Family-focused treatment of bipolar disorder: 1-year effects of a psychoeducational program in conjunction with pharmacotherapy.

BACKGROUND: Few studies have examined the combined effects of psychosocial treatment and pharmacotherapy for bipolar disorder. This study used a randomized, controlled design to examine a 9-month, manual-based program of family-focused psychoeducational treatment (FFT). METHODS: Bipolar patients (N = 101) were recruited shortly after an illness episode and randomly assigned to 21 sessions of FFT (n = 31) or to a comparison treatment involving two family education sessions and follow-up crisis management (CM; n = 70). Both treatments were delivered over 9 months; patients were simultaneously maintained on mood stabilizing medications. Patients were evaluated every 3 months for 1 year as to relapse status, symptom severity, and medication compliance. RESULTS: Patients assigned to FFT had fewer relapses and longer delays before relapses during the study year than did patients in CM. Patients in FFT also showed greater improvements in depressive (but not manic) symptoms. The most dramatic improvements were among FFT patients whose families were high in expressed emotion. The efficacy of FFT could not be explained by differences among patients in medication regimes or compliance. CONCLUSIONS: Family-focused psychoeducational treatment appears to be an efficacious adjunct to pharmacotherapy for bipolar disorder. Future studies should evaluate family treatment against other forms of psychotherapy matched in amount of therapist-patient contact.

Preliminary evidence of the reliability and validity of the prospective life-chart methodology (LCM-p).

This article describes the use of the NIMH prospective life-charting methodology (NIMH LCM-p) in the context of a formal double-blind, clinical trial and provides preliminary evidence of its reliability and validity. Subjects included in this report were 30 outpatients with bipolar I and II disorder who completed the first 2 years of a long-term maintenance study: 1 year on carbamazepine or lithium and a crossover to the other in the second year. The LCM-p follows the same types of guidelines and principles utilized in the previously described retrospective life-chart process, allowing for continuity of illness assessment prior and subsequent to study entry. In the LCM-p, daily ratings of severity of mood symptoms based on the degree of associated functional incapacity, provide a more detailed topography of manic and depressive fluctuations. Inter-rater reliability was examined by comparing the severity of daily LCM-p ratings assigned by two raters. In order to assess the validity, we correlated the LCM-p ratings with well-standardized scales, including Hamilton and Beck Depression Ratings, Young Mania Ratings and the Global Assessment Scale (GAS). The Kappa scores for inter-rater reliability demonstrated significant and satisfactory strength of agreement with no fall off over 14 days prior to the rating interview. Strong correlations were found: (1) between the LCM-p average severity for depression rating and the mean Hamilton Depression Rating (r = 0.86, p < .001), and the Beck Depression Inventory (r = 0.73, p < .001); 2) between the LCM-p average severity for mania rating and the Young Mania Rating Scale (r = 0.61, p < .001); and (3) between the LCM-p average severity and the GAS (r = -0.81, p < .001). These preliminary data suggest the reliability and validity of the NIMH-LCM-p in assessing manic and depressive episode severity. It also provides a useful continuous daily measure of affective illness-related symptom fluctuations that allows for detailed prospective assessment of frequency and pattern of illness, treatment response, and continuity with retrospective life chart assessments.

A multidimensional approach to analysis of cerebrospinal fluid biogenic amines in schizophrenia: I. Comparisons with healthy control subjects and neuroleptic-treated/unmedicated pairs analyses.

Recent hypotheses and findings indicate that measurements of interactions between cerebrospinal fluid (CSF) biogenic amine systems, rather than measurement of CSF biogenic amine metabolites, better correlate with clinically important findings in schizophrenia. To test hypotheses, we used a recent technological advance in high performance liquid chromatography with electrochemical detection and combined it with multivariate statistical analyses to study biogenic amine concentrations in CSF in schizophrenia. This approach enabled the study of the interactions of several metabolites of each of the three major neurotransmitter pathways (dopaminergic, noradrenergic, and serotonergic) to test existing hypotheses regarding the neurobiochemical basis of schizophrenia. Twenty biogenic amines, their metabolites, and other compounds from 24 medication-free schizophrenic patients and 12 normal control subjects were simultaneously measured using a recently developed technique of gradient high performance liquid chromatography coupled with a 16-channel electrochemical array detector. After covariation for storage time, results of a stepwise discriminant function analysis comparing the control and patient groups identified tryptophan, tryptophol, and epinephrine as discriminating variables. Hotelling's paired T2 test from a subgroup of schizophrenic patients studied while they were and were not receiving neuroleptic treatment did not yield any significant differences between subgroups. A discussion of the findings and a comparison with previous studies of CSF biogenic amines in schizophrenia are presented.

A multidimensional approach to analysis of cerebrospinal fluid biogenic amines in schizophrenia: II. Correlations with psychopathology.

As part of a multidimensional study of cerebrospinal fluid biogenic amine metabolites in schizophrenia, the relationship between neurochemical measures and psychopathology assessed using the Psychiatric Symptom Assessment Scale (PSAS) was analyzed. In a group of 20 unmedicated patients, 3,4-dihydroxyphenylacetic acid (DOPAC) was a predictor of symptom severity in a stepwise multiple regression model. Values of 3-hydroxykynurenine and metanephrine in the unmedicated state predicted clinical response in a stepwise multiple regression model, as measured by improvement in PSAS mean item score following 6 weeks on a standard dose of neuroleptic. In a subgroup of 14 patients in whom both off- and on-medication concentrations of cerebrospinal fluid biogenic amines and metabolites were measured, change in 3-hydroxykynurenine predicted clinical outcome in a multiple regression model. These findings point toward the need to examine the role of the kynurenine pathway of tryptophan metabolism in the pathophysiology of schizophrenia.

CSF concentrations of neurotensin in schizophrenia: an investigation of clinical and biochemical correlates.

Neurotensin (NT), a peptide which colocalizes with dopamine in some midbrain and hypothalamic neurons, has been speculated to play a role in schizophrenic illness and in the action of antipsychotic drugs. Previous work suggested a bimodal distribution of NT in patients with schizophrenia, with a subgroup having low drug-free NT concentrations which normalize with neuroleptic treatment. We studied 15 schizophrenic patients with CSF samples collected both off and on neuroleptic medication, 12 with only drug-free (DF) samples, and 10 controls. There was no significant difference in CSF NT concentrations between patients and controls, or between patients off and on medication. However, 7 patients with DFNT CSF concentrations below the patient mean showed an increase with neuroleptic treatment. Moreover, NT was significantly lower for women. Significant correlations with NT concentrations in CSF were found with deficit symptoms in patients, and with the age of the CSF sample for all subjects. There was no correlation between CSF NT concentrations and patient age, duration of illness, or levels of amine metabolites (MHPG, 5HIAA, HVA).

Event-related potential abnormalities correlate with structural brain alterations and clinical features in patients with chronic schizophrenia.

Patients with schizophrenia appear to have abnormalities in both brain structures and information processing. Several recent reports have suggested that correlations exist between such measures. We examined the volume of several brain regions using magnetic resonance imaging (MRI), and also assessed both information processing, using brain event-related potentials (ERPs), and clinical symptomatology in sixteen medicated patients with schizophrenia. Subjects were tested using auditory and visual discrimination tasks. From the ERPs elicited by stimuli presented with relative probabilities of 0.1, the N100, N200, and P300 components were identified and measured. All subjects also had MRI scans that included 12 contiguous coronal sections, each 1 cm thick. From these scans, the following structures were identified and the volume or area quantified: third ventricle, lateral ventricles (partial), amygdala and hippocampus (one slice), partial brain volume (in one slice through the parietal lobe), and total prefrontal and temporal lobe gray and white matter in both cortical regions. Significant correlations were found between hippocampal area and the amplitude of the auditory and visual N200, and between the right hippocampus and the visual P300. Lower but significant correlations were seen between auditory P300 and measures of left temporal lobe structures. Auditory P300 amplitude correlated inversely with positive symptoms of schizophrenia. These preliminary results suggest that the ERP abnormalities in patients with schizophrenia are associated with temporal lobe pathology.

Cerebrospinal fluid oxytocin concentration in schizophrenic patients does not differ from control subjects and is not changed by neuroleptic medication.

Cerebrospinal fluid (CSF) oxytocin concentrations in 20 neuroleptic-treated schizophrenic patients, 31 neuroleptic-withdrawn schizophrenic patients, and 15 normal control subjects were compared. Neither within-subject comparisons of CSF oxytocin concentration measurements made during neuroleptic treatment and withdrawal (n = 11), nor comparison of the combined neuroleptic-withdrawn and neuroleptic-treated patient group (n = 40) with control subjects (n = 15) differed significantly, suggesting that CSF oxytocin concentration is not altered in schizophrenia.

Medial temporal lobe structures in schizophrenia: relationship of size to duration of illness.

Reductions in the size of medial temporal lobe structures in schizophrenia have been demonstrated using magnetic resonance imaging. It is not clear whether these neuropathological changes are present premorbidly or if they reflect an adult-onset progressive process. In this study, quantitative measures were made of the lateral ventricles, third ventricle, amygdala, hippocampus, and cerebral hemispheres from coronal MRI images on 33 patients with schizophrenia and 41 normal controls. Images were selected a priori from the region of the temporal lobe in which we had previously demonstrated reduced volume of temporal lobe gray matter in a separate sample of patients. Results showed a decrease in amygdala, hippocampal, and amygdala-hippocampal size bilaterally and an increase in third and lateral ventricular volume. Advancing age in normals was associated with a decrease in the size of medial temporal structures and an increase in lateral ventricular size. In schizophrenia, there was a correlation between age and lateral ventricle size, but duration of illness was not associated with reductions in medial temporal tissue or ventricular enlargement. These results are consistent with prior evidence from neuroimaging and postmortem studies of medial temporal pathology in schizophrenia and support hypotheses that neuropathological changes in schizophrenia are not progressive.

Interleukin-1 alpha and interleukin-2 in cerebrospinal fluid of schizophrenic subjects.

1. It has been postulated that the interrelated processes of neurodegeneration, neuroplasticity, and neuroimmunological abnormalities may play a role in the pathophysiology of schizophrenia. Since, interleukins are produced in the central nervous system and have cytokine and growth promoting properties, they are an obvious choice to consider in these neural processes. 2. Cerebrospinal fluid obtained from schizophrenic patients, on and off medications, and from normal controls was assayed for interleukin-1 alpha (IL-1 alpha) and interleukin-2 (IL-2) using a sensitive enzyme-linked immunoassay. 3. IL-1 alpha concentration were below the detection limits of the assay in both controls and schizophrenics. 4. IL-2 levels were under 1 ng/ml CSF in nearly all subjects. There was no significant difference in IL-2 levels between medicated and medication-free schizophrenics or when patients were compared to controls.

6-[18F]fluoro-L-dopa and cerebral blood flow in unilaterally MPTP-treated monkeys.

Intravenous administration of 15O-labeled water and 6-[18F]-L-fluorodopa were used to assess abnormal striatal activity in monkeys after long-term recovery of unilateral lesions of the dopaminergic nigro-striatal system induced by the neurotoxin MPTP. PET data were examined in relation to behavioral and biological parameters. Cerebral blood flow and 6-[18F]-L-DOPA uptake were found to be significantly reduced in the lesioned striatum, compared to the unaffected side and to normal controls. There was no correlation between cerebral blood flow and any of the behavioral parameters. The uptake rate constant of 18F-DOPA from blood to striatum and the ratios of striatum to occipital areas were highly correlated to the concentrations of homovanillic acid in the cerebrospinal fluid of the same animals but not to the rotational behavior. This MPTP-induced model of striatal dopamine deficiency in primates presents similarities with idiopathic Parkinson's disease and may be used to evaluate the effects of dopaminergic lesions and transplants on brain function.

Cerebrospinal fluid and serum levels of neuron-specific enolase in patients with schizophrenia.

Some patients with schizophrenia appear to have brain abnormalities, including enlarged third and lateral ventricles and reduced volumes of temporal lobe structures. These abnormalities could be attributed to a developmental abnormality or a neurodegenerative process. Neuron-specific enolase (NSE), a protein that is found primarily in neurons and neuroendocrine cells, has been used as an index of neuronal damage or degeneration. Levels of NSE in cerebrospinal fluid (CSF) and serum from 50 patients with acute and chronic schizophrenia were compared with those in normal and neurological control subjects. A double-antibody, solid phase iodinated radioimmunoassay was used to determine NSE levels. There was no evidence of elevated levels in patients with schizophrenia, whereas control subjects with neurological illnesses had increased levels of NSE in CSF. Because NSE is rapidly cleared from CSF, however, elevated levels could have been missed. Unmedicated patients tended to have lower levels than medicated patients.

Evidence of dysfunction of a prefrontal-limbic network in schizophrenia: a magnetic resonance imaging and regional cerebral blood flow study of discordant monozygotic twins.

OBJECTIVE: The authors previously reported that in monozygotic twins discordant for schizophrenia the affected twin almost invariably had a smaller anterior pes hippocampus, measured with magnetic resonance imaging (MRI), and invariably had less regional cerebral blood flow (rCBF) in the dorsolateral prefrontal cortex during performance of the Wisconsin Card Sorting Test. The present study was an investigation of the relationship between hippocampal pathology and prefrontal hypofunction in the same twin pairs. METHOD: Nine pairs of monozygotic twins discordant for schizophrenia underwent MRI scanning for determination of anterior hippocampal volume and xenon-inhalation rCBF testing for determination of prefrontal physiological activation associated with the Wisconsin Card Sorting Test. RESULTS: The differences within twin pairs on the MRI and rCBF measures were strongly and selectively correlated. Specifically, the more an affected twin differed from the unaffected twin in left hippocampal volume, the more they differed in prefrontal physiological activation during the Wisconsin Card Sorting Test. In the affected twins as a group, prefrontal activation was strongly related to both left and right hippocampal volume. These relationships were not found in the group of unaffected twins. CONCLUSIONS: This finding is consistent with the notion that schizophrenia involves pathology of and dysfunction within a widely distributed neocortical-limbic neural network that has been implicated in, among other activities, the performance of cognitive tasks requiring working memory.

Blood-CSF barrier permeability and central nervous system immunoglobulin G in schizophrenia.

The ratio of albumin in cerebrospinal fluid (CSF) to serum may serve as an index of the integrity of the blood-CSF barrier, with increases in this ratio indicating increased permeability. The ratio of immunoglobulin G (IgG) in CSF to serum (divided by the albumin ratio to correct for variance in blood-CSF permeability) represents an index of the endogenous production of IgG in the central nervous system (CNS), with increases reflecting a possible infectious and/or autoimmune process stimulating central IgG synthesis. We analyzed simultaneously collected CSF and serum samples from 46 schizophrenic subjects, 8 of whom were studied both on and off neuroleptic treatment, and samples from 20 normal controls. The data indicated increases in CSF/serum albumin ratios or CSF/serum IgG indices in 22% and 20%, respectively, of the schizophrenic patients. Only 3 patients showed elevations in both indices. Comparison of values on and off neuroleptics indicated no significant effect of neuroleptics on these indices.

A clinical trial of nifedipine in schizophrenia and tardive dyskinesia.

Effects of the dihydropyridine calcium channel inhibitor nifedipine on chronic schizophrenia and tardive dyskinesia were studied in an 8-week double-blind crossover trial. Four of the ten patients had tardive dyskinesia, and three of these were not receiving neuroleptics. No effects on symptoms of chronic schizophrenia were found using Psychiatric Symptom Assessment Scale ratings. In the four patients with tardive dyskinesia, an average improvement in total Abnormal Involuntary Movement Scale scores of 57% was observed. These data suggest that dihydropyridine calcium channel inhibitors may be effective in the treatment of tardive dyskinesia in schizophrenic patients.

Chronic cocaine and rat brain catecholamines: long-term reduction in hypothalamic and frontal cortex dopamine metabolism.

The short- (1 h after last treatment) and long- (1, 6, and 12 weeks after treatment) term effects of repeated cocaine administration on catecholamine metabolism were evaluated in the rat brain. The concentrations of norepinephrine (NE), dopamine (DA) and their metabolites were measured in the hypothalamus, frontal cortex, septum, striatum and nucleus accumbens. Except for a short-term increase in hypothalamic NE content, NE and its major metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG), did not change after chronic cocaine treatment in any of the brain regions analysed. The immediate (short-term) effects of chronic cocaine administration on DA metabolism included significant reductions in DOPAC in the frontal cortex, septum, nucleus accumbens, striatum and hypothalamus. In addition, DA was reduced in the frontal cortex and nucleus accumbens. In none of these brain regions was the concentration of HVA significantly changed. The short-term reductions in DA metabolism observed in the striatum and nucleus accumbens disappeared within one week of termination of cocaine treatment. Following cocaine treatment there were, however, reductions in frontal cortex DOPAC, 1 and 6 weeks following withdrawal, and in HVA 12 weeks after withdrawal. The combined molar concentrations of DOPAC and HVA at the three withdrawal periods (1, 6 and 12 weeks) were reduced, suggesting attenuated frontal cortex DA turnover. In the hypothalamus, DA metabolites were reduced after 6 weeks withdrawal. Twelve weeks after cocaine withdrawal hypothalamic HVA, as well as DOPAC plus HVA, were significantly increased suggesting compensation had taken place. The clinical effects following cocaine withdrawal in humans may be related to long-term changes in DA metabolism similar to those found in rat brain.

Anatomical abnormalities in the brains of monozygotic twins discordant for schizophrenia.

Recent neuroradiologic and neuropathological studies indicate that at least some patients with schizophrenia have slightly enlarged cerebral ventricles and subtle anatomical abnormalities in the region of the anterior hippocampus. Using magnetic resonance imaging (MRI), we studied 15 sets of monozygotic twins who were discordant for schizophrenia (age range, 25 to 44 years; 8 male and 7 female pairs). For each pair of twins, T1-weighted contiguous coronal sections (5 mm thick) were compared blindly, and quantitative measurements of brain structures were made with a computerized image-analysis system. In 12 of the 15 discordant pairs, the twin with schizophrenia was identified by visual inspection of cerebrospinal fluid spaces. In two pairs no difference could be discerned visually, and in one the twin with schizophrenia was misidentified. Quantitative analysis of sections through the level of the pes hippocampi showed the hippocampus to be smaller on the left in 14 of the 15 affected twins, as compared with their normal twins, and smaller on the right in 13 affected twins (both P less than 0.001). In the twins with schizophrenia, as compared with their normal twins, the lateral ventricles were larger on the left in 14 (P less than 0.003) and on the right in 13 (P less than 0.001). The third ventricle also was larger in 13 of the twins with schizophrenia (P less than 0.001). None of these differences were found in seven sets of monozygotic twins without schizophrenia who were studied similarly as controls. We conclude that subtle abnormalities of cerebral anatomy (namely, small anterior hippocampi and enlarged lateral and third ventricles) are consistent neuropathologic features of schizophrenia and that their cause is at least in part not genetic. Further study is required to determine whether these changes are primary or secondary to the disease.