Maintenance treatment of bipolar disorders

Conventional antipsychotic drugs, although efficacious in the treatment of mania, have not demonstrated a significant usefulness in the maintenance treatment of bipolar disorder. This has primarily been due to a tendency to induce depressive symptoms and depressive recurrences in this group of patients in the course of long-term administration. However, the picture has changed following the introduction of second-generation antipsychotics. These drugs have pro-depressant properties (if any) that are much weaker than conventional antipsychotics. Furthermore, their tolerability, especially in long-term treatment, is more favorable compared to classical antipsychotics. Clinical observations of the action profile of second-generation antipsychotic drugs in the treatment of schizophrenia have pointed to a possibility of these agents possessing mood-stabilizing properties. The first such suggestion was made by Zarate (1995) in connection with clozapine. The prevention of manic and depressive recurrences in bipolar disorder is a hallmark of the definition of mood-stabilizers.     

Long-term pharmacological treatment of bipolar disorders

Several lines of clinical, genetic, and pharmacological evidence point to an association between bipolar and psychotic disorders. The goals of maintenance and prophylactic treatment of bipolar disorder include the prevention of new episodes and the improvement of social, family, and occupational functioning. This goal can be mainly achieved by using long-term adequate pharmacological treatment that is tolerable to patients. Among mood-stabilizers, the main drugs used for such treatment, the role of atypical antipsychotics has greatly increased in recent years. Lithium still remains the drug that has produced the most convincing evidence of prophylactic action and has undergone the longest periods of observation. There has also been good confirmation for the maintenance efficacy of such anticonvulsant drugs as carbamazepine, valproate, and lamotrigine, the last having the strongest properties for prophylaxis of depressive episodes. The case for the usefulness of second-generation antipsychotic drugs in the long-term treatment of bipolar disorder has been rapidly accumulating. Based on controlled trials, the best evidence for maintenance efficacy exists for olanzapine. The vast majority of patients with bipolar illness experience inadequate response to monotherapy with mood-stabilizing drugs during long-term treatment. Some issues connected with polypharmacy targeting optimal maintenance results are discussed. In addition, the long-term management and the role of antidepressants in treatment of non-bipolar I illness is also briefly described.     

Diagnosis of bipolar disorders: focus on bipolar disorder I and bipolar disorder II

Bipolar disorders are currently divided into 4 entities: bipolar I, bipolar II, cyclothymic disorder, and bipolar disorder not otherwise specified, as described in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). These subtypes of bipolar disorders cover a spectrum of severities, frequencies, and durations of manic and depressive symptoms. The differential diagnosis among these and with regard to other disorders with similar symptom features remains the foundation for treatment of bipolar disorders. It is clear that much diversity exists within these major subtypes, such that designations like "rapid cycling" and "bipolar III" are being put forward and probed for clinical relevance. Some of the concerns and advantages of including these less-established manifestations of bipolar disorders in our diagnostic thinking are discussed here, and the utility and drawbacks of our current diagnostic protocols are considered.     

Treatment of bipolar depression

Antidepressants have insufficient effect in 20-40% of patients treated for depressive disorders. This is particularly true for psychotic and agitated depression. When administered on a long-term basis, antidepressants cause a switch into mania in 25-40% of patients and induce rapid cycling. Classical antipsychotics have exhibited good therapeutic efficacy in the treatment of various forms of depression, especially psychotic and agitated forms, albeit burdened with many, above all extrapyramidal, side effects. When administered over long periods of time, classical antipsychotics may have a depressogenic effect. Second-generation antipsychotics have started to be increasingly used in this indication for a variety of reasons including: their antidepressant effect attributable to raised concentrations of catecholamines in the prefrontal cortex, their impact on serotonin transmission, their antipsychotic effect due to their mode of action including the mesolimbic blockade of dopamine D2 receptors, and the low incidence of extrapyramidal and other side effects. The following text encompasses the results of controlled trials using second-generation antipsychotics in the treatment of acute depressive disorders.     

A model for the dynamics of bipolar disorders

Bipolar disorders are characterized by recurrent, alternating episodes of mania and depression. To examine the dynamical bases of this cyclical illness we consider a minimal model for bipolar disorders based on the observation that the two poles of the disease are mutually exclusive. We assume that the propensities to mania and depression, which are correlated with the activity of two putative neural circuits that promote, respectively, the manic or the depressive state, inhibit each other. When mutual inhibition is sufficiently strong, the model predicts bistability: the bipolar system is then either in a depressive or in a manic state and can display abrupt switches between these stable states. We consider two simple mechanisms which, when added to mutual inhibition, allow the model to pass from bistability to oscillations. Self-sustained oscillations provide a mechanism for the spontaneous, recurrent switching between mania and depression. The model can generate oscillations with a variety of waveforms, including simple periodic oscillations with comparable or unequal durations of the manic and depressive episodes, or small-amplitude oscillations around one of the two states preceding large-amplitude periodic changes in the propensities to mania or depression. The model provides a theoretical framework that covers the bipolar spectrum, i.e., cycling between the two poles of the disease, or evolution to either mania or depression or to an intermediate state without alternating between the two poles of the disease. The model accounts for the clinical observation that antidepressants can trigger the transition to mania or increase the frequency of bipolar cycling.     

Serological markers in unipolar and bipolar affective disorders

ABO blood groups and haptoglobin types have been studied with special reference to their association with unipolar and bipolar affective disorders. The associations of serogenetic markers show statistically significant differences between unipolars and controls, bipolars and controls, and unipolars and bipolars. The results are largely in agreement with those reported in previous studies.     

Regeneration of plants from protoplasts of rapid cycling Brassica oleracea L.

Rapid cycling Brassica species have great potential in plant genetic research because of their short life cycles and their minimal space requirements. Rapid cycling B. oleracea can be grown with up to six generations per year. Protoplast culture of this genotype can be applied for gene transfer by direct DNA uptake and by protoplast fusion. We here report on fast regeneration of flowering plants from protoplasts of rapid cycling B. oleracea. Regeneration frequencies of 27–65% were achieved with multiple shoots developing from individual calli. The regenerated plants were grown to maturity, and flowering and other morphological characteristics were monitored. The regenerants flowered within a similar time frame as plants grown from seeds. The ploidy level of regenerated and seed-grown plants was measured by flow cytometry. Many (20–45%) of the regenerants were tetraploid. Although only few seeds could be obtained from the tetraploids, large numbers of seeds with good germination were recovered from the diploid regenerants.Abbreviations MS-3,0 Murashige and Skoog medium containing 3% sucrose and no growth regulators - MES 1-morpholino-ethane sulfonate     

Association between circadian genes,bipolar disorders and chronotypes

Abnormalities in circadian rhythms play an important role in the pathogenesis of bipolar disorders (BD). Previous genetic studies have reported discrepant results regarding associations between circadian genes and susceptibility to BD. Furthermore, plausible behavioral consequences of at-risk variants remain unclear since there is a paucity of correlates with phenotypic biomarkers such as chronotypes. Here, we combined association studies with a genotype/phenotype correlation in order to determine which circadian genes variants may be associated with the circadian phenotypes observed in patients with BD. First, we compared the allele frequencies of 353 single nucleotide polymorphisms spanning 21 circadian genes in two independent samples of patients with BD and controls. The meta-analysis combining both samples showed a significant association between rs774045 in TIMELESS (OR?=?1.49 95%CI[1.18–1.88]; p?=?0.0008) and rs782931 in RORA (OR?=?1.31 95%CI[1.12–1.54]; p?=?0.0006) and BD. Then we used a “reverse phenotyping approach” to look for association between these two polymorphisms and circadian phenotypes in a subsample of patients and controls. We found that rs774045 was associated with eveningness (p?=?0.04) and languid circadian type (p?=?0.01), whereas rs782931 was associated with rigid circadian type (p?=?0.01). Altogether, these findings suggest that these variants in the TIMELESS and RORA genes may confer susceptibility to BD and impact on circadian phenotypes in carriers who thus had lower ability to properly adapt to external cues.     

Performance evaluation of thermal cyclers for PCR in a rapid cycling condition

The performance of thermal cyclers for polymerase chain reactions (PCR) is of great concern in terms of the reliability of PCR-based assays, particularly when rapid cycling conditions are applied to small volume reactions. In this work, the precision of the temperature controls during rapid thermal cycling was measured in 19 commercial thermal cyclers of 8 different models. The temperatures of test solutions in specific locations in each thermal block were simultaneously monitored at 1 s intervals during thermal cycling. A temperature-sensitive multiplex PCR was run in parallel to assess undesirable PCR results caused by poor temperature control. Under the given conditions (20 s of annealing time and 20 microL reaction volume), a majority of the tested instruments showed prominent curving, undershooting, and/or overshooting in their temperature profiles, which substantially influenced the results of the temperature-sensitive multiplex PCR. Variations between wells were also observed in most instruments. It is strongly hoped that these problems will be addressed by manufacturers and that they will make substantial improvements in the precision and efficiency of thermal cyclers. In the meantime, users of thermal cyclers might be able to avoid unexpected poor outcomes of sensitive PCR-based assays by designing their PCR protocols with these findings in mind.     

Evidence for rapid microscale bacterial redox cycling of iron in circumneutral environments

The potential for microscale bacterial Fe redox cycling was investigated in microcosms containing ferrihydrite-coated sand and a coculture of a lithotrophic Fe(II)-oxidizing bacterium (strain TW2) and a dissimilatory Fe(III)-reducing bacterium (Shewanella alga strain BrY). The Fe(II)-oxidizing organism was isolated from freshwater wetland surface sediments which are characterized by steep gradients of dissolved O₂ and high concentrations of dissolved and solid-phase Fe(II) within mm of the sediment–water interface, and which support comparable numbers (10⁵–10⁶ mL⁻¹) of culturable Fe(II)-oxidizing and Fe(III)-reducing reducing. The coculture systems showed minimal Fe(III) oxide accumulation at the sand-water interface, despite intensive O₂ input from the atmosphere and measurable dissolved O₂ to a depth of 2 mm below the sand–water interface. In contrast, a distinct layer of oxide precipitates formed in systems containing Fe(III)-reducing bacteria alone. Examination of materials from the cocultures by fluorescence in situ hybridization indicated close physical juxtapositioning of Fe(II)-oxidizing and Fe(III)-reducing bacteria in the upper few mm of sand. Our results indicate that Fe(II)-oxidizing bacteria have the potential to enhance the coupling of Fe(II) oxidation and Fe(III) reduction at redox interfaces, thereby promoting rapid microscale cycling of Fe. This revised version was published online in August 2006 with corrections to the Cover Date.     

Treatment of urea cycle disorders

Recent advances in the treatment of inborn errors of urea synthesis have significantly decreased mortality. Treatment has included combining a high-quality low-protein diet with supplements of deficient metabolites and stimulation of alternate pathways of waste nitrogen excretion. Long-term alternate pathway therapy, using sodium benzoate and sodium phenylacetate, has generally been unassociated with signs of toxicity. However, acute intoxications have simulated hyperammonemic crises. Neurologic outcome appears to be primarily a function of duration of neonatal hyperammonemic coma, although ongoing accumulation of urea cycle intermediates may also play a role. Early recognition and treatment are critical if a good outcome is to be possible.     

Differences in hypothyroidism between lithium-free and -treated patients with bipolar disorders

The majority of the previous studies of thyroid abnormalities in bipolar patients was conducted in populations containing various proportions of lithium-treated subjects. In the present study, we sought to determine whether there exist differences in hypothyroid profile between lithium-free and -treated bipolar patients. Bipolar patients never treated with lithium and carbamazepine (n=78) and those currently in lithium therapy (n=53) were included in this study. Serum concentrations of total thyroxine (T(4)), total triiodothyronine (T(3)), and thyroid-stimulating hormone (TSH) were compared between lithium-free and -treated patients. The rate of hypothyroidism in lithium-free patients was significantly lower than those treated with lithium (6.3%-10.8% vs. 28.0%-32.1%). Significant changes in the three thyroid indices indicative of hypothyroidism were consistently associated with longer illness duration in lithium-free manic patients, but with greater severity of mania and more mood episodes in their lithium-treated counterparts. In lithium-free depressed patients, more episodes were associated with lower T(4) levels; whereas in their lithium-treated counterparts, longer illness duration was associated with higher TSH levels and females with lower T(3) levels. These results suggest that bipolar patients with and without lithium exposure differ in prevalence and association of hypothyroidism and may have different response to thyroid hormone therapy.