Bipolar Manic-depressive Disorder Research Articles

Litio en Psiquiatría. / Lithium in Psychiatry.

Background: Lithium is a light, metallic element and minerals containing it are most abundant in the Andes. John Cade introduced lithium carbonate for the treatment of mania in 1949, opening the era of modern clinical psychopharmacology. Lithium remains the most extensively studied mood-stabilizing agent. It has had a revolutionary impact in supporting bipolar manic-depressive disorder as a discrete diagnosis, and on psychiatric therapeutics. Methods: We survey the development of lithium treatment in psychiatry, including findings concerning effects on suicide. Results: Lithium is the most extensively studied treatment for bipolar disorder and the prototypical mood-stabilizing agent, despite emergence of anticonvulsants and modern antipsychotics. In addition to limiting recurrences of mania, and some reduction of recurrences of bipolar depression, lithium has demonstrated protective effects against suicide. All treatments for bipolar disorder have notable limitations, including sometimes serious adverse effects, incomplete prevention of recurrences of mania and limited prevention of depression, which accounts for three-quarters of the approximately 50% time-ill in long-term follow-up with standard treatments. Lithium can be toxic in untreated overdoses; safe dosing requires monitoring of serum concentrations. Lithium also may have mild teratogenic effects, but far less than those of anticonvulsants used for bipolar disorder. Conclusions: Lithium opened the era of modern psychopharmacology and continues as the best-established mood-stabilizing treatment for bipolar disorder as well as having strong evidence of suicide-preventing effects.

Kynurenines: from the perspective of major psychiatric disorders

Psychiatric disorders are documented to be associated with a mild pro-inflammatory state. Pro-inflammatory mediators could activate the tryptophan breakdown and kynurenine pathway with a shift toward the neurotoxic arm where excitotoxic N-methyl-D-aspartate receptor agonist quinolinic acid is formed. An unbalanced metabolism in terms of neuroprotective and neurotoxic effects, such as reduced kynurenic acid to kynurenine ratio, has been demonstrated in the major psychiatric disorders such as unipolar depression, bipolar manic-depressive disorder and schizophrenia, and in drug-induced neuropsychiatric side effects such as interferon-α treated patients. The changes in serum or plasma are shown to be associated with central changes such as in the cerebrospinal fluid and certain brain areas. While currently available antidepressants and mood stabilizers could not efficiently improve these neurochemical changes within the same period that could induce clinical improvement, some antipsychotic treatments could reverse certain metabolic imbalances. Some of these changes were tested also in animal models. In this review the role of this unbalanced kynurenine metabolism through interactions with other neurochemicals is discussed as a major contributing pathophysiological mechanism in psychiatric disorders. Moreover, the biomarker role of kynurenine metabolites and future therapeutic opportunities are also discussed.

Cell pathology in mood disorders.

In new, exciting, neuroanatomic studies on postmortem tissues from patients with mood disorders, quantitative cytomorphologic differences can be shown at the microscopic level. These investigations provide direct evidence that mood disorders are characterized by marked reductions in glial cell number and density in addition to subtle alterations in the density and size of cortical neurons in frontolimbic brain regions. Importantly, this corresponds with clinical neuroimaging studies and preclinical animal studies that suggest cell atrophy, cell loss, or impairments in neuroplasticity and cellular resilience may underlie the neurobiology of major depressive disorder and bipolar manic-depressive disorder. Because this represents a departure from modern efforts to understand mood disorders, published reports are scarce and based on rather small sample sizes. This article reviews the current findings from postmortem studies on glial and neuronal cell counts in primary mood disorders and discusses a possible link between cellular changes and the action of psychotherapeutic drugs.

Review: long term lithium treatment lowers suicide risk in major affective disorder

(2001) Acta Psychiatr Scand 104, 163. Tondo L, Hennen J, Baldessarini RJ. . Lower suicide risk with long-term lithium treatment in major affective illness: a meta-analysis. . Sep; . :...

Review: long term lithium treatment lowers suicide risk in major affective disorder

(2001) Acta Psychiatr Scand 104, 163. Tondo L, Hennen J, Baldessarini RJ. . Lower suicide risk with long-term lithium treatment in major affective illness: a meta-analysis. . Sep; . :...

Health values of patients with bipolar disorder.

Despite a growing number of studies of patients' health values (utilities), little is known about health values of patients with mental illness, particularly bipolar (manic-depressive) disorder. We administered a computerized rating scale, time tradeoff, and standard gamble to 53 patients. Patients were asked to rate or value their current state of health overall and then their current mental health. In addition, we administered the SF-36; Inventory of Depressive Symptoms (IDS-C); Positive and Negative Syndrome Scale (PANSS); Young Mania Rating Scale (YMRS); and Global Assessment of Functioning Scale. The patients' median (25th, 75th percentile) age was 43 (37, 50); 62% were female. Mean (+/- SD) health ratings for current overall health were 68.0 (+/- 20.3) vs. 61.0 (+/- 25.7) for current mental health (p-value for difference = 0.02). On the time tradeoff, scores for current overall health averaged 0.71 (+/- 0.37) vs. 0.61 (+/- 0.39) for current mental health (p = 0.02); on the standard gamble, mean scores were 0.77 (+/- 0.32) for current overall health vs. 0.70 (+/- 0.35) for current mental health (p = 0.11). In univariate analyses, rating scale, time-tradeoff, and standard gamble scores for both current overall health and for current mental health were correlated with the SF-36 and all psychiatric scale (magnitude of r = 0.22-0.76) except the YMRS (magnitude of r < or = 0.13). In multivariable analyses, health values for current overall health were related to factors different from those that were related to health values for current mental health (R2 = 0.38-0.65), and none of the health value measures was related to the YMRS. Health values of patients with bipolar disorder are higher for their current health overall than for their current state of mental health. Health values are related to certain health status attributes and to level of depression but perhaps not to level of mania.

Rapid cycling in women and men with bipolar manic-depressive disorders.

This study investigated risks for rapid cycling, as defined by DSM-IV, in women and men with bipolar disorders. The results of 10 studies with a total of 2,057 bipolar patients were meta-analyzed by pooled contingency methods. The proportions of women and men among rapid-cycling cases averaged 72% and 28%, respectively, but the risk of rapid cycling was inconsistently more frequent among women (29.6%) than among men (16.5%). The mean number of episodes per year was much higher in rapid-cycling patients before and during lithium treatment but was similar in rapid-cycling men and women. Rapid cycling was only moderately, and inconsistently, more common in bipolar women than men.

Recurrence Risk in Bipolar Manic-Depressive Disorders after Discontinuing Lithium Maintenance Treatment: An Overview

Lithium remains unequaled in its research support as a standard maintenance treatment for bipolar manic-depressive disorders. It has important beneficial effects on recurring bipolar depression as well as mania, and in both types I and II bipolar syndromes, with powerful antisuicide effects not demonstrated with alternative mood-stabilisers. Data collected from numerous studies indicate that discontinuing lithium maintenance treatment is followed by sharply increased morbidity and possibly mortality, particularly in the first 6 to 12 months. However, we found that gradual discontinuation markedly reduced, and not merely delayed, recurrences of mania or depression after discontinuing lithium, with an even stronger effect in bipolar type II than type I patients. Secondary long-term retreatment with lithium following discontinuation yielded only minor average losses of benefits. Increased early recurrence risk may also arise after stopping long-term treatment with other neuropsychotropic drugs. Such reactions probably reflect physiological adaptations of the brain to pharmacodynamic effects, and their impact may be limited by slow drug discontinuation. The phenomenon of high early post-treatment discontinuation recurrence risk has clinical and scientific implications for the design, management and interpretation of treatment protocols that involve discontinuing long-term treatments in disorders requiring maintenance pharmacotherapy with centrally neuropharmacologically active drugs.

A patient who changed my practice: Personality disorder or bipolar disorder?

The case of a man originally diagnosed as having a personality disorder is presented. Follow-up over many years revealed that he was really suffering from a bipolar manic-depressive disorder which responded well to lithium. His later life was characterized by stability.

Visual field defects in neuropsychiatric disorders

Unusual evanescent modest visual field anomalies have previously been defined in patients with Tourette syndrome and their blood relatives. These anomalies include nasal and temporal steps, occasional enlarged blind spots, baring of the blind spot, and a curious partial or complete 'ringing' of the blind spot by a narrow isopter. Additionally, some individuals show two different time-based losses in sensitivity.In order to determine whether this unique set of visual field anomalies is limited to Tourette syndrome, an extended masked study is being conducted in cooperation with the Psychiatric Service at Children's Hospital, Oakland, CA. A number of categories of clearly defined neuropsychiatric disorders and normals are being studied. Parents, proband children, and siblings are being examined.Nearly identical visual field anomalies have now been found in at least two more groups of patients. They are obsessive-compulsive disorder and bipolar (manic-depressive) disorder. The frequency of visual field anoma...

Discontinuation of maintenance treatment in bipolar disorder: risks and implications.

There is abundant evidence for substantial long-term prophylactic efficacy of lithium in bipolar manic-depressive disorders. Interruption of such treatment carries an extraordinarily high risk of recurrence within several months, even after several years of stability. Even a sharp reduction in dose may carry some risk. Gradual discontinuation of lithium was accompanied by markedly reduced risk of early recurrence. There is suggestive evidence that the phenomenon of high risk of recurrence after abrupt interruption of maintenance treatment may occur with other disorders and treatments, including neuroleptics in schizophrenia and possibly antidepressants in recurrent depression. The phenomenon of discontinuation-associated iatrogenic risk of early recurrence of major psychiatric illness has clear clinical implications. These include the need to evaluate safer methods of interrupting long-term maintenance treatment, particularly when clinical indications for rapid cessation are compelling and gradual discontinuation is not feasible. Questions also arise concerning interpretation of existing experimental studies of maintenance treatments that require interruption of treatment, reduction of dose, or crossover to a placebo, as well as the ethical and scientifically unambiguous design of future studies of this kind.

Is puerperal psychosis the same as bipolar manic-depressive disorder? A family study.

The first degree relatives of three groups of women were interviewed; 51 women who had had an illness within two weeks of childbirth and no non-puerperal episodes (the puerperal group), 33 who had puerperal and non-puerperal episodes (the mixed group), and 19 women with bipolar manic-depressive disorder who had non-puerperal episodes only (the manic-depressive group). Over 60% of the affected relatives in all three groups had affective illnesses; in the main these were not puerperal. There were significantly more first degree relatives who had had general practitioner or hospital treatment for psychiatric illness in the puerperal group and in the mixed group than in the manic-depressive group. The puerperal patients had a better prognosis in terms of their illness (number of relapses and time on medication), work functioning and social functioning than the manic-depressive group and the mixed group. The mixed group had an earlier age of onset than the manic-depressive group and the puerperal group. The hypothesis that puerperal psychosis is the same as bipolar manic-depressive disorder was not upheld. The mixed group and the puerperal group were similar with respect to the risk in first degree relatives but differed in terms of prognosis. There were no significant differences between the groups with respect to puerperal episodes in first-degree relatives, although the rate of puerperal psychosis in the first-degree relatives of the puerperal patients was significantly greater than in the general population. The hypothesis that there is a specific genetically determined puerperal psychosis was not supported. Women who had had an illness with an onset within two weeks of childbirth (mixed and puerperal) subsequently had an illness following 36% of their childbirths. In women who had had puerperal and non-puerperal episodes (mixed) the risk was higher; over 50% of deliveries in these women were followed by psychiatric illness.

Lithium and the kidney: Is one daily dose better than two?

Lithium is used in psychiatry both to treat manic episodes and to prophylax against mood swings in bipolar manic-depressive disorders. Lithium is still the only drug known with this latter, prophylactic, property, and the number of patients in ongoing lithium therapy is, therefore, very large. Since lithium is administered to patients for years, it is important that it be given in a way which leads to the best psychotropic effect with a minimum of side effects. This has been achieved in most psychiatric clinics by giving lithium in divided doses as a slow-release preparation. In recent years, however, results have shown that this may not be the best administration schedule, since evidence suggests that fewer renal side effects may be produced if lithium is given once daily (in the evening) in conventional lithium carbonate tablets. In this article, it is hypothesized that the therapeutic effect of lithium against mood swings is preserved, with fewer side effects, if lithium is given with larger intervals between doses, (e.g., every second or third day), provided that the drug is administered in such a way as to produce therapeutic lithium concentrations lasting for ten to 15 hours after each lithium intake. An administration schedule for this new method of lithium therapy is described.

Renal function and lithium treatment: Initial and follow-up tests in manic-depressive patients

Assessment of renal function was carried out in an unselected sample of patients with bipolar manic-depressive disorder receiving lithium for an average period of 4.5 years. Overall, glomerular filtration rate (GFR) fell within the established normal range based on sex and age, whereas measures of urinary concentrating ability were generally impaired. There was no relationship between duration of lithium treatment and either GFR or impairment of urinary concentrating ability. Moreover, there was no evidence of a progressive impairment of glomerular or tubular function in patients re-tested after 2 years. The results of this study confirm the safety of lithium administration in the majority of patients and emphasize the importance of careful clinical monitoring to avoid lithium intoxication.

Bipolar manic-depressive psychoses: results of a genetic investigation.

Ninety-five patients with bipolar manicdepressive disorders were followed from 1959 to 1975, and their first-degree relatives (N=617) were studied. In the search for heterogeneity of bipolar illness the patients were subclassified according to various criteria: sex, age at onset, number of episodes, and longitudinal syndrome subtypes (Dm, MD, Md), and the genetic findings were used as an external criterion.

Course of unipolar depressive, bipolar manic-depressive, and schizoaffective disorders. Results of a prospective longitudinal study (author's transl)

A prospective longitudinal study of the course of affective disorders was conducted from 1959-1975, based on 159 unipolar depressions, 95 bipolar manic-depressive disorders and 150 schizoaffective psychoses. These three groups of patients did not differ significantly from each other in respect of age (approximately 60 years) and sex distribution. On the other hand, there are marked differences in respect of period of observation and duration of the disorder as a result of differences in the age when the disease became manifest for the first time. Unipolar depressions take a much more favourable course than bipolar and schizoaffective ones, the last two resembling each other in many characteristic aspects. Unipolar depressions begin on the average when the patient is 45 years old, whereas onset of the bipolar disorders is at the age of 35 and of the schizoaffective psychosis at 32. The duration of disease of unipolar depressions is markedly shorter than that of the other two groups. In many cases, unipolar depressions will also recover spontaneously (in about 40% of the cases.) In this group, however, we also find the definitely highest incidence rate of suicides (10% for the whole group, 13-14% for patients hospitalised for the first time.) With an average observation period since the first manifestation of the disease of 19 27 years (depending on the disease group) we observed in unipolar depressions four phases in 19 years, in bipolar depressions 9 in 26 and in the schizoaffective psychoses 7 in 27. Here, too, the course of the unipolar disorders is relatively favourable, but there is an additional bias in favour of a more optimistic pattern apart from the incidence of suicides, because of the high age of first manifestation in this group of diseases. A future study will have to show more accurately whether unipolar depressives who fell ill early will be cured more frequently than patients in whom the disease became manifest at a larger age. So far, the suicide incidence is equal in both groups. The duration of the phase was mainly arrived at by intra-individual mean values, which, in turn, were averaged for entire disease groups. Viewed in this sense, unipolar depressive phases have an average duration of 5.95 months, whereas bipolar diseases last for 4.4 and schizoaffective psychoses for 4.65 months. Chronicity in the sense of a duration exceeding twelve or twenty four months is often observed. The last observed phase of the disorder lasted for more than a year in 24.5% of the unipolar, 17.9% of the bipolar and 18.0% of the schizoaffective patients. Within these subgroups, there is a duration of the last phase of more than two years in 17.0% in the unipolar, 13.7% in the bipolar, 12.0% in the schizoaffective patients, i.e. about two-thirds of the one-year phases can last also for more than two years. The time spacings of successive phase beginnings (cycles) revealed a systematic reduction. Initially, they are large, eg more than five years in unipolar disorders and about 4 years in bipolar disorders, but shorten down relatively quickly according to an exponential curve, which is why the phases of the disorder follow one another at shorter and shorter intervals, until a certain limit value, which is intraindividually different, has been attained. However, all patients do not continually suffer from new relapses; there are in fact spontaneous ,,healings", which have been defined as free interval of at least five years since manifestation of the last episode. Such a free interval was observed in 44% of the unipolar, 17% of the bipolar and 37% of the schizoaffective disorders. Despite these partly favourable courses, it must be placed on record that in the majority of cases the disease is still active at an average age of 60 at the point of follow-up. Hence, we cannot expect that further permanent medication eg with lithium for the purpose of prophylaxis, can be omitted when the patient has reached the age of 60. The number of full remissions is far from satisfactory. Contrary to the originally optimistic assumption by Kraepelin that affective psychoses have a good prognosis, it is definite that especially bipolar disorders, particularly of course the schizoaffective ones which are nearer to schizophrenia, register complete remission in a minority of cases only. Complete remissions are seen in unipolar cases in about 41%, in bipolar in 36% and in the schizoaffective psychoses in 27% of the cases. This unfavourable prognostic finding agrees with those made by Shobe and Brion (1971), Tsuang and Winokur (1975) as well as Welner et al.(1977). Modern research into the course of endogenous psychoses shows that the previous notions with regard to the prognosis of schizophrenia were too unfavourable and those regarding the prognosis of the affective disorders were too optimistic.

The relative prophylactic efficacy of lithium against manic and depressive recurrences in bipolar patients.

The relative prophylactic efficacy of lithium against manic and depressive recurrences was examined in 61 patients (22 males, 39 females) with bipolar manic-depressive disorders by comparing the number of manic and depressive episodes for each patient during equally long periods before and during lithium treatment. In all the patients, the percentage of depressive episodes during lithium was smaller than that of manic episodes. The better antidepressive than antimanic prophylactic effect of lithium was significant only in male patients, while the reduction of manic episodes during lithium was greater in females. The fraction of patients without depressive episodes on lithium was greater in the male group. The results obtained with this study design indicate that lithium is an effective antidepressive prophylactic agent in bipolar patients. Sex differences are also implicated in response to lithium prophylaxis.

Ancestral secondary cases on paternal and maternal sides in bipolar affective illness.

An analysis of the distribution of ancestral secondary cases of affective illness in families of patients with bipolar manicdepressive disorder was undertaken. Twenty probands with at least two affectively ill second degree relatives were available for study. Probands with both parents affected were excluded. The distribution of unilateral to bilateral pairs of all affected relatives, both excluding and including parents, of probands showed no significant differences from that expected in polygenic inheritance. However, separation into bipolar family history, positive or negative, showed significant differences from the expected ratio of unilateral to bilateral pairs in a bipolar family history positive group consistent with a single dominant gene inheritance.

Bipolar manic-depressive disorder: A reassessment of course and outcome

A review of follow-up studies of patients with bipolar manic-depressive disorder shows that this illness has a less favorable outcome than is generally considered, both from the standpoint of clinical course and that of social functioning.

Deficiency of erythrocyte sodium pump activity in bipolar manic-depressive psychosis

The mean sodium pump activity in erythrocytes of 25 subjects with a history of bipolar manic-depressive disorder was significantly lower than that of 44 control subjects. A lower mean sodium pump activity was manifest during both the active manic phase of the disease and during remission. It was not due to medication with either lithium or phenothiazines. There was a large overlap of individual values with individual control values, indicating that the assay is not, at present, of use for diagnostic purposes.