FFM conscientiousness and openness domains loaded onto a single factor and were positively associated with the obsessive-compulsive PD and negatively associated with the antisocial and borderline PDs. Exploring the relationships between these two personality systems will improve our conceptualization and understanding of the DSM PDs.

Adult↗

Attitudes towards mental illness: the influence of education and experience.

Female nursing students who had completed an instructional and experiential training program were compared on their perception, beliefs and opinions about mental illness with students who had just entered the same program. The results showed that students who had completed their training were better able to perceive the presence and severity of mental illness. Both groups favoured psychosocial etiology and psychosocial forms of treatment. There was no difference in their attitudes towards the mentally ill and both groups shared an overall optimism about prognosis. The implications of the lack of sophisticated knowledge about psychiatric disorders among mental health professionals are discussed.

Adult↗

Disorders with overvalued ideas.

The overvalued idea, first described by Wernicke, refers to a solitary, abnormal belief that is neither delusional nor obsessional in nature, but which is preoccupying to the extent of dominating the sufferer's life. Disorders conforming to his definition are well documented, though their recognition as such has been variable, and they may not be as rare as is often thought. As well as sharing a distinctive phenomenology, the conditions develop in similar settings and carry a uniformly poor prognosis. Their pathogenesis is obscure and difficult to account for in conventional terms.

Anorexia Nervosa↗

Kallmann's syndrome and schizophrenia.

OBJECTIVE: Kallmann's Syndrome is a heritable disorder characterized by the association of hypogonadotropic hypogonadism and anosmia or hyposmia. A common pathogenesis for KS and schizophrenia had been proposed based on shared pathologies of these two disorders, although no such clinical associations have ever been reported. METHOD: We report a 35 year old man with schizophrenia and Kallmann's Syndrome. The patient presented with signs and symptoms of hypogonadism, severe hyposmia and normal endocrine functions of the anterior pituitary. Hyposmia has been attributed to the absence of the olfactory bulbs and tracts and atrophy of the olfactory gyri, but normal olfactory mucosa. The patient presented with paranoid schizophrenia with persecutory delusions, auditory hallucinations, thought disorder, depersonalization, and gradual but marked global deterioration. RESULTS: Psychiatric evaluation revealed an entirely different psychopathological and personality profile between the patient and the six other Kallmann patients studied. Cycle sequencing analysis revealed a normal sequence of all 14 exons of the KAL gene. In conclusion, based on the presented case, Kallmann's Syndrome and schizophrenia represent a rare clinical association rather than a syndrome with a common pathogenesis, which if present should be confined to the olfactory dysfunction.

Adult↗

A genome-wide search for schizophrenia susceptibility genes.

We completed a systematic genome-wide search for evidence of loci linked to schizophrenia using a collection of 70 pedigrees containing multiple affected individuals according to three phenotype classifications: schizophrenia only (48 pedigrees; 70 sib-pairs); schizophrenia plus schizoaffective disorder (70 pedigrees; 101 sib-pairs); and a broad category consisting of schizophrenia, schizoaffective disorder, paranoid or schizotypal personality disorder, psychosis not otherwise specified (NOS), delusional disorder, and brief reactive psychosis (70 pedigrees; 111 sib-pairs). All 70 families contained at least one individual affected with chronic schizophrenia according to DSM-III-R criteria. Three hundred and thirty-eight markers spanning the genome were typed in all pedigrees for an average resolution of 10.5 cM (range, 0-31 cM) and an average heterozygosity of 74.3% per marker. The data were analyzed using multipoint nonparametric allele-sharing and traditional two-point lod score analyses using dominant and recessive, affecteds-only models. Twelve chromosomes (1, 2, 4, 5, 8, 10, 11, 12, 13, 14, 16, and 22) had at least one region with a nominal P value <0.05, and two of these chromosomes had a nominal P value <0.01 (chromosomes 13 and 16), using allele-sharing tests in GENEHUNTER. Five chromosomes (1, 2, 4, 11, and 13) had at least one marker with a lod score >2.0, allowing for heterogeneity. These regions will be saturated with additional markers and investigated in a new, larger set of families to test for replication.

Chromosome Mapping↗

Quetiapine, clozapine, and olanzapine in the treatment of tardive dyskinesia induced by first-generation antipsychotics: a 124-week case report.

Our report of a patient with severe tardive dyskinesia (TD) who has been exposed to both typical antipsychotic and clozapine, olanzapine and quetiapine during a 124-week follow-up period supports the possible beneficial effect of atypical antipsychotics on pre-existing symptoms of TD. Persistently high AIMS scores during all the periods of treatment with typical antipsychotics contrast strongly with the drop in scores that occurs in strict chronological sequence after switching to both clozapine (45%), olanzapine (27.8%) and quetiapine (85%). Since the reversal to haloperidol from the three atypical agents was systemically associated with a return to high AIMS scores, it seems likely that the improvement noted with clozapine, olanzapine and quetiapine represents a temporary symptomatic effect rather than a sustained resolution of the disorder. The olanzapine-clozapine-quetiapine rank order of increasing effectiveness against TD symptoms suggests that this property, although shared by the atypical antipsychotics, is to some degree drug-specific. Patient- and/or drug-dependent mechanisms may be involved in this gradient of effect.

Amphetamine-Related Disorders↗

Psychotherapeutic management techniques in the treatment of outpatients with schizophrenia.

Successful outpatient treatment of schizophrenic disorders largely depends on the patient's ability to form a treatment alliance with mental health professionals. However, even in the context of competent pharmacotherapy, symptoms of schizophrenia often persist under this alliance. The authors review five common syndromes occurring during the course of treatment of patients with schizophrenia that interfere with the therapeutic alliance: paranoia, denial of illness, stigma, demoralization, and terror from awareness of having psychotic symptoms. Mental health clinicians can use specific psychotherapeutic management techniques for these symptoms. Examples of these techniques include "sharing mistrust" for paranoid patients, providing patients who deny their illness with alternate points of view, making admiring and approving statements to demoralized patients, and normalizing experiences of stigmatized patients. The techniques do not require advanced psychotherapy training and can be used, with ongoing supervision, by bachelor's-level mental health workers.

Adult↗

Personality disorders among the relatives of schizophrenia patients.

In light of current linkage studies in schizophrenia, research on the "schizophrenia spectrum" deserves increased attention for an exact determination of the affected phenotype: Those disorders that have a much higher prevalence among biological relatives of schizophrenia patients are supposed to share common etiological factors with "core" schizophrenia. However, there is controversy over which of the DSM-III-R personality disorders should be included in the spectrum. In a controlled family study of inpatients with a DSM-III-R diagnosis of schizophrenia (n = 101), schizophreniform and schizoaffective disorders (n = 69), and unipolar major depression (n = 160), familial rates of personality disorders were assessed through personal interviews and compared with prevalence rates in 109 control families from the community. As predicted, schizotypal personality disorder occurred more frequently in the nonpsychotic relatives of schizophrenia probands (2.1%) than in the families of unscreened controls (0.3%). Paranoid personality disorder was more frequent in relatives of probands with unipolar depression (2.9%) than in relatives of schizophrenia patients (1.7%), and controls revealed the lowest rate (0.9%). Schizoid personality disorder, however, was extremely rare in all sample groups (between 0.3% and 0.7%), providing no sufficient statistical power for detection of group differences. Further analysis of the DSM-III-R criterion symptoms of schizotypal personality disorder demonstrated that items describing "negative" symptomatology are the main source of familial aggregation, but "psychotic-like" personality features are also contributing factors.

Adult↗

Spontaneous recurrence of methamphetamine-induced paranoid-hallucinatory states in female subjects: susceptibility to psychotic states and implications for relapse of schizophrenia.

In this study, we examined the relationship between increased sensitivity to stress associated with noradrenergic hyperactivity and dopaminergic changes, and susceptibility to subsequent spontaneous recurrences of methamphetamine (MAP) psychosis (i.e., flashbacks). The subjects were 81 physically healthy females. Plasma monoamine metabolite levels were assayed in: 19 flashbackers, of whom 11 experienced a single flashback and 8 exhibited subsequent flashbacks; 20 non-flashbackers with a history of MAP psychosis; 8 subjects with persistent MAP psychosis; and 23 MAP users and 11 non-user controls. All 19 flashbackers had undergone frightening and stressful experiences during previous MAP use. Mild psychosocial stressors then triggered their flashbacks. During flashbacks, plasma norepinephrine levels increased, with a small increase in plasma levels of 3-methoxytyramine, which is an index of dopamine release. Among the 19 flashbackers, the 8 with subsequent episodes had increased NE levels and slightly increased 3-methoxytyramine levels, while the 11 with a single episode displayed small increases in norepinephrine and 3-methoxytyramine levels. Thus, noradrenergic hyperactivity and increased dopamine release in response to mild psychosocial stressors may be responsible for the development of flashbacks. Robust noradrenergic hyperactivity with slightly increased DA release in response to mild stress may induce susceptibility to subsequent flashbacks. Flashbacks and schizophrenia may share the pathophysiology of susceptibility to recurrence of paranoid-hallucinatory states such as stress sensitization, and also noradrenergic hyperactivity and enhanced DA release. Thus, flashbacks may provide an appropriate model of susceptibility to paranoid-hallucinatory states of schizophrenia. The model psychosis is a potential tool for validating basic neurobiological concepts thought to be related to the schizophrenia. A better understanding of the neurobiological mechanisms of susceptibility to recurrence could provide useful information in the development of strategies for preventing relapse.

Adult↗

[Clinical example of recovery from psychosis in the context of the theory of psychosis as a state of aberrant salience].

According to the theory proposed by S. Kapur psychosis is a state of aberrant salience. Dopamine and mesolimbic system play the key role in the occurrence of psychosis. According to Kapur dopamine mediates the conversion of neural representations of an external stimulus from a neutral into attractive or aversive. In the psychosis this physiological role of the dopamine is changed. Dopamine starts to create a process of salience acquisition; instead of mediate it as it is in normal circumstances. According to Kapur delusions are cognitive explanations that the individual imposes on the experience of aberrant salience. Pharmacological agents share the psychological effect-dampening salience. But antipsychotics only provide the state of attenuated salience and symptomatic improvement needs further psychological and cognitive resolution. The case of a patient with paranoid psychosis during treatment with risperidone was analyzed in the context of Kapur's theory. Reports of experiences given by patients can support the theory and make it valuable in the conceptualization of the process of step-by-step recovery from psychosis.

Adult↗

Diagnostic differences in psychogeriatric patients in Toronto, New York and London, England.

National statistics on psychiatric illness in the elderly patient from Canada, the United States and the United Kingdom suggest great differences in morbidity in these three centres. The present study shows that these differences stem mainly from different diagnostic habits in the three countries, but also there were more alcoholics in the Canadian sample. In particular, the diagnostic bias of the New York psychiatrists towards diagnosing most elderly patients as senile was not shared by their Toronto colleagues. Some patients were psychiatrically well, in spite of receiving a psychiatric diagnosis, and could have been helped without hospitalization. In addition, some depressed patients were labelled senile. Recommendations include improvement of catchment and treatment facilities for the elderly alcoholic and the provision of psychogeriatric diagnostic centres.

Affective Symptoms↗

Mesolimbic activity associated with psychosis in schizophrenia. Symptom-specific PET studies.

Hallucinations and paranoid delusions are prominent among the positive symptoms of schizophrenia. Such psychotic symptoms are notable for their aberrant representations of, and relation to, the external world and for the emotional/motivational valence associated with the representations. As mesolimbic structures, including the amygdala and ventral striatum, are thought to play a significant role in imparting emotional valence to external stimuli, we here examine the mesolimbic findings of H215O PET studies designed to probe the functional neuroanatomy of psychosis. Patients with schizophrenia (including those with active hallucinations, those with active paranoid delusions, and those without active positive symptoms at the time of scanning) and healthy control subjects were studied. An event-related PET paradigm was used to identify the neural correlates of hallucinations, and a modified emotional stroop paradigm (with threat versus neutral words) was used to test the hypothesis that paranoid patients would have increased mesolimbic activity in response to threat, and even in response to neutral stimuli. The findings suggest that the positive psychotic symptoms of hallucinations and delusions share similar functional neuroanatomical features of increased mesotemporal and ventral striatal activity in the setting of decreased prefrontal activity. The pattern is evident even in a neutral context, unlike the case for normal subjects, who show such features only in response to threat. The implications of these findings for a pathophysiology of psychosis will be discussed in the context of the behavioral neuroanatomical literature in animals and humans.

Corpus Striatum↗

Effects of neuroleptic medications on speech disorganization in schizophrenia: biasing associative networks towards meaning.

BACKGROUND: While some cognitive accounts of disorganized speech, or thought disorder, in schizophrenia have emphasized failures in working memory/discourse planning or selective attention, we have suggested that thought disorder resides in the semantic system. In this study we assessed the effect of neuroleptic medication on thought disorder and semantic processing. METHODS: Seventeen patients with schizophrenia were assessed while receiving neuroleptic medications and in crossover fashion, placebo. A number of measures were obtained: clinically rated thought disorder (using the Thought, Language and Communication Scale); working memory letter number span); lexical integrity (naming and receptive vocabulary); and, semantic priming of intracategorical word pairs. RESULTS: Semantic priming measures improved with neuroleptic medication, as did clinically rated thought disorder. No other measure changed significantly. Priming selectively covaried with changes in thought disorder. CONCLUSION: Changes in spreading semantic activation, measured in a semantic priming paradigm and presumably brought about by neuroleptics' influence on dopaminergic neuromodulatory systems, might reflect changes in the biases of pre-existing associative networks that favour or increase the accessibility of representations related by shared features. This study also has implications for the architecture of normal language in that a dissociation between the lexical and semantic levels was observed, due to the selective compromise of tasks demanding semantic processing.

Adult↗