Dopamine in manic depressive illness. A pharmacological synthesis

If the clinical symptoms of mania are a consequence of increased activity in central dopaminergic (DA) pathways in predisposed individuals, then drugs increasing DA neurotransmission should precipitate or exacerbate mania in such people, whereas drugs which reduce DA neurotransmission should ameliorate manic symptoms. Of the drugs which enhance DA neurotransmission, those which increase synthesis of DA (levodopa), those which promote DA release (amphetamine), and those which act directly as agonists or DA receptors (bromocriptine) have all been shown to precipitate mania. Conversely, drugs which reduce DA neurotransmission by inhibiting synthesis (alpha-methylparatyrosine) or by blocking DA receptors (pimozide) are effective in reducing manic symptoms. DA systems are not working in isolation; evidence is presented showing an influence on manic illness of central cholinergic and GABA-ergic processes. It is suggested that there is an interacting set of neurotransmitter pathways linking the limbic system and the ventral tegmental (A10) area involving DA, acetylcholine and GABA upon which drugs can act to influence the course of a manic illness.     

Vanadium: a possible aetiological factor in manic depressive illness

The effect of Vitamin C in manic-depressive psychosis was assessed by a double-blind, placebo controlled, crossover trial. Both manic and depressed patients were significantly better following a single 3 g dose of Vitamin C than following a placebo. Preliminary results of a double-blind, crossover comparison of normal vanadium intake with reduced intake in manic and depressed subjects are reported. Both manic and depressed patients were significantly better on reduced intake. These results are in keeping with the suggestion that vanadium may be an aetiological factor in manic depressive illness.     

Prediction of treatment response in bipolar, manic disorder

We examined the records of 53 patients with a diagnosis of bipolar affective disorder, manic. Thirteen patients were refractory to lithium carbonate treatment. Clinical variables hypothesized to have value in predicting response including the presence of elation, grandiosity, paranoia, irritability, delusions and hallucinations did not predict treatment response.     

Systematic chromosome examination of two families with schizophrenia and two families with manic depressive illness

Systematic and detailed chromosome analysis, combined with a semistructured interview, was performed in 2 families with schizophrenia and in 2 families with manic depressive illness. Prometaphase technique did not reveal any subtle structural chromosome abnormalities. However, in standard techniques, gain and loss of sex chromosomes were observed. This occurred in patients at a younger age than in unaffected persons. This gives rise to the suspicion that sex chromosome aneuploidy may somehow be related to the development of psychosis. But since the data set is small, especially with respect to schizophrenia, further studies are needed to elucidate this observation. In one family, cosegregation of the disease locus with a marker on chromosome 21 was seen. Therefore, further research should determine if chromosome 21 contains a gene for manic depressive illness. © 1996 Wiley-Liss, Inc.     

Oxcarbazepine as add-on treatment in patients with bipolar manic, mixed or depressive episode

OBJECTIVES: The aim of this preliminary open-label trial was to evaluate the efficacy and safety of oxcarbazepine (OXC) as adjunctive therapy in 18 patients with bipolar disorder who did not respond satisfactorily to lithium. METHODS: Eighteen patients with bipolar I (n=16) and bipolar II (n=2) disorder were treated openly with OXC for a 8-week period as add-on treatment to the existing lithium regimen. After the 8-week trial, all patients continued the treatment with OXC, and were followed-up prospectively. Outcome measures included the Clinical Global Impression-Bipolar Version Scale, the Bech-Rafaelsen Mania-Melancholia Scale and the Brief Psychiatric Rating Scale. These scales were administered at baseline and at the end of weeks 2, 4 and 8. Patients were subsequently assessed every 4 months for a period of time ranging from 4 to 12 months with the Longitudinal Interval Follow-up Evaluation. RESULTS: The mean dose of OXC at the end of week 8 was 919.4 mg/day (SD+/-335.7). Eleven of the 18 patients were considered responders. The remaining seven patients were rated as nonresponders. Of the eleven responders to the 8-week trial, seven patients remained mood-stabilized for the entire period of follow-up. CONCLUSIONS: OXC appeared to be significantly effective as add-on strategy in 60% of patients after 8 weeks of treatment. A substantial proportion (66.3%) of the 8-week trial responders maintained a satisfactory mood stabilization during the follow-up. Despite several limitations, our study suggests the potential usefulness of OXC as adjunctive therapy to lithium both in acute and long-term treatment of bipolar disorder.     

Profiles of "manic" symptoms in bipolar I, bipolar II and major depressive disorders

BACKGROUND: Classical authors such as Kraepelin, as well as the emerging literature during the past decade, indicate that manic-like signs and symptoms are present to a variable degree in all mood disorders. Current nosography does not differentiate between them and only the number of symptoms or severity is used for classification. This is particularly true for mania and hypomania. This paper will analyze the patterns of manic symptoms in bipolar I (BP-I), bipolar II (BP-II) and major depressive disorders (MDD), to test the hypothesis that mania and hypomania have different profiles, and ascertain which excitatory manic phenomena do occur in unipolar MDD. METHODS: Six hundred and fifty-two inpatients (158 BP-I, 122 BP-II and 372 MDD) were assessed using the operational criteria for psychotic illness checklist (OPCRIT) [Arch. Gen. Psychiatry 48 (1991) 764] with a lifetime perspective. Manic or hypomanic symptoms were investigated and compared between BP-I, BP-II and MDD. RESULTS: When compared with BP-II, BP-I disorder had a higher prevalence of reckless activity, distractibility, psychomotor agitation, irritable mood and increased self-esteem. These five symptoms correctly classified 82.8% of BP-I and 80.1% of BP-II patients. One or two manic symptoms were observed in more than 30% of major depressive patients; psychomotor agitation was the most frequent manifestations present in 18% of the MDD group. LIMITATIONS: We did not control for severity of symptoms, nor for neuroleptic use that could produce akathisia. CONCLUSIONS: This study suggests that mania and hypomania can be differentiated in their symptom profiles, and highlights the presence of few manic symptoms, particularly psychomotor agitation, in MDD. From the standpoint of number of manic signs and symptoms, controlling for psychomotor agitation did not substantially change the predictive power of the remaining manic symptoms. Given that excitatory manic signs and symptoms are present to a decreasing degree in BP-I, BP-II and MDD, these disorders can be proposed to lie along a dimensional model. Overall, these data are compatible with the concept of a bipolar spectrum, whereby each of the affective subtypes requires specific genetic factors.     

Long-term naturalistic treatment of depressive symptoms in bipolar illness with divalproex vs. lithium in the setting of minimal antidepressant use

OBJECTIVE: Risks have been associated with the long-term use of antidepressant in the treatment of bipolar disorder. We review our naturalistic experience with divalproex versus lithium in treating depressive symptoms of bipolar illness. METHOD: All patients with bipolar disorder treated with lithium or divalproex were identified in a university outpatient psychiatry clinic sample over one year (n=38 patients, 41 treatment trials). Treatment response was based on standard prospective symptom rating scales. Mean duration of follow-up was 90 weeks. RESULTS: Lithium and divalproex were equally effective and tolerated in the total sample. Antidepressant effects were noted despite sparing use of standard antidepressant agents (19% received them). Lithium non-responders responded well to divalproex (50%), and vice versa (44%). Divalproex monotherapy (24%) was more common than lithium monotherapy (7%, P=0.07) and was notably effective in treating depressive symptoms, with a 7/10 response on the CGI-BP and improvement on the HDRS (14.8+/-9.2 to 7.6+/-7.8, P=0.003, duration of prospective follow up 26.7 weeks). CONCLUSIONS: Lithium and divalproex were equally effective and tolerated in this naturalistic sample, but responders may represent distinct subgroups. Both agents, but particularly divalproex, demonstrated long-term antidepressant effects, with limited adjunctive standard antidepressant use.     

Serum neurotrophin-3 is increased during manic and depressive episodes in bipolar disorder

Accumulating evidence suggest that neural changes and cognitive impairment may accompany the course of bipolar disorder. Such detrimental effects of cumulative mood episodes may be related to changes in neurotrophins that take place during mood episodes but not during euthymic phases. The present study investigated serum neurotrophin-3 (NT-3) levels in patients with bipolar disorder during manic, depressed, and euthymic states, using an enzyme-linked immunosorbent assay (sandwich-ELISA). Serum NT-3 levels were increased in manic (p<0.001) and depressed (p<0.001) BD patients, as compared with euthymic patients and normal controls. These findings suggest that the NT-3 signaling system may play a role in the pathophysiology of BD.     

Previous pattern of course of the illness as a predictor of response to lithium prophylaxis in bipolar patients

The response to lithium prophylaxis was assessed in a sample of bipolar patients subdivided into the following groups on the basis of the previous pattern of course of their illness: MDI (sequence mania-depression-free interval), DMI (sequence depression-mania-free interval), CC-LC (continuous circular course with long cycles), CC-RC (continuous circular course with rapid cycles), IRR (irregular course). A significant reduction of the mean number of morbid episodes and of the mean total morbidity during lithium treatment was observed only in patients with a previous MDI or IRR course. The percentage of responders to prophylaxis was significantly different among the five groups, and the difference could be mainly ascribed to the high response rate in the MDI group and the low response rate in the DMI and CC-RC groups. These results suggest that the classification of bipolar patients according to the previous pattern of course of their illness may be useful for the prediction of lithium response.     

Prevalence and clinical significance of subsyndromal manic symptoms, including irritability and psychomotor agitation, during bipolar major depressive episodes

BackgroundThere is increasing evidence that subsyndromal manic symptoms occur frequently during bipolar major depressive episodes (MDEs) and may be a subtle form of ‘depressive mixed state.’ This paper examines the prevalence and clinical characteristics of MDEs with subsyndromal manic symptoms. The specific effects of overt irritability and psychomotor agitation are examined.MethodsBipolar (type I or II) patients with an MDE at intake (N = 142) were compared based on the presence or absence of concurrent subsyndromal manic symptoms. The groups were further subdivided by the presence of symptoms of overt irritability and/or psychomotor agitation.ResultsSubsyndromal manic symptoms during bipolar MDEs were highly prevalent (76.1%), and were associated with significantly increased severity of depression/dysphoria in the intake episode, longer episode duration, and more suicidal ideation and behavior (past, current, and during long-term follow-up). Overt irritability and psychomotor agitation were the most prevalent subsyndromal manic symptoms (co-occurring in 57% and 39% of MDEs, respectively), and accounted for most of the negative effects associated with subsyndromal manic symptoms.LimitationsThe findings need to be confirmed in larger samples, which also examine the relationship to adequate antidepressant and/or mood stabilizing treatment.ConclusionsThe presence of one or more subsyndromal manic symptoms appears to be the modal presentation of bipolar MDEs and a marker for a subtle form of bipolar mixed depressive state. In particular, patients with symptoms of overt irritability and/or psychomotor agitation should be monitored closely to avoid serious clinical outcomes such as longer affective episodes, exacerbation of manic symptoms syndromal mania, and heightened suicidality.     

Oxidative stress parameters in unmedicated and treated bipolar subjects during initial manic episode: a possible role for lithium antioxidant effects

Studies have proposed the involvement of oxidative stress and neuronal energy dysfunctions in the pathophysiology of bipolar disorder (BD). This study evaluates plasma levels of the oxidative/energy metabolism markers, thiobarbituric acid reactive substances (TBARS), superoxide dismutase (SOD), catalase (CAT), and neuron-specific enolase (NSE) during initial episodes of mania compared to controls in 75 subjects. Two groups of manic subjects (unmedicated n=30, and lithium-treated n=15) were age/gender matched with healthy controls (n=30). TBARS and antioxidant enzymes activity (SOD and CAT) were increased in unmedicated manic patients compared to controls. Conversely, plasma NSE levels were lower during mania than in the controls. In contrast, acute treatment with lithium showed a significant reduction in both SOD/CAT ratio and TBARS levels. These results suggest that initial manic episodes are associated with both increased oxidative stress parameters and activated antioxidant defenses, which may be related to dysfunctions on energy metabolism and neuroplasticity pathways. Antioxidant effects using lithium in mania were shown, and further studies are necessary to evaluate the potential role of these effects in the pathophysiology and therapeutics of BD.     

Serum brain-derived neurotrophic factor is decreased in bipolar disorder during depressive and manic episodes

Genetic and pharmacological studies have suggested that brain-derived neurotrophic factor (BDNF) may be associated with the pathophysiology of bipolar disorder (BD). The present study investigated serum BDNF levels in manic, depressed, euthymic BD patients and in matched healthy controls, using an enzyme-linked immunosorbent assay (sandwich-ELISA). Serum BDNF levels were decreased in manic (p = 0.019) and depressed (p = 0.027) BD patients, as compared with euthymic patients and controls. Serum BDNF levels were negatively correlated with the severity of manic (r = −0.37, p = 0.005) and depressive (r = −0.30, p = 0.033) symptoms. These findings further support the hypothesis that the BDNF signaling system may play a role in the pathophysiology of BD.     

Increased serum glial cell line-derived neurotrophic factor immunocontent during manic and depressive episodes in individuals with bipolar disorder

Glial cell line-derived neurotrophic factor (GDNF) is a neurotrophic factor from the transforming growth factor β family, which plays a role in the development and function of hippocampal cells. Preclinical studies suggest that changes in neurotrophic growth factor systems might be involved in the pathophysiology of mood disorders including bipolar disorder (BD) [E.J. Nestler, M. Barrot, R.J. DiLeone, A.J. Eisch, S.J. Gold, L.M. Monteggia, Neurobiology of depression, Neuron 34 (2002) 13–25]. This is the first study to analyze GDNF immunocontent in BD subjects across different mood states, including mania, depression, and remission (euthymia). Fourty-four bipolar patients (14 depressed, 15 manic, and 15 euthymic) and 14 healthy controls, diagnosed according to the Structural Clinical Interview for DSM-IV were studied. Serum GDNF immunocontent was measured using Western blotting. Serum GDNF immunocontent was increased in manic (F = 42.31; p = 0.001; one-way ANOVA) and depressed (F = 42.31; p = 0.004; one-way ANOVA) bipolar patients, but not in euthymic patients as compared with controls. Our results indicate that changes in GDNF immunocontent occur during acute major affective episodes in bipolar subjects. These results further support the role of neurotrophins in the pathophysiology of bipolar disorder. Whether the observed increase in GDNF immunocontent correspond to a pathological or an adaptive response remains to be determined.     

Increased serum glial cell line-derived neurotrophic factor immunocontent during manic and depressive episodes in individuals with bipolar disorder

Activation of the cardiac "sympathetic afferent" reflex (CSAR) has been reported to depress the arterial baroreflex and enhance the arterial chemoreflex via a central mechanism. In the present study, we used single-unit extracellular recording techniques to examine the effects of stimulation of cardiac sympathetic afferents on baro- or chemosensitive neurons in the nucleus tractus solitarius (NTS) in anesthetized rats. Of 54 barosensitive NTS neurons tested for their response to epicardial application of capsaicin (0.4 microg), 38 were significantly (P<0.01) inhibited by 38% while 16 did not respond. Of 42 NTS chemosensitive neurons tested for their response to capsaicin, 33 were significantly (P<0.01) excited by 47% while 9 did not respond. In addition, of 12 both barosensitive and chemosensitive NTS neurons tested for capsaicin, 2 were excited, 7 were inhibited, and 3 did not respond. In conclusion, this study indicates that CSAR activation inhibited NTS barosensitive neurons and excited NTS chemosensitive neurons, suggesting that the NTS plays an important role in processing the interactions between these cardiovascular reflexes.     

Relationship between prior course of illness and neuropsychological functioning in patients with bipolar disorder

BACKGROUND: This study investigated the relationship between prior course of illness and neuropsychological deficits in relatively high functioning outpatients with bipolar disorder. METHOD: Forty-nine bipolar I or II patients, in a relatively euthymic state during treatment with mood stabilizers, were administered neuropsychological tests that assessed a variety of functions, including verbal memory, sustained attention and vigilance, and intelligence. A detailed retrospective life chart was completed for each patient using the NIMH Life Chart Method" to define variables reflecting duration and severity of illness, and frequency of episodes. RESULTS: Stepwise multiple regression analyses show that several different measures of a more severe course of prior illness related to greater duration and a larger number of affective episodes and hospitalizations were associated with poorer performance on tests of abstraction, attention and memory. CONCLUSION: The results indicate that bipolar patients with a more severe prior course of illness and a greater number of affective episodes have more impaired neuropsychological functioning. The direction of causality and the pathophysiological mechanisms remain to be explored.     

Stability and course of neuropsychological deficits in manic and depressed bipolar patients compared to patients with Major Depression

BACKGROUND: Neuropsychological functioning varies across different subgroups of patients with affective disorders; yet there have only been a few studies pointing out distinctive neuropsychological profiles and following-up possible changes in this functioning. The aim of this study was to compare neuropsychological functioning across remitted manic or depressed patients with bipolar disorder compared to remitted patients with Major Depression and to explore the course of their cognitive functioning. METHODS: 30 patients with Major Depression, 17 manic bipolar patients, and 22 depressed bipolar patients were assessed for memory, attention, and executive functions using the Auditory Verbal Learning Test (AVLT), the Modified Card Sorting Test (MCST), the Attention Network Test (ANT), and Stop-Signal Task. Neuropsychological assessment was performed at discharge and seven weeks after discharge. RESULTS: The three groups showed different neuropsychological performance at discharge. Regarding selective attention and speed of responding the manic bipolar patients displayed poorer performance than the other two groups. Furthermore, follow-up assessment revealed that although all patient groups demonstrated an overall improvement, some deficits (especially in executive functions) remain. Manic bipolar patients showed again the worst performance. Depressed bipolar patients, however, were not observed to show a poorer outcome than depressed unipolar patients. CONCLUSIONS: This study provides further evidence for distinct neuropsychological functioning in patients with affective disorders depending on their state of illness. Furthermore, it supports the hypothesis that especially manic bipolar patients stay impaired in certain cognitive functions after remission. These findings may be of clinical relevance regarding treatment and prevention programs and emphasize the need of further research investigating stability and course of patients with mood disorders.