Michael J. Gitlin

Sociotropy/autonomy and vulnerability to specific life events in patients with unipolar depression and bipolar disorders.

Followed samples of unipolar and bipolar patients for a 6-month period, with independent assessment of symptoms and life events. Patients were initially categorized into subtypes using Becks Sociotropy/Autonomy Scale, with the prediction that onset or exacerbation of symptoms, as well as more total symptoms, would occur for sociotropic individuals experiencing more negative interpersonal events than achievement events, and for autonomous-achievement patients experiencing more achievement events than interpersonal events. Results were confirmed for unipolars, indicating that the course of disorder was associated with the occurrence of personally meaningful life events, but not for bipolars. Further research is recommended to examine whether the effect is equally robust for both subtypes of unipolars, whether longer study duration may be required for bipolars, and whether a cognitive self-schema mechanism may account for the specific vulnerability to a subset of stressful events.

Clinical aspects of depression in chronic pain patients.

It has been widely recognized that an appreciable proportion of chronic pain patients have depressive disorders. Although numerous studies and several literature reviews have examined the relationship between chronic pain and depression, disorders of mood come in many forms, and little attention has been paid to the different types of depressive disorders found among patients with chronic pain. In this article, the different ways in which a chronic pain patient may manifest depression are discussed. Diagnostic criteria for major depression, dysthymia, and atypical depression are described, and the relevance of these disorders and of masked depression to chronic pain is discussed. The medical illnesses and medications that can cause symptoms of depressive disorders are also briefly described. Depressive disorders and their concomitants are an integral part of the experience of chronic pain and are important in developing an optimal treatment plan. For these reasons, they should be carefully evaluated in all patients with chronic pain.

The vulnerability/stress model of schizophrenic relapse: a longitudinal study

A tentative model for conceptualizing the interplay of vulnerability factors, stressors, and protective factors in the course of schizophrenia is discussed. A study of the initial years after a first schizophrenic episode is testing the predictive role of key factors. During an initial 1‐year period of depot antipsychotic medication, independent life events and expressed emotion were found to predict the likelihood of psychotic relapse. Initial analyses indicate that independent life events play less of a role in relapse prediction during a medication‐free period. These results suggest that maintenance antipsychotic medication raises the threshold for return of psychotic symptoms, such that relapses are less likely unless major environmental stressors occur. A low expressed emotion environment may be a protective factor.

Neurocognitive predictors of work outcome in recent-onset schizophrenia.

While the role of neurocognitive impairment in predicting functional outcome in chronic schizophrenia is now widely accepted, the results that have examined this relationship in the early phase of psychosis are surprisingly rather mixed. The predictive role of cognitive impairment early in the illness is of particular interest because interventions during this initial period may help to prevent the development of chronic disability. In a University of California, Los Angeles (UCLA) longitudinal study, we assessed schizophrenia patients with a recent first episode of psychosis using a neurocognitive battery at an initial clinically stabilized outpatient point and then followed them during continuous treatment over the next 9 months. Three orthogonal cognitive factors were derived through principal components analysis: working memory, attention and early perceptual processing, and verbal memory and processing speed. All patients were provided a combination of maintenance antipsychotic medication, case management, group skills training, and family education in a UCLA research clinic. A modified version of the Social Adjustment Scale was used to assess work outcome. Multiple regression analyses indicate that the combination of the 3 neurocognitive factors predicts 52% of the variance in return to work or school by 9 months after outpatient clinical stabilization. These data strongly support the critical role of neurocognitive factors in recovery of work functioning after an onset of schizophrenia. Cognitive remediation and other interventions targeting these early cognitive deficits are of major importance to attempts to prevent chronic disability.

Treatment-resistant bipolar disorder

Despite the remarkable increase in medications validated as effective in bipolar disorder, treatment is still plagued by inadequate response in acute manic or depressive episodes or in long-term preventive maintenance treatment. Established first-line treatments include lithium, valproate and second-generation antipsychotics (SGAs) in acute mania, and lithium and valproate as maintenance treatments. Recently validated treatments include extended release carbamazapine for acute mania and lamotrigine, olanzapine and aripiprazole as maintenance treatments. For treatment-resistant mania and as maintenance treatments, a number of newer anticonvulsants, and one older one, phenytoin, have shown some promise as effective. However, not all anticonvulsants are effective and each agent needs to be evaluated individually. Combining multiple agents is the most commonly used clinical strategy for treatment resistant bipolar patients despite a relative lack of data supporting its use, except for acute mania (for which lithium or valproate plus an SGA is optimal treatment). Other approaches that may be effective for treatment-resistant patients include high-dose thyroid augmentation, clozapine, calcium channel blockers and electroconvulsive therapy (ECT). Adjunctive psychotherapies show convincing efficacy using a variety of different techniques, most of which include substantial attention to education and enhancing coping strategies. Only recently, bipolar depression has become a topic of serious inquiry with the dominant controversy focusing on the place of antidepressants in the treatment of bipolar depression. Other than mood stabilizers alone or the combination of mood stabilizers and antidepressants, most of the approaches for treatment-resistant bipolar depression are relatively similar to those used in unipolar depression, with the possible exception of a more prominent place for SGAs, prescribed either alone or in combination with antidepressants. Future work in the area needs to explore the treatments commonly used by clinicians with inadequate research support, such as combination therapy and the use of antidepressants as both acute and adjunctive maintenance treatments for bipolar disorder.

Psychiatric history and stress: Predictors of severity of unipolar depression.

Unipolar depression is frequently a recurrent or chronic disorder. In studies on predicting its course, outcomes are typically linked to either psychiatric features or stressful life events. In order to integrate the 2 approaches, 51 unipolar patients were assessed periodically over at least 1 year for symptoms, stressful events, and chronic stressors. It was hypothesized that adverse family history and early age of onset impair role functioning and coping capabilities, thereby contributing to stressful circumstances that predict severity of depressive reactions. Results of causal modeling analyses supported a model in which background factors were associated with severity of depressive outcomes as mediated by their effects on stress variables. Such a model implicates the self-perpetuating nature of clinical depression, both for the individual and across generations.

Lithium and the kidney: an updated review.

Despite the availability of alternative agents, lithium continues to be the standard against which all mood stabilisers, prescribed for acute and maintenance treatment of bipolar (and, to a lesser extent, unipolar) mood disorders, are compared. As a medication often used on a maintenance basis for a lifelong disorder, the potential for lithium to cause long term organ toxicity has generated appropriate concern. Foremost among these concerns are its renal effects.Lithium adversely affects renal tubular function, causing polyuria secondary to a deficit in urine concentrating ability. This effect is probably progressive for the first decade of lithium therapy, i.e. it correlates with duration of lithium therapy. Although this effect of lithium is probably functional and reversible early in treatment, it may become structural and irreversible over time. In contrast, the effect of lithium on glomerular function is not progressive.Conclusions in this area are hampered by the evidence that patients with psychiatric disorders who are not receiving lithium also show defects in certain aspects of renal function. Despite the generally sanguine data on glomerular function, a very small group of patients may develop renal insufficiency due to lithium (possibly in conjunction with other somatic factors) in the form of interstitial nephritis. However, for the vast majority of patients, the renal effects of lithium are benign.Current strategies for minimising the renal effects of lithium include: (i) assiduously avoiding episodes of renal toxicity; (ii) monitoring serum lithium concentrations in order to achieve optimal efficacy at the lowest possible concentration; (iii) monitoring serum creatinine levels on a yearly basis, getting further medical evaluation when the serum creatinine level consistently rises above 140 mmol/L (1.6 mg/dl); and (iv) possibly administering lithium once a day.

Dysregulated brain development in adult men with schizophrenia: A magnetic resonance imaging study

BACKGROUND Recent imaging evidence suggests that normal brain development/maturation of the frontal lobes and association areas is a well-regulated process consisting of continued myelination and expansion of white matter volumes into the late 40s accompanied by complementary reductions in gray matter volumes. The possibility that a dysregulation of this process may contribute to the syndrome of schizophrenia was investigated using magnetic resonance imaging. METHODS Fifty-two normal adult males and 35 males with schizophrenia underwent magnetic resonance imaging. Coronal images were acquired using pulse sequences that maximized myelin signal. The age-related change in the gray to white matter ratio was used as a measure of developmental dysregulation in the schizophrenic subjects and contrasted to the age-related changes of the normal control group. RESULTS Regression analyses on frontal and temporal gray to white matter ratio yielded highly significant interactions of diagnosis and age for both regions (p =.0003 and p =.01, respectively). In the normal group, both frontal and temporal gray to white matter ratios decreased significantly and linearly across the age range. In contrast, neither ratio showed meaningful age-related change in the schizophrenia group. Thus, differences in gray to white matter ratio between the groups increased markedly with age, driven primarily by the absence of a white matter volume expansion in the patient group. CONCLUSIONS The absence of the normal complementary volume changes in the gray and white matter with age in the schizophrenic sample suggests that this dynamic developmental process is dysregulated in adult schizophrenic subjects. The importance of myelination to the continued maturation and normal functioning of the brain has implications for the diagnosis, treatment, and prognosis of schizophrenia.

Failure of T3 to potentiate tricyclic antidepressant response

Despite a lack of documented efficacy in controlled trials, triiodothyronine (T3) is frequently administered as an adjunctive therapy for tricyclic resistant depressions. In this study, we tested the efficacy of T3 as an adjunctive treatment using a double-blind, placebo-controlled crossover design. Sixteen depressed patients who were unresponsive to 4 weeks of imipramine therapy (mean dose = 206 +/- 54 mg daily, mean combined blood level = 220 +/- 132 ng/dl) received T3 25 micrograms and placebo for 2 weeks each. There was no evidence of a T3 effect using both Hamilton depression scores and global improvement. No subgroup of responders using baseline TRH stimulation tests could be identified. T3 treatment lowered plasma free T4 (P = 0.001) and TSH (P greater than 0.02) while raising plasma T3 levels (P less than 0.01), indicating the physiological effect of the drug.

Differential effects of typical and atypical antipsychotics on brain myelination in schizophrenia

CONTEXT Imaging and post-mortem studies provide converging evidence that patients with schizophrenia have a dysregulated developmental trajectory of frontal lobe myelination even in adulthood. Atypical antipsychotics have been shown to have a wide spectrum of efficacy across multiple psychiatric diseases and to be particularly efficacious in treatment resistant cases of disorders such as schizophrenia. OBJECTIVE To test the a priori hypothesis that antipsychotic medications may differentially impact frontal lobe myelination in patients with schizophrenia. DESIGN, SETTING, AND PARTICIPANTS Participants ranged in age from 18-35 years, were all male, and were recruited by a single group of investigators using the same criteria. Two cohorts of subjects with schizophrenia early in their disease who were treated either with oral risperidone (Ris) or fluphenazine decanoate (Fd) were imaged in conjunction with cohorts of healthy controls. Each cohort was imaged using a different MRI instrument using identical imaging sequences. MAIN OUTCOME MEASURE MRI measures of frontal lobe white matter volume. RESULTS We estimated differences due to differences in the MRI instruments used in the two studies in the two healthy control groups matched to the patient samples, adjusting for age and other covariates. We then statistically removed those differences (which we assumed were due to instrument effects) from the data in the schizophrenia samples by subtraction. Relative to the differences seen in controls, the two groups of schizophrenic patients differed in their pattern of frontal lobe structure with the Ris-treated group having significantly larger white matter volume than the Fd group. CONCLUSIONS The results suggest that the choice of antipsychotic treatment may differentially impact brain myelination in adults with schizophrenia. Prospective studies are needed to confirm this finding. MRI can be used to dissect subtle differences in brain tissue characteristics and thus could help clarify the effect of pharmacologic treatments on neurodevelopmental and pathologic processes in vivo.