This issue of CNS Spectrums explores the boundaries and relationship between anxiety and psychosis from various perspectives. Anxiety may be conceived as being secondary to psychosis, or psychosis emerging from an anxiety disorder. Anxiety might also be a symptom, or part and parcel, of a psychotic illness. Finally, pharmacologic treatment of psychosis might precipitate an anxiety disorder, or psychopharmacologic approaches to anxiety disorders might precipitate psychosis. Thus, the relationship between these two symptom clusters may be complex and multidetermined.

First, I would like to thank Stefano Pallanti, MD, of both the Institute of Neurosciences at the University of Florence Medical School and the Mount Sinai School of Medicine, for defining the challenge, assembling an international cohort of experts, and guest editing this issue.

In this issue, Rossi and colleagues present original research derived from a study of 400 inpatients that examines the pattern of comorbidity among obsessive-compulsive personality disorder (OCPD) and other personality disorders. Of interest, the highest co-occurence of OCPD is with the cluster A disorders (paranoid and schizoid)—the “odd” cluster.

Pallanti and colleagues describe the development of social phobia in 12 patients with paranoid schizophrenia during clozapine treatment. Two thirds of these patients had significant improvement of social phobic symptoms with fluoxetine augmentation of clozapine. This new observation is certainly reminiscent of the induction of obsessive-compulsive symptomatology with atypical neuroleptic treatment in schizophrenia.

The National Institute of Mental Health (NIMH) has embarked upon a new venture—effectiveness trials, large-scale trials to test more than one treatment option for individuals affected with diverse major mental disorders. The launch follows a recent report by the NIMH National Advisory Mental Health Council, which emphasized the failure within routine clinical care to widely implement findings of randomized, controlled efficacy trials (RCTs)—perhaps, in part, because of reduced generalizability that leaves real-world application unclear.

Efficacy trials do not answer a number of key clinical questions, including: (1) Are the treatments as effective and safe in representative patient groups? (2) How does the new treatment fit within the treatment armamentarium? (3) When should the new treatment be combined with existing interventions? (4) What are the long-term benefits? (5) Do treatments differ regarding their effectiveness in patients with comorbid general medical or psychiatric disorders? (6) How do these newer treatments affect costs of routine care? Effectiveness trials can address a number of these issues and incorporate a broad range of outcomes, including symptom reduction, day-to-day function, side effect burden, and patient satisfaction.

With a major aim of effectiveness trials being increased generalizability, selection of participants is crucial. Since symptomatic volunteers, who are typically used in efficacy RCTs for major depressive disorder, may be more responsive to either the nonspecific aspects of treatment or to the treatment itself than self-declared patients with concomitant comorbidities, setting minimal exclusion criteria, recruiting large samples of patients from representative practices, and excluding symptomatic volunteers assures that patients are representative, while protecting the internal validity of the trial. In addition, treatments must be reasonably well delivered so that outcomes can be attributed to the treatment per se and not to improper implementation of an otherwise effective treatment. Frequent clinic visits, patient/family educational efforts, universal access to all protocol recommended treatments (including psychotherapy), and adequate provider compensation can ensure that treatments are reasonably well delivered.

The aim of this study was to examine the pattern of comorbidity among obsessive-compulsive personality disorder (OCPD) and other personality disorders (PDs) in a sample of 400 psychiatric inpatients. PDs were assessed using the Semistructured Clinical Interview for DSM-III-R Personality Disorders (SCID-II). Odds ratios (ORs) were calculated to determine significant comorbidity among OCPD and other axis II disorders. The most elevated odds ratios were found for the cooccurrence of OCPD with cluster A PDs (the “odd” PDs, or paranoid and schizoid PDs). These results are consistent with those of previous studies showing a higher cooccurrence of OCPD with cluster A than with cluster C (“anxious”) PDs. In light of these observations, issues associated with the nosologic status of OCPD within the Diagnostic and Statistical Manual of Mental Disorders clustering system remain unsettled.

The concept of anxiety as a distinct comorbid disorder in schizophrenia has recently been rediscovered after having been neglected for a long period of time due to both theoretical and clinical approaches adopted from the appearance of the first edition of the Diagnostic and Statistical Manual of Mental Disorders in 1950. This rediscovery was accentuated by the fact that the concept of comorbidity in various psychiatric disorders has recently won widespread favor within the scientific community, and that the use of atypical neuroleptic medication to treat patients with schizophrenia has been reported to lead to the emergence of anxiety symptoms. Of the atypical neuroleptic medications used to treat schizophrenia, clozapine has most frequently been reported to induce anxiety symptoms. In this paper, 12 cases of patients with paranoid schizophrenia who developed social phobia during clozapine treatment are reported, and their response to fluoxetine augmentation is assessed. Premorbid personality disorders were also investigated; patients were assessed using the Structured Clinical Interview for DSM-III-R—Patient Version and the Structured Clinical Interview for DSM-IV Axis II Personality Disorders (DSM-III-R=Diagnostic and Statistical Manual of Mental Disorders, Third Edition Revised; DSM-IV=Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition). In addition, the Scale for the Assessment of Negative Symptoms, the Scale for the Assessment of Positive Symptoms, the Liebowitz Social Anxiety Scale (LSAS), the Frankfurt Beschwerde Fragebogen (Frankfurt Questionnaire of Complaints), and the Brief Psychiatric Rating Scale were used to rate clinical symptomatology. All patients were reevaluated after 12 weeks of cotreatment with clozapine and fluoxetine. In 8 (66.6%) of the 12 cases, symptoms responded (≥35% LSAS score reduction) to an adjunctive regimen of fluoxetine. Furthermore, in 7 (58.3%) of the 12 cases, an anxious personality disorder (avoidant=33.3%; dependent=25%) was identified, but no significant differences in the prevalence of comorbid personality disorders emerged in comparison with a group of 16 patients with paranoid schizophrenia treated with clozapine who did not show symptoms of social phobia. The clinical relevance of the assessment and treatment of anxiety disorders is discussed in light of a clinical therapeutic approach that overcomes the implicit hierarchy of classification. Considering that the onset of anxiety-spectrum disorders (such as social phobia) can occur during the remission of psychotic symptoms in clozapine-treated patients with schizophrenia, a comprehensive approach to pharmacological therapy for patients with schizophrenia (or, at least for those treated with clozapine) should be adopted.

Psychotic anxiety has not been systematically included in standard psychopathologic and diagnostic literature, presumably because anxiety is implicitly perceived to be an emphatically comprehensible consequence of the cognitive symptoms of psychosis. This review gives an overview of neurophysiologic studies that indicate different pathogenic mechanisms for different types of psychosis. Convergent and complementary structural and functional imaging findings, biochemical and neuropsychological data allow conjecture as to neurophysiologic-psychopathologic links in cycloid psychosis. Intriguing results suggest that in cycloid psychosis, a generalized hyperasousal related to the tonus of the noradrenergic system may be the basic disturbance causing the delusionary and perceptual psychotic distortions. The findings are specific for cycloid psychoses, which are diagnosed as polymorphous psychosis in the International Classification of Diseases and Related Health Problems, 10th Edition. Furthermore, these findings are consistent with the author's hypothesis that the emotional derailment is the primary disturbance in cycloid psychosis (anxiety-elation). In contrast, cognitive disturbances are secondary and remit after the exceptional emotional state is rebalanced.

Recent data suggest that the presence of psychotic symptoms in patients suffering from posttraumatic stress disorder (PTSD) may represent an underrecognized and unique subtype of PTSD. Among combat veterans with PTSD, 30% to 40% report auditory or visual hallucinations and/or delusions. The presence of psychotic symptoms in PTSD is associated with a more severe level of psychopathology, similar to that of chronic schizophrenia. In this review, the differential diagnosis of psychotic symptoms in PTSD is discussed, including possible comorbid schizophrenia, psychotic depression, substance-induced psychosis, and personality disorder. A recent biologic study supporting the existence of a unique subtype of PTSD with psychotic features is also addressed, as are the similarities between PTSD with psychotic features and psychotic depression disorder. Finally, data on the treatment implications of psychotic symptoms in PTSD are presented. The intriguing recent findings on psychotic symptoms in PTSD need further investigation in noncombat-related PTSD populations before findings can be generalized to all individuals with PTSD.

Abnormalities of brain hemispheric organization have been found in a variety of psychiatric disorders. Despite the great amount of data collected and the number of theoretical models elaborated, the role of these abnormalities in the pathogenesis of these disorders remains controversial. This article briefly reviews current concepts of hemispheric functioning, discusses the role of abnormalities of brain hemispheric organization in schizophrenia and in two anxiety disorders (panic disorder and obsessive-compulsive disorder), and outlines a developmental perspective that accounts for the observed abnormalities.