Samuel Gershon

Dopamine and depression

The dopamine hypothesis of schizophrenia and the emphasis on other neurotransmitters, most notably norepinephirne, serotonin, and acetylcholine, in the pathogenesis of depression, have focused attention away from substantial evidence implicating dopamine in affective disorders. The clinical evidence includes alterations in depressive symptoms with aging (concomitant with possible changes in dopamine metabolism), potential dopaminergic involvement in several subtypes of depression, similarities between some of the symptoms of Parkinsons disease and those of depression (including psychomotor retardation and diminished motivation), and potential dopaminergic abnormalities in seasonal mood disorder. The biochemical evidence in patients with deprission derives from studies of homovanillic acid, a dopamine metabolite, indicating diminished dopamine turnover. In addition, there is a considerable amount of pharmacologic evidence regarding the efficacy of antidepressants with dopaminergic effects in the treatment of depression. We conclude that dopamine likely contributes significantly to the pathophysiology of depression. However, the role of dopamine in this syndrome must be understood in the context of existing theories involving other neurotransmitters which may act independently, and interact with dopamine and other neurochemicals, to contribute to depression.

Increased cerebrospinal fluid glutamine levels in depressed patients

BACKGROUND There is increasing evidence for an association between alterations of brain glutamatergic neurotransmission and the pathophysiology of affective disorders. METHODS We studied the association between cerebrospinal fluid (CSF) metabolites, including glutamine, in unipolar and bipolar depressed patients versus control subjects using a proton magnetic resonance spectroscopy technique. Cerebrospinal fluid samples were obtained from 18 hospitalized patients with acute unmedicated severe depression without medical problems and compared with those of 22 control subjects. RESULTS Compared with the control group, the depressed patient group had significantly higher CSF glutamine concentrations, which correlated positively with CSF magnesium levels. CONCLUSIONS These findings suggest an abnormality of the brain glial-neuronal glutamine/glutamate cycle associated with N-methyl-D-aspartate receptor systems in patients with depression.

The role of dopamine in mood disorders

The findings on dopamine in mood disorders suggest that decreased dopamine activity is involved in depression, while increased dopamine function contributes to mania. This report reviews the considerable preclinical and clinical evidence supporting this hypothesis, with particular emphasis on specific subtypes of depression. We also discuss the importance of integrating these dopamine findings with dopamine brain circuitry and with other neurotransmitter theories of affective disorders.

Fluoxetine in adolescents with major depression and an alcohol use disorder: An open-label trial

Recently, a first placebo-controlled study of an selective serotonin reuptake inhibitor (SSRI) medication was conducted among a sample of adolescents with major depression by Emslie et al. [Arch. Gen. Psychiatry 54 (1997) 1031.]. That study demonstrated efficacy for fluoxetine vs. placebo for treating adolescents with major depression. However, to date, no studies have been conducted to assess the efficacy of fluoxetine or any other SSRI medication in adolescents with major depression in combination with an alcohol use disorder (AUD). In this study, the authors investigated whether fluoxetine decreases the depressive symptoms and the drinking of adolescents with comorbid major depression and an AUD. The authors conducted a 12-week open-label study of fluoxetine (20 mg) in 13 adolescents with current comorbid major depression and an AUD. A significant within-group decrease (improvement) was found for both depressive symptoms and drinking during the course of the study. The fluoxetine was well tolerated during the study. These data suggest promise for fluoxetine for decreasing both the depressive symptoms and the drinking of adolescents with comorbid major depression and an AUD.

Serotonergic Anxiolytics in the Treatment of Panic Disorder: A Controlled Study With Buspirone

The efficacy of buspirone for panic disorder was tested in 60 patients who met Diagnostic and Statistical Manual of Mental Disorders (3rd ed.) criteria for panic disorder or agoraphobia with panic attacks. Patients were randomly assigned to treatment with buspirone (mean dose 29.5 mg/day), imipramine (mean dose 140 mg/day), or placebo, and treated for 8 weeks after a 4- to 7-day placebo lead-in period. Patients with 4 or fewer attacks per month and those without attacks at the baseline visit were excluded from panic frequency comparisons. Both buspirone and imipramine tended to be better than placebo on total number of panic attacks, global psychopathology, and the Hamilton Anxiety rating scale, but end point differences among treatments were not statistically significant. At the end of the study, 25% of the buspirone patients were panic-free, as were 7% of the imipramine patients and 14% of the placebo patients; again, these differences were not statistically significant. The results of this study were inconclusive, partly because of the relatively small number of patients (10-11) completing the study in each treatment group, and partly because of a robust placebo response in this population. Possible reasons for this high placebo response are discussed, as well as suggestions for changes in study design for future studies.

The lithium ion : A foundation for psychopharmacological specificity

The idea of lithiums specificity for bipolar disorder was proposed in Cades original work in 1949. Since then, many controlled studies have been performed, examining lithium for treatment of bipolar disorder and other psychiatric conditions. This review was undertaken to determine if the suggestion of lithiums specificity has support in the controlled studies conducted after Cades initial proposal. Studies were selected in a Medline search, dating back to 1966 and also identified from the bibliography of some of these papers. The controlled trials with lithium for the treatment of mania and bipolar depression, unipolar depression, schizophrenia, and schizoaffective disorder were reviewed. The published studies with lithium in other neuropsychiatric conditions were also considered. Additionally, we reviewed literature on other therapeutic agents proposed for bipolar disorder, looking at their comparative effectiveness to lithium. The data analyzed give strong support for lithiums being most effective in bipolar disorder, with minimal or no therapeutic effects in other neuropsychiatric disorders. The neurochemical underpinnings of this specificity are being investigated, without conclusive findings to date. The study of this paradigm of specificity in neuropsychopharmacology research may lead to meaningful contributions to understanding the pathophysiology of bipolar disorder and may help to develop newer treatments for this condition.

Reporting outcomes in clinical trials for bipolar disorder: a commentary and suggestions for change.

OBJECTIVE Newer outcome measures and statistical reporting that better translate efficacy data to evidence-based psychiatric care are needed when evaluating clinical trials for bipolar disorder. Using efficacy studies as illustrations, the authors review and recommend changes in the reporting of traditional clinical outcomes both in the acute and maintenance phases of bipolar disorder. METHODS Definitions of response, remission, relapse, recovery, and recurrence are reviewed and recommendations for change are made. These suggestions include reporting the numbers needed to treat or harm (NNT or NNH), and a ratio of the two, likelihood of help or harm (LHH), as an important element of the effect size (ES). Moreover, models of prediction that conduct sensitivity or specificity analyses and utilize decision trees to help predict positive and negative outcomes of interest (for instance, excessive weight gain, or time to remission) using positive or negative predictive values (PPV or NPV) are reviewed for potential value to clinicians. Finally, functional and cognitive assessments are recommended for maintenance studies of bipolar disorder. RESULTS The examples provided in this manuscript underscore that reporting the NNT or NNH, or alternative effect sizes, or using PPV or NPV may be of particular value to clinicians. Such reports are likely to help translate efficacy-driven clinical data to information that will more readily guide clinicians on the benefits and risks of specific interventions in bipolar disorder. CONCLUSIONS The authors opine that reporting these newer outcomes, such as NNT or NNH, area under the receiver operating curve (AUC), or PPV or NPV will help translate the results of clinical trials into a language that is more readily understood by clinicians. Moreover, assessing and evaluating functional and cognitive outcomes will not only inform clinicians about potential differences among therapeutic options, but likely will make it easier to communicate such differences to persons with bipolar illness or to their families. Finally, we hope such scientific and research efforts will translate to optimism for recovery-based outcomes in persons with bipolar disorder.

Brain lithium concentrations in bipolar disorder patients: preliminary 7Li magnetic resonance studies at 3 T

BACKGROUND This study was conducted to investigate the feasibility of human brain (7)Li MRS investigations at a high magnetic field (3 T), and to further explore the relationship between brain and serum lithium measures in lithium-treated bipolar patients. METHODS Eight bipolar disorder type I patients (5 males, 3 females; mean age +/- SD = 33 +/- 9 years) were studied. A 3-T scanner, using a dual-tuned ((1)H and (7)Li) echoplanar imaging (EPI) compatible radiofrequency (RF) birdcage coil was used. (7)Li magnetic resonance spectroscopy (MRS) signal was acquired at the frequency of 49.64 MHz using an imaging selective in vivo spectroscopy (ISIS) sequence (TR = 15 sec, 128 averages), and quantitation was obtained in reference to an external standard. RESULTS The mean +/- SD oral lithium dose was 1265 +/- 442 mg/day, and the mean +/- SD 12-hour serum level was 0.69 +/- 0.19 mEq/L. The measured brain lithium concentrations varied from 0.23 to 0.55 mEq/L (mean +/- SD = 0.35 +/- 0.11 mEq/L). The brain-serum ratios varied from 0.30 to 0.80 (mean +/- SD = 0.52 +/- 0.16). Subjects on single daily doses of lithium at bedtime (n = 5) had higher brain-serum lithium ratios compared with those on twice-a-day schedules (n = 3) (0.61 +/- 0.12 and 0.37 +/- 0.07, respectively; Mann--Whitney U test, Z = -2.24, p =.03). CONCLUSIONS This study demonstrated for the first time the feasibility of (7)Li MRS human studies at 3 T. Future studies should examine a possible role for this methodology in investigations of lithium refractoriness and prediction of treatment outcome in bipolar patients.

The effects of lithium on a potential cycling model of bipolar disorder

1. Although bipolar disorder constitutes a major public health problem, with a high risk of suicide and an economic cost exceeding that of unipolar depression, it has received comparatively little attention, particularly at the basic science level. Perhaps as a result of this neglect, there is currently no animal model able to simulate the cyclicity which is its defining characteristic. 2. Consequently, drug development in this area is meager and has proceeded serendipitously rather than empirically. 3. The authors have recently reported that repeated exposure to cocaine and other stressors can induce an oscillation or cycling in a host of neurochemical and physiological systems. 4. In order to test whether such cycling might be of potential relevance to bipolar disorder, the authors examined whether cocaine-induced cyclicity of amphetamine-evoked efflux of dopamine from slices of rat nucleus accumbens and striatum and/or cocaine induced oscillation of a behavior, stress-induced hypoalgesia, could be prevented by lithium, the agent of choice in treating this disease. 5. The authors report that prophylactic treatment with lithium, completely and specifically prevented oscillations in each instance. This may represent an important initial step toward the development of the first cycling model of bipolar disorder.

THA-historical aspects: Review of pharmacological properties and therapeutic effects

The authors reviewed historical data in the development of THA, as well as recent data on its pharmacological properties and therapeutic effects on cognitive dysfunction. A medline search was conducted to identify the trials conducted with THA in Alzheimers disease (AD) patients. The findings seem to lend support to some palliative action of THA, especially at higher doses, but in these doses about 2/3 of the patients experience significant adverse reactions. The significance of these findings is discussed, with emphasis on the their relevance for the management of AD patients.