Substance use disorders in patients with posttraumatic stress disorder: a review of the literature.

OBJECTIVE: Alcohol use disorders and other substance use disorders are extremely common among patients with posttraumatic stress disorder (PTSD). This article reviews studies pertaining to the epidemiology, clinical phenomenology, and pathophysiology of comorbid PTSD and substance use disorders. METHOD: Studies were identified by means of computerized and manual searches. The review of research on the pathophysiology of PTSD and substance use disorders was focused on studies of the hypothalamic-pituitary-adrenal axis and the noradrenergic system. RESULTS: High rates of comorbidity suggest that PTSD and substance use disorders are functionally related to one another. Most published data support a pathway whereby PTSD precedes substance abuse or dependence. Substances are initially used to modify PTSD symptoms. With the development of dependence, physiologic arousal resulting from substance withdrawal may exacerbate PTSD symptoms, thereby contributing to a relapse of substance use. Preclinical work has led to the proposal that in PTSD, corticotropin-releasing hormone and noradrenergic systems may interact such that the stress response is progressively augmented. Patients may use sedatives, hypnotics, or alcohol in an effort to interrupt this progressive augmentation. CONCLUSIONS: Vigorous control of withdrawal and PTSD-related arousal symptoms should be sought during detoxification of patients with comorbid PTSD and substance use disorders. Inclusion of patients with comorbid PTSD and substance use disorders in neurobiologic research and in clinical trials will be critical for development of effective treatments for this severely symptomatic patient population.

Smooth pursuit eye-tracking impairment in childhood-onset psychotic disorders.

OBJECTIVE: Although childhood-onset schizophrenia is relatively rare, a sizable group of children with severe emotional disturbances have transient psychotic symptoms that fall outside of current syndrome boundaries. The relationship of this group of children to those with childhood-onset schizophrenia and other childhood psychiatric disorders is unclear. In this study, the authors compared smooth pursuit eye tracking, a biological trait marker associated with schizophrenia, of children and adolescents with psychotic disorder not otherwise specified to that of children with childhood-onset schizophrenia and healthy comparison subjects. METHOD: By means of infrared oculography, smooth pursuit eye movements during a 17 degrees /second visual pursuit task were quantitatively and qualitatively compared in 55 young adolescents (29 with childhood-onset schizophrenia and 26 with psychotic disorder not otherwise specified) and their respective independent healthy comparison groups (a total of 38 healthy subjects). RESULTS: Subjects with childhood-onset schizophrenia had qualitatively poorer eye tracking, higher root mean square error, lower gain, and a greater frequency of catch-up saccades than healthy children. Subjects with psychotic disorder not otherwise specified also had qualitatively poorer eye tracking, higher root mean square error, and lower gain than healthy children, but saccade frequency did not differ significantly. CONCLUSIONS: Children with childhood-onset schizophrenia exhibit a pattern of eye-tracking dysfunction similar to that reported for adult patients. Similar abnormalities were seen in the subjects with psychotic disorder not otherwise specified except that they did not exhibit a greater frequency of catch-up saccades. Prospective longitudinal neurobiological and clinical follow-up studies of both groups are currently underway to further validate the distinction between these two disorders. Also, family studies are planned to establish whether eye-tracking dysfunction represents a trait- or state-related phenomenon in subjects with psychotic disorder not otherwise specified.

Quantitative morphology of the caudate and putamen in patients with cocaine dependence.

OBJECTIVE: Deficits in dopaminergic function may contribute to hypertrophy of striatal structures associated with typical neuroleptic treatment. In light of a body of research that has associated chronic cocaine use with extrapyramidal symptoms and striatal dopaminergic depletion, the authors looked for evidence of striatal dysmorphology in patients with chronic cocaine dependence. METHOD: Caudate, putamen, and total brain volumes were quantified by means of magnetic resonance imaging in 25 cocaine-dependent and 20 healthy subjects. RESULTS: Normalized caudate and putamen volumes were 3.40% and 9.18% larger, respectively, in the cocaine-dependent subjects. CONCLUSIONS: These observations suggest that deficits in dopaminergic function associated with cocaine dependence may contribute to striatal hypertrophy.

Quantitative medial temporal lobe brain morphology and hypothalamic-pituitary-adrenal axis function in cocaine dependence: a preliminary report.

Preclinical and clinical studies have shown that cocaine increases plasma adrenocorticotropin hormone (ACTH) and cortisol. Chronic elevation of plasma cortisol exerts direct toxic effects upon hippocampal neurons and exacerbates hippocampal damage resulting from ischemia and seizures. The authors tested for evidence of hippocampal damage in patients with chronic cocaine dependence. Medial temporal lobe and total brain volumes were quantified using magnetic resonance imaging (MRI) in 27 patients with cocaine dependence and 16 healthy subjects. Basal and ovine corticotropin releasing hormone (oCRH) stimulated ACTH and cortisol levels were also examined in a subset of 8 healthy and 9 cocaine dependent subjects after 21 days of abstinence. No evidence for decreased hippocampal or total brain volume in cocaine dependence was observed. Similarly, basal and oCRH stimulated ACTH and cortisol levels in cocaine dependent patients did not differ from those in healthy subjects.

Abnormal neurologic maturation in adolescents with early-onset schizophrenia.

OBJECTIVE: This study evaluated neurologic functioning in adolescents with schizophrenia with onset of psychosis before age 13. METHOD: The authors administered a structured neurologic examination to 21 adolescents with early-onset schizophrenia and 27 healthy age- and sex-matched comparison subjects. RESULTS: The adolescents with schizophrenia had a high frequency of neurologic abnormalities. Neurologic signs decreased with age in the healthy comparison subjects but not in the subjects with schizophrenia. CONCLUSIONS: The adolescents with schizophrenia had a high burden of neurologic impairment and a pattern of abnormalities similar to that of adults with schizophrenia. The persistence of neurologic signs in the adolescents with schizophrenia, which faded with age in the healthy comparison adolescents, supports earlier evidence of a delay in or failure of normal brain development during adolescence.

Childhood-onset schizophrenia/autistic disorder and t(1;7) reciprocal translocation: identification of a BAC contig spanning the translocation breakpoint at 7q21.

Childhood-onset schizophrenia (COS) is defined by the development of first psychotic symptoms by age 12. While recruiting patients with COS refractory to conventional treatments for a trial of atypical antipsychotic drugs, we discovered a unique case who has a familial t(1;7)(p22;q21) reciprocal translocation and onset of psychosis at age 9. The patient also has symptoms of autistic disorder, which are usually transient before the first psychotic episode among 40-50% of the childhood schizophrenics but has persisted in him even after the remission of psychosis. Cosegregating with the translocation, among the carriers in the family available for the study, are other significant psychopathologies, including alcohol/drug abuse, severe impulsivity, and paranoid personality and language delay. This case may provide a model for understanding the genetic basis of schizophrenia or autism. Here we report the progress toward characterization of genomic organization across the translocation breakpoint at 7q21. The polymorphic markers, D7S630/D7S492 and D7S2410/D7S646, immediately flanking the breakpoint, may be useful for further confirming the genetic linkage for schizophrenia or autism in this region. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:749-753, 2000. Published 2000 Wiley-Liss, Inc.

Prediction of dopamine transporter binding availability by genotype: a preliminary report.

OBJECTIVE: Evidence of a relationship between genotype and binding availability was assessed for the dopamine and serotonin transporter genes. METHOD: The authors assessed dopamine transporter genotype at the SLC6A3 3' variable number of tandem repeats (VNTR) polymorphism and serotonin transporter genotype at the SLC6A4 promotor VNTR polymorphism in 30 healthy subjects who also underwent single photon emission computed tomography with [(123)I]beta-CIT. RESULTS: Subjects homozygous for the 10-repeat allele at the SLC6A3 locus demonstrated significantly lower dopamine transporter binding than carriers of the nine-repeat allele. There was no effect of SLC6A4 genotype upon serotonin transporter binding. CONCLUSIONS: These findings suggest that genetic variation at the SLC6A3 3' VNTR polymorphism may modify dopamine transporter function.

Childhood-onset psychotic disorders: magnetic resonance imaging of volumetric differences in brain structure.

OBJECTIVE: Although childhood-onset schizophrenia is rare, children with brief psychotic symptoms and prominent emotional disturbances commonly present diagnostic and treatment problems. Quantitative anatomic brain magnetic resonance images (MRIs) of a subgroup of children with psychotic disorder not otherwise specified were compared with those of children with childhood-onset schizophrenia and healthy comparison subjects. METHOD: Anatomic MRIs were obtained for 71 patients (44 with childhood-onset schizophrenia and 27 with psychotic disorder not otherwise specified) and 106 healthy volunteers. Most patients had been treated with neuroleptics. Volumetric measurements for the cerebrum, anterior frontal region, lateral ventricles, corpus callosum, caudate, putamen, globus pallidus, and midsagittal thalamic area were obtained. RESULTS: Patients had a smaller total cerebral volume than healthy comparison subjects. Analysis of covariance for total cerebral volume and age found that lateral ventricles were larger in both patient groups than in healthy comparison subjects and that schizophrenia patients had a smaller midsagittal thalamic area than both subjects with psychotic disorder not otherwise specified and healthy comparison subjects. CONCLUSIONS: Pediatric patients with psychotic disorder not otherwise specified showed a pattern of brain volumes similar to those found in childhood-onset schizophrenia. Neither group showed a decrease in volumes of temporal lobe structures. Prospective longitudinal magnetic resonance imaging and clinical follow-up studies of both groups are currently underway to further validate the distinction between these two disorders.

Elevated central serotonin transporter binding availability in acutely abstinent cocaine-dependent patients.

OBJECTIVE: Recent work has underscored the role of serotonergic neurotransmission in chronic neural adaptations to cocaine dependence. The authors tested for evidence of serotonergic dysfunction during acute abstinence from cocaine, a period of high risk for relapse in cocaine dependence. METHOD: Binding availability of dopamine transporters and serotonin transporters was measured in 15 cocaine-dependent subjects during acute abstinence and in 37 healthy comparison subjects by using [(123)I]beta-CIT and single photon emission computed tomography. RESULTS: Significant increases in diencephalic and brainstem serotonin transporter binding (16.7% and 31.6%, respectively) were observed in cocaine-dependent subjects. Brainstem serotonin transporter binding was significantly inversely correlated with age across diagnostic groups. CONCLUSIONS: These findings provide further evidence of serotonergic dysfunction during acute abstinence from chronic cocaine use. Age-related decline in brainstem serotonin transporter binding may underlie the poor response to selective serotonin reuptake inhibitor antidepressants seen in some elderly depressed patients.

Neuropsychological deficits in pediatric patients with childhood-onset schizophrenia and psychotic disorder not otherwise specified.

OBJECTIVE: Children with transient psychotic symptoms and serious emotional disturbances who do not meet current criteria for schizophrenia or other presently recognized diagnostic categories commonly present diagnostic and treatment problems. Clarifying the connections between children with narrowly defined schizophrenia and children with a more broadly defined phenotype (i.e., Psychotic Disorder Not Otherwise Specified, PD-NOS) has implications for understanding the pathophysiology of schizophrenia. In this study, the neuropsychological test performance of a subgroup of children with atypical psychosis was compared with that of patients with childhood-onset schizophrenia (COS). METHOD: Cognitive function was assessed with neuropsychological test battery regimens in 51 neuroleptic-nonresponsive patients within the first 270 at NIMH testing (24 PD-NOS, 27 COS) were included in this analysis. Seventeen (39%) of 44 COS subjects were unavailable for this study as their IQ tested <70. The PD-NOS patients were younger than the COS patients at the time of testing (12.0+/-2.8 vs 14.4+/-1.8years, respectively, p<0.004). The test levels of these groups were compared with each other. RESULTS: The neuropsychological test results for the PD-NOS and COS patients were 1-2standard deviations below normative data across a broad array of cognitive functions. There were no overall differences in the test levels for the six summary scales (F=2.82, df=1, 36, p=0.10) or in the profile shape (F=1.70, df=5, 180, p=0.14) between the PD-NOS and COS groups. For the COS patients, there was a significant difference between their mean full-scale WISC IQ (84.7+/-16.2) and their average standard scores for both the spelling (97.7+/-16.1, n=23, t=4.0, p=0.001) and reading decoding subtests (97.7+/-13.7, n=23, t=3.7, p=0.001) of the Kaufman Test of Educational Achievement. CONCLUSIONS: Treatment-refractory PD-NOS and COS patients share a similar pattern of generalized cognitive deficits, including deficits in attention, learning and abstraction which are commonly observed in adult patients with schizophrenia. These data support a hypothesis that at least some of the PD-NOS cases belong within the schizophrenic spectrum, which is of importance for future genetic studies planned for this cohort.

Including children and adolescents with schizophrenia in medication-free research.

OBJECTIVE: There has been an increasing focus on the ethical issues raised by studies requiring the withdrawal of effective medication in schizophrenic adults. This article examines the risks and benefits of a medication-free period for pediatric patients with treatment-refractory schizophrenia who are participating in an ongoing study. METHOD: Between April 1993 and March 1998, 31 children and adolescents were admitted with a diagnosis of treatment-resistant, childhood-onset schizophrenia. Parental consent was obtained so that patients could participate in a medication-free research period. Patients were evaluated at screening, at the end of a 4-week washout, at the completion of a 6- to 8-week atypical neuroleptic trial, and at a 2- to 4-year follow-up. RESULTS: At the completion of a 4-week drug-free period, seven patients (23%) were diagnosed with another disorder on the basis of data gained from the drug-free period and their lack of schizophrenic symptoms. Their revised diagnoses were posttraumatic stress disorder (N = 1), an atypical psychosis labeled "multidimensionally impaired" (N = 4), and personality disorder (N = 2). At follow-up, three of these patients remained free of neuroleptic therapy. For eight patients (26%), the washout was curtailed because of rapid and severe deterioration of their schizophrenic symptoms. CONCLUSIONS: For children and adolescents with treatment-refractory schizophrenia, a medication-free period can be conducted safely for at least 4 weeks for inpatients. Such trials are useful on clinical grounds and for providing homogeneous patient groups for research. This study also highlights the necessity of having access to hospitalization to observe children and adolescents with psychotic symptoms while medication free.

Current concepts in pharmacotherapy of substance abuse.

The cost to society of alcohol, tobacco, and illicit drug dependence is enormous. Although the importance of treatment for substance abuse to public health is increasingly acknowledged, pharmacotherapy is generally underutilized. However, the selection of medications for clinical testing is increasingly guided by the rapidly evolving science of addictive drugs and behavior. The benefit of medication for smoking cessation is firmly established, particularly for nicotine replacement and antidepressant therapy. Naltrexone is an important addition to the pharmacopoeia, and acamprosate may soon be approved as well. Although no new medications are approved for cocaine and amphetamine abuse, a variety of candidate treatments have shown promise in ongoing studies. Opiate substitution therapy is highly effective for rehabilitation of heroin addiction, and several alternative forms will soon be available; alternative forms of opiate detoxification have also received attention. Overall, there is increasing recognition that physicians have an obligation to identify and treat all forms of substance dependence, although knowledge of the efficacy of the available treatments is steadily increasing.

HLA antigens in childhood onset schizophrenia.

Evidence of immune system abnormalities in adult schizophrenia has prompted examination of the human leukocyte antigen (HLA) system. Childhood onset schizophrenia offers a unique opportunity to test neurodevelopmental hypotheses of schizophrenia, including those which implicate components of the immune system. In the present study, class I and II HLA antigens were typed using sequence-specific primers and the polymerase chain reaction in 28 childhood onset schizophrenics and 51 ethnically matched healthy subjects. Groups were compared for frequencies of HLA antigens reported to be associated with schizophrenia and/or autoimmune disorders. We hypothesized that antigen frequencies would differ between schizophrenic and healthy children, suggesting that some dimension of the neurodevelopmental disturbance experienced by these children may be mediated by subtle abnormalities of immune function. There were no significant differences between schizophrenic and healthy subjects in the frequency of any antigen tested. These findings do not support HLA-associated pathology in childhood onset schizophrenia.

Progressive reduction of temporal lobe structures in childhood-onset schizophrenia.

OBJECTIVE: A previous cross-sectional study of brain morphology in childhood-onset schizophrenia indicated sparing of the temporal lobes from processes reducing total cerebral volume in this population. In the present study, subjects with childhood-onset schizophrenia and healthy subjects were rescanned at 2-year follow-up to determine whether this pattern of temporal lobe sparing persists with ongoing illness. METHOD: Anatomic brain magnetic resonance imaging scans were acquired for 10 adolescent patients with average onset of schizophrenia at 10.4 years (SD = 1.7) and 17 healthy adolescents. Scans were obtained on initial admission and at 2-year follow-up by using identical equipment and measurement methodology. RESULTS: Schizophrenic subjects showed significantly greater decreases than healthy subjects in right temporal lobe, bilateral superior temporal gyrus and posterior superior temporal gyrus, right anterior superior temporal gyrus, and left hippocampal volumes during the follow-up interval. Decline in right posterior superior temporal gyrus was associated with high total scores on the Scale for the Assessment of Positive Symptoms at baseline and at follow-up. CONCLUSIONS: Progressive reduction of temporal lobe structures occurs with ongoing illness in childhood-onset schizophrenia.

Cerebellum in attention-deficit hyperactivity disorder: a morphometric MRI study.

Clinical, neuroanatomic, neurobehavioral, and functional brain-imaging studies suggest a role for the cerebellum in cognitive functions, including attention. However, the cerebellum has not been systematically studied in attention-deficit hyperactivity disorder (ADHD). We quantified the cerebellar and vermal volumes, and the midsagittal areas of three vermal regions, from MRIs of 46 right-handed boys with ADHD and 47 matched healthy controls. Vermal volume was significantly less in the boys with ADHD. This reduction involved mainly the posterior inferior lobe (lobules VIII to X) but not the posterior superior lobe (lobules VI to VII). These results remained significant even after adjustment for brain volume and IQ. A cerebello-thalamo-prefrontal circuit dysfunction may subserve the motor control, inhibition, and executive function deficits encountered in ADHD.

Childhood-onset schizophrenia: an open-label study of olanzapine in adolescents.

OBJECTIVE: Olanzapine, a potent 5-HT2a/2c, dopamine D1D2D4 antagonist with anticholinergic activity, has a profile of known receptor affinity similar to that of clozapine. This pilot study examined the efficacy of olanzapine for treatment-refractory childhood-onset schizophrenia in eight patients who had received 8-week open-label trials. For comparison, data are included from 15 patients who had received 6-week open-label clozapine trials using identical rating instruments (largely by the same raters) in the same treatment setting. METHOD: Twenty-three children and adolescents with an onset of DSM-III-R schizophrenia by age 12 for whom at least two different typical neuroleptics had been ineffective participated in the two separate studies. Some of the patients were intolerant of clozapine, although it had been effective (n = 4). Patients receiving olanzapine were evaluated over 8 weeks with the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Positive Symptoms, the Scale for the Assessment of Negative Symptoms, and the Clinical Global Impressions Scale for Improvement. RESULTS: For the eight patients who received olanzapine trials, at week 8 there was a 17% improvement in the BPRS total score, a 27% improvement in the Scale for the Assessment of Negative Symptoms, and a 1% improvement in the Scale for the Assessment of Positive Symptoms, relative to "ideal" admission status on typical neuroleptics. In contrast, the magnitude of the effect sizes for each of the clinical ratings was larger at week 6 of the previous clozapine trial than for an 8-week olanzapine trial, relative to admission status on typical neuroleptics. For the four children who had received both clozapine and olanzapine, BPRS total scores were significantly lower at week 6 of clozapine treatment compared with week 6 of olanzapine treatment (p = .03). CONCLUSION: These data provide preliminary evidence for the efficacy of olanzapine for some children and adolescents with treatment-refractory schizophrenia, but they also suggest the need for a more rigorous double-blind comparison of these two atypical antipsychotics.

Research update: childhood-onset schizophrenia: implications of clinical and neurobiological research.

Childhood-onset schizophrenia is a rare, clinically severe form of schizophrenia, which is associated with disrupted cognitive, linguistic, and social development well before the appearance of frank psychotic symptoms. This disruption of multiple developmental domains signals the important opportunity these patients present for examining neurodevelopmental and other etiologic hypotheses of schizophrenia. The present research update reviews studies of the phenomenology and neurobiology of childhood-onset schizophrenia conducted since 1994. Findings from these studies indicate that children can be diagnosed with schizophrenia using unmodified DSM-III, -IIIR, and -IV criteria, and that the atypical neuroleptic clozapine is an effective medication for this treatment refractory group. Neuropsychologic and neurobiologic studies generally support continuity with adult-onset schizophrenia, with evidence of more severe premorbid impairment. Longitudinal studies show preliminary evidence of progressive ventricular enlargement and more prolonged deterioration in intellectual function than is seen in the adult-onset disorder. If replicated, these observations, together with the insidious onset of this disorder, would suggest that the pathologic underpinning of childhood-onset schizophrenia is not a single static lesion or event but may be a continuous or multi-event process.

Attention deficits in childhood-onset schizophrenia: reaction time studies.

The hypothesis of continuity between childhood-onset and adult schizophrenia was tested by comparing the performance of 15 patients with childhood-onset schizophrenia and 52 age-matched controls on 2 reaction time paradigms that have been used to study adult schizophrenia. On simple reaction time to tones with regular and irregular preparatory intervals of 2, 4, and 8 s, patients showed greater effects of the length of the preparatory interval in the regular condition and greater effects of the preparatory interval (girls only) and the preceding preparatory interval in the irregular series. On simple reaction time to random lights and tones, patients were faster on ipsimodal sequences than cross-modal sequences compared with controls. Overall, patients were much slower than controls in both paradigms. The results suggest similar attention dysfunction as is found in adult schizophrenia and thus are consistent with the continuity hypothesis.

Chromosome 22q11.2 interstitial deletions among childhood-onset schizophrenics and "multidimensionally impaired".

Since its first description almost a century ago schizophrenia with childhood onset, a rare yet devastating disorder, has been diagnosed in children as young as age 5. Recently, the velocardiofacial syndrome, whose underlying cause is interstitial deletions of 22q11.2, was found in 2 of 100 cases of schizophrenics with adult onset [Karayiorgou et al., Proc Natl Acad Sci USA 92: 7612-7616, 1995]. No study has documented the prevalence of velocardiofacial syndrome and the 22q11.2 deletion in a population of schizophrenics with childhood onset. Here we describe the result of such a study in a sample originally selected for a trial of atypical antipsychotic drugs. A separate group of patients was also included in the study; they can best be accounted for as a variant of childhood-onset schizophrenia (COS) and had been provisionally termed "multidimensionally impaired." Fluorescent in situ hybridization screening of 32 COS and 21 multidimensionally impaired patients revealed 1 COS patient with an interstitial deletion spanning at least 2.5 megabases.

Brief report: association of sex chromosome anomalies with childhood-onset psychotic disorders.

OBJECTIVE: An apparent excess of sex chromosome aneuploidies (XXY, XXX, and possibly XYY) has been reported in patients with adult-onset schizophrenia and with unspecified psychoses. This study describes the results of cytogenetic screening carried out for pediatric patients meeting DMS-III-R criteria for childhood-onset schizophrenia (COS) and a subgroup of patients with childhood-onset psychotic disorder not otherwise specified, provisionally labeled by the authors as multidimensionally impaired (MDI). METHOD: From August 1990 to July 1997, karyotypes were determined for 66 neuroleptic-nonresponsive pediatric patients (28 MDI, 38 COS), referred to the National Institute of Mental Health for an inpatient treatment trial of clozapine. RESULTS: Four (6.1%) of 66 patients (3 MDI, 1 COS) were found to have sex chromosome anomalies (mosaic 47,XXY; 47,XXY; 47,XYY; mosaic 45,XO, respectively), which is higher than the expected rate of 1 per 426 children or 2.34 per 1,000 in the general population (4/66 versus 1/426, chi 2 = 19.2, df = 1, p = .00001). All cases had been previously undiagnosed. CONCLUSIONS: These findings lend support to a hypothesis that a loss of balance of gene products on the sex chromosomes may predispose affected individuals to susceptibility to additional genetic and environmental insults that result in childhood-onset psychotic disorders. Karyotyping of children with psychotic disorders should be routine.