Elevated Prevalence of Generalized Anxiety Disorder in Adults With 22q11.2 Deletion Syndrome

Seminars in Psychiatric Genetics

Of 316 patients with a major depressive disorder who were followed for between 6 months and 2 years, 80 (25%) had a preexisting chronic minor depression of at least 2 years' duration. The chronic minor depression reduced the apparent effect of the known predictors of recovery and relapse from the major depressive disorder and predicted a very pernicious course for the chronic depression. Furthermore, the longer the patient continued to suffer from a chronic minor depression after recovering from the major depression, the greater the probability that relapse into another major depression would preempt recovery from the chronic depression.

The author develops a nosologic framework for understanding the psychopathology of low-grade chronic depressions: 1) late-onset primary depressions with residual chronicity, 2) chronic secondary dysphorias, having a variable onset age and considered part of the symptomatic picture of nonaffective "neurotic" disorders or reactions to longstanding incapacitating medical diseases, and 3) early-onset characterologic depressions, which include a) character-spectrum disorders developing in the setting of tempestuous early object relationships and b) subaffective dysthymic disorders, conceptualized as genetically attenuated forms of primary affective illnesses. Differences in family history, REM latency, and pharmacologic responsiveness are presented in support of these distinctions. The author also proposes operational criteria to identify a thymoleptic-responsive subaffective dysthymic group.

The authors conducted a blind DSM-III family study based on probands diagnosed from long-term follow-up information as having schizophreniform disorder, schizoaffective disorder, or psychotic affective illness. The pattern of psychopathology in relatives of schizophreniform probands closely resembled that found previously in relatives of schizophrenic probands. Relatives of schizoaffective probands had an excess risk for schizophrenia, other psychoses, and bipolar illness. The pattern of illness found in relatives of the probands meeting Research Diagnostic Criteria for mainly schizophrenic schizoaffective disorder appeared indistinguishable from that of relatives of schizophrenic probands. Relatives of probands with psychotic affective disorder had an excess risk for schizophrenia and for unipolar and bipolar affective disorder.

Ethics of Modality Choice

Corticotropin-releasing factor (CRF) is a newly sequenced neuropeptide thought to be a principal stimulus to pituitary corticotropin (ACTH) secretion. Evidence obtained from laboratory animals and primates is reviewed which indicates that CRF not only stimulates the pituitary-adrenal axis but also influences several aspects of CNS function which may be of relevance to psychiatric illness. Clinically, experience in administering ovine CRF to more than 150 individuals shows that CRF can be helpful in resolving differential diagnostic dilemmas in patients with various disorders of the hypothalamic-pituitary-adrenal axis and in furthering an understanding of the pathophysiology of conditions such as Cushing's disease and depression.

Alzheimer's Disease: Optimizing Drug Development Strategies

Dr. Meltzer and Mr. Cola Reply

Evil or Ill? Justifying the Insanity Defense

Issues in clozapine treatment were considered in terms of implications for resource management. A critical review of the literature on time course and pattern of response to clozapine was used to address treatment of negative symptoms, late responders, and extent of clinical benefit in ordinary settings. Superior efficacy of clozapine for partial and poor neuroleptic responders is observed in about one-half of the cases. Response is rapid once a therapeutic dose is reached, and the data do not support the proposition that some patients first respond only after 3-12 months of therapy. The cumulative benefit over several months of treatment and the broad range of symptoms involved in response are similar to those for typical neuroleptic drugs, suggesting that clozapine's superiority is based on greater effectiveness rather than a unique profile of treatment effects. Clozapine appears to be effective for secondary, but not primary, negative symptoms. Modal response is moderate, and extensive rehabilitation and clinical services are required to substantially enhance functional outcome. Many more patients merit trials with clozapine. Economic costs and adverse drug effects can be minimized by selecting patients most likely to benefit and discontinuing clozapine treatment when benefit is not observed within 2-4 months. Appropriate patients include 1) those with good responses to typical neuroleptics who experience substantial adverse effects and 2) those whose disorders respond poorly to standard neuroleptics and are defined by psychotic symptoms, thought disorder, and hostility. Treatment of primary negative symptoms is not supported by the current experimental data.

Drs. Chouinard and Jones Reply

To The Editor: Most national estimates of adult DSM-IV substance use disorder (e.g., National Epidemiologic Survey on Alcohol and Related Conditions [1], and National Survey on Drug Use and Health [2]) are based on household samples that exclude prison and jail inmates, populations known to have high rates of substance use disorders. To estimate the effect of excluding inmates, we present estimates of alcohol and drug use disorders for household and inmate populations and calculate the change in the overall prevalence of substance use disorder when these two populations are pooled. Prevalence estimates for the combined U.S. household and inmate population are weighted averages of the survey-weighted prevalence estimates for the household population, state prison population, federal prison population, and jail population (1, 3–5). As seen in Table 1, details about interviewing and how weighted averages and standard errors were calculated are reported (also see the data supplement accompanying the online version of this letter). Table 1 Effect of Adding the Inmate Population to Household Prevalence and Population Estimates of the Prevalence of Past 12 Month DSM-IV Alcohol and Drug Use Disorders in U.S. Adults Including inmates increased overall projected estimates of the number of persons in the United States aged ≥18 years with an alcohol use disorder by 877,000, from 17,580,000 to 18,457,000, a 5.0% increase over the base. Estimates of the number with an illicit drug use disorder increased by 1,043,000, from 4,159,000 to 5,202,000, a 25.1% increase. Overall prevalence of the specific alcohol abuse and dependence disorders increased over the base by 4.2% and 5.9% respectively, and illicit drug abuse and dependence increased by 12.0% and 53.8%. High rates of DSM-IV substance use disorders among inmates combined with a large inmate population means that many persons with alcohol and drug use disorders are missed by major U.S. national general population surveys. The undercount for both alcohol and illicit drug disorders is significant, but proportionately the undercount for alcohol disorders is modest while the proportionate undercount for illicit drug disorders, particularly illicit drug dependence (i.e., addiction), is large. These results likely would be accentuated for substances such as cocaine, methamphetamine, and heroin, which are rare in the household population (2) but common among inmates (4–5). In addition, prevalence rates may be particularly underestimated for men and for those minority populations that are overrepresented in the inmate population. To improve accuracy and cover the full range of cases, the U.S. surveillance system may need to be modified. In addition, further investigation of the effect of incarceration on estimates for specific subpopulations is warranted.

The effects of D-cycloserine added to clozapine were assessed and compared with previous results for D-cycloserine plus conventional neuroleptics. Ten schizophrenic outpatients receiving clozapine entered consecutive 2-week trials of placebo and D-cycloserine at 5, 15, 50, and 250 mg/day. Clinical evaluations were videotaped and scored by a rater blind to the sequence of assessments. There was a significant dose effect of D-cycloserine on scores on the Scale for the Assessment of Negative Symptoms (SANS); the 50-mg dose produced a mean 21% increase in SANS score. The patients had significantly higher baseline serum glutamate concentrations than the patients receiving typical neuroleptics in the previous trial. Baseline glutamate level and change in glycine level significantly correlated with response of negative symptoms to 50-mg D-cycloserine. The improvement of negative symptoms with D-cycloserine previously observed in patients receiving typical neuroleptics did not occur in patients treated with clozapine.

Drs. Rubinow and Roy-Byrne Reply

Although attention deficit hyperactivity disorder is a common disorder of childhood, its status as a disorder in adults is not clear. The authors reasoned that if the adult diagnosis of the disorder is a valid clinical entity, it should be similar to the childhood disorder with regard to patterns of psychiatric and cognitive findings. Eighty-four adults with a clinical diagnosis of childhood-onset attention deficit hyperactivity disorder confirmed by structured interview who were referred for treatment were studied. Findings were compared with those from a preexisting study group of referred children with attention deficit hyperactivity disorder, nonreferred adult relatives of those children who also had attention deficit hyperactivity disorder, and adults without the disorder who were relatives of normal children. Subjects were evaluated with a comprehensive battery of psychiatric, cognitive, and psychosocial assessments. The referred and nonreferred adults with attention deficit hyperactivity disorder were similar to one another but more disturbed and impaired than the comparison subjects without the disorder. The pattern of psychopathology, cognition, and functioning among the adults with attention deficit hyperactivity disorder approximated the findings for children with the disorder. These results show that referred and nonreferred adults with attention deficit hyperactivity disorder have a pattern of demographic, psychosocial, psychiatric, and cognitive features that mirrors well-documented findings among children with the disorder. These findings further support the validity of the diagnosis for adults.