Therapeutics For Bipolar Disorder Research Articles

Non-canonical pathways in the pathophysiology and therapeutics of bipolar disorder.

Bipolar disorder (BD) is characterized by extreme mood swings ranging from manic/hypomanic to depressive episodes. The severity, duration, and frequency of these episodes can vary widely between individuals, significantly impacting quality of life. Individuals with BD spend almost half their lives experiencing mood symptoms, especially depression, as well as associated clinical dimensions such as anhedonia, fatigue, suicidality, anxiety, and neurovegetative symptoms. Persistent mood symptoms have been associated with premature mortality, accelerated aging, and elevated prevalence of treatment-resistant depression. Recent efforts have expanded our understanding of the neurobiology of BD and the downstream targets that may help track clinical outcomes and drug development. However, as a polygenic disorder, the neurobiology of BD is complex and involves biological changes in several organelles and downstream targets (pre-, post-, and extra-synaptic), including mitochondrial dysfunction, oxidative stress, altered monoaminergic and glutamatergic systems, lower neurotrophic factor levels, and changes in immune-inflammatory systems. The field has thus moved toward identifying more precise neurobiological targets that, in turn, may help develop personalized approaches and more reliable biomarkers for treatment prediction. Diverse pharmacological and non-pharmacological approaches targeting neurobiological pathways other than neurotransmission have also been tested in mood disorders. This article reviews different neurobiological targets and pathophysiological findings in non-canonical pathways in BD that may offer opportunities to support drug development and identify new, clinically relevant biological mechanisms. These include: neuroinflammation; mitochondrial function; calcium channels; oxidative stress; the glycogen synthase kinase-3 (GSK3) pathway; protein kinase C (PKC); brain-derived neurotrophic factor (BDNF); histone deacetylase (HDAC); and the purinergic signaling pathway.

Patients With Drug-Naive Bipolar Disorder in Remission After 8 Weeks of Treatment Had Decreased Serum Uric Acid Concentrations.

Background: Evidence indicates that the serum concentration of uric acid (UA) in patients may relate both to the pathophysiology and therapeutics of bipolar disorder (BPD). The purpose of this study was to examine the changes and clinical significance of serum UA concentrations in first-episode manic patients suffering from BPD.Methods: Seventy-six drug-naive patients with first-episode bipolar mania and 76 age- and gender-matched healthy subjects were recruited. Young Mania Rating Scale and Hamilton Depression Rating Scale were used to assess clinical symptoms. We tested serum UA concentrations by sandwich enzyme-linked immunosorbent assay at baseline and at the end of 8-week treatment in BPD patients and in the control group.Results: After 8-week quetiapine and sodium valproate treatment, this study revealed that the serum UA concentrations in remitted patients were significantly lower than nonremitted patients; however, those remitted patients still had higher serum UA than healthy controls. We discovered that the baseline UA concentration was higher in nonremitted than remitted patients after 8 weeks of treatment. Finally, a positive association was found between serum UA and symptom relief in the first episode of manic disorder patients.Conclusion: Patients with first-episode BPD had high levels of serum UA, which responds to treatment mainly in remitted patients. Our results suggest that serum UA concentrations might present potentially a trait marker in bipolar patients.

Effects of GADL1 overexpression on cell migration and the associated morphological changes

Lithium has been used for maintenance treatment of bipolar disorder, but drug response varies among patients. Single-nucleotide polymorphisms in glutamate decarboxylase–like protein 1 (GADL1) are found to be associated with lithium response in Han Chinese bipolar patients. In this study, we assessed GADL1 function using a neuroblastoma cell line that stably overexpressed GADL1. Genes encoding factors involved in cell migration, such as FN1, ITGA2, ITGAV and CCL2, were downregulated in GADL1-overexpressing cells. GADL1 overexpression indeed suppressed cell migration. Cell migration speed and perimeter length exhibited similar trends, both of which were decreased under GADL1 overexpression or lithium treatment but increased upon stimulation with CCL2. Secreted GADL1 or its enzyme product, taurine, in the conditioned medium might exert only mild effects on the observed changes. Compared with SH-SY5Y cells, GADL1-overexpressing cells were much more sensitive to CCL2 treatment but less sensitive to lithium, indicating that the level of GADL1 expression can affect cell sensitivity to lithium or CCL2 treatment. Together, these results suggest that cell migration and related morphological changes might provide good indicators of the sensitivity toward lithium treatment, and the GADL1 stable overexpression cell line might serve as a useful platform to screen novel therapeutics for bipolar disorder.

Mice with reduced DAT levels recreate seasonal-induced switching between states in bipolar disorder.

Developing novel therapeutics for bipolar disorder (BD) has been hampered by limited mechanistic knowledge how sufferers switch between mania and depression-how the same brain can switch between extreme states-described as the "holy grail" of BD research. Strong evidence implicates seasonally-induced switching between states, with mania associated with summer-onset, depression with winter-onset. Determining mechanisms of and sensitivity to such switching is required. C57BL/6J and dopamine transporter hypomorphic (DAT-HY 50% expression) mice performed a battery of psychiatry-relevant behavioral tasks following 2-week housing in chambers under seasonally relevant photoperiod extremes. Summer-like and winter-like photoperiod exposure induced mania-relevant and depression-relevant behaviors respectively in mice. This behavioral switch paralleled neurotransmitter switching from dopamine to somatostatin in hypothalamic neurons (receiving direct input from the photoperiod-processing center, the suprachiasmatic nucleus). Mice with reduced DAT expression exhibited hypersensitivity to these summer-like and winter-like photoperiods, including more extreme mania-relevant (including reward sensitivity during reinforcement learning), and depression-relevant (including punishment-sensitivity and loss-sensitivity during reinforcement learning) behaviors. DAT mRNA levels switched in wildtype littermate mice across photoperiods, an effect not replicated in DAT hypomorphic mice. This inability to adjust DAT levels to match photoperiod-induced neurotransmitter switching as a homeostatic control likely contributes to the susceptibility of DAT hypormophic mice to these switching photoperiods. These data reveal the potential contribution of photoperiod-induced neuroplasticity within an identified circuit of the hypothalamus, linked with reduced DAT function, underlying switching between states in BD. Further investigations of the circuit will likely identify novel therapeutic targets to block switching between states.

Translational Research in Bipolar Disorders

Translational Research in Bipolar Disorders

Lithium increases nitric oxide levels in subjects with bipolar disorder during depressive episodes

BackgroundAltered nitric oxide (NO) signaling has been associated with the pathophysiology of Bipolar Disorder (BD), directly affecting neurotransmitter release and synaptic plasticity cascades. Lithium has shown to regulate NO levels in preclinical models. However, no study has addressed peripheral NO levels in unmedicated BD. Also, lithium's effects on NO levels have not been studied in humans. MethodsPlasma NO was evaluated in subjects with BD I and II during a depressive episode (n = 26). Subjects had a score of ≥18 in the 21-item Hamilton Depression Rating Scale and were followed-up during a 6-week trial with lithium. Plasma NO levels were also compared to matched healthy controls (n = 28). NO was determined by chemiluminescence method. ResultsLithium treatment significantly increased plasma NO levels after 6 weeks of treatment in comparison to baseline levels in bipolar depression (p = 0.016). Baseline NO levels during depressive episodes showed no difference when matching up to healthy controls (p = 0.66). ConclusionThe present findings suggest that lithium upregulates NO signaling in unmedicated BD with short illness duration. Further studies with larger samples are needed to confirm the effects of lithium on NO pathway and its association with synaptic plasticity and therapeutics of BD.

Leukocyte telomerase activity and antidepressant efficacy in bipolar disorder

Telomeres are DNA-protein complexes that cap linear DNA strands, protecting DNA from damage. Recently, shorten telomeres length has been reported in bipolar disorder (BD) and depression. The enzyme telomerase regulates telomeres׳ length, which has been associated with cellular viability; however it is not clear how telomerase may be involved in the pathophysiology and therapeutics of BD. In the present study, leukocyte telomerase activity was assessed in 28 medication-free BD depressed individuals (DSM-IV-TR criteria) at baseline and after 6 weeks of lithium therapy (n=21) also matching with 23 healthy controls. There was no difference between telomerase activity in subjects with BD depression (before or after lithium) and controls. Improvement of depressive symptoms was negatively associated with telomerase activity after 6 weeks of lithium therapy. This is the first study describing telomerase activity in BD research. Overall, telomerase activity seems not directly involved in the pathophysiology of short-term BD. Lithium׳s antidepressant effects may involve regulation at telomerase activity. Further studies with larger samples and long-term illness are also warranted.

Protein kinase C regulates mood-related behaviors and adult hippocampal cell proliferation in rats

The neurobiological mechanisms underlying the pathophysiology and therapeutics of bipolar disorder are still unknown. In recent years, protein kinase C (PKC) has emerged as a potential key player in mania. To further investigate the role of this signaling system in mood regulation, we examined the effects of PKC modulators in behavioral tests modeling several facets of bipolar disorder and in adult hippocampal cell proliferation in rats. Our results showed that a single injection of the PKC inhibitors tamoxifen (80 mg/kg, i.p.) and chelerythrine (3 mg/kg, s.c.) attenuated amphetamine-induced hyperlocomotion and decreased risk-taking behavior, supporting the efficacy of PKC blockade in acute mania. Moreover, chronic exposure to tamoxifen (10 mg/kg/day, i.p., for 14 days) or chelerythrine (0.3 mg/kg/day, s.c., for 14 days) caused depressive-like behavior in the forced swim test, and resulted in a reduction of cell proliferation in the dentate gyrus of the hippocampus. Finally, we showed that, contrary to the PKC inhibitors, the PKC activator phorbol 12-myristate 13-acetate (PMA) enhanced risk-taking behavior and induced an antidepressant-like effect. Taken together, these findings support the involvement of PKC in regulating opposite facets of bipolar disorder, and emphasize a major role for PKC in this disease.

Adjunctive Gabapentin for Treatment-Resistant Insomnia of Bipolar Disorder

We report a case with bipolar II disorder having mixed features, in which refractory insomnia persisted. We diagnosed his case as mixed depression with mood fluctuations because increased impulsivity and buying sprees became remarkable, with diminished ability to think or concentrate. Switching to carbamazepine and risperidone improved his mood fluctuations and impulsivity. Nevertheless, his intermittent awakening (fragmentation of the sleep-wake rhythm), related dysfunctional beliefs, anxiety about sleep, and mild impulsivity persisted. The addition of various benzodiazepine sleeping drugs, bromovalerylurea, and antipsychotics did not improve insomnia. His intractable insomnia was markedly responsive to gabapentin, engendering further improvement of mood symptoms. Eventually, its efficacy achieved his reinstatement at work. Results of this case suggest the clinical use of gabapentin for treating bipolar disorder, especially in cases with intractable insomnia, which is a very important point in the symptoms and therapeutics of bipolar disorder.

Lithium increases plasma brain-derived neurotrophic factor in acute bipolar mania: A preliminary 4-week study

Several studies have suggested an important role for brain-derived neurotrophic factor (BDNF) in the pathophysiology and therapeutics of bipolar disorder (BPD). The mechanisms underlying the therapeutic effects of lithium in BPD seem to involve a direct regulation of neurotrophic cascades. However, no clinical study evaluated the specific effects of lithium on BDNF levels in subjects with BPD. This study aims to investigate the effects of lithium monotherapy on BDNF levels in acute mania. Ten subjects with bipolar I disorder in a manic episode were evaluated at baseline and after 28 days of lithium therapy. Changes in plasma BDNF levels and Young Mania Rating Scale (YMRS) scores were analyzed. A significant increase in plasma BDNF levels was observed after 28 days of therapy with lithium monotherapy (510.9 ± 127.1 pg/mL) compared to pre-treatment (406.3 ± 69.5 pg/mL) ( p = 0.03). Although it was not found a significant association between BDNF levels and clinical improvement (YMRS), 87% of responders presented an increase in BDNF levels after treatment with lithium. These preliminary data showed lithium's direct effects on BDNF levels in bipolar mania, suggesting that short-term lithium treatment may activate neurotrophic cascades. Further studies with larger samples and longer period may confirm whether this biological effect is involved in the therapeutic efficacy of lithium in BPD.

Increased uric acid levels in drug-naïve subjects with bipolar disorder during a first manic episode

Recent evidence suggests that purinergic system dysfunction may play a role in the pathophysiology and therapeutics of bipolar disorder (BPD). Uric acid is a key nitrogenous end product of purine metabolism. In addition to being a potential marker of treatment response, high levels of uric acid may represent a state marker during mania. In this study, we assessed the presence of purinergic dysfunction in 20 treatment-naïve first episode patients with BPD who were experiencing a manic episode. Patients were matched with 24 healthy controls. We found that acutely manic patients had significantly higher levels of plasma uric acid (4.85 ± 1.60 mg/dL) compared to healthy controls (2.96 ± 0.63 mg/dL, p < 0.001; F = 28.1). No association between uric acid levels with severity of manic symptoms was observed. These results support the role of purinergic system dysfunction in BPD early in the course of illness, and suggest that this phenomenon is not the result of chronicity or medication exposure. Overall, our findings suggest a novel mechanism in the pathophysiology of BPD.

A Double-Blind, Randomized, Placebo-Controlled 4-Week Study on the Efficacy and Safety of the Purinergic Agents Allopurinol and Dipyridamole Adjunctive to Lithium in Acute Bipolar Mania

The therapeutics for bipolar disorders are still far from adequate, and new options with improved effectiveness, safety, and tolerability in a wide range of patients are necessary. Preliminary data have suggested a role for dysfunctions targeting the purinergic system in mood disorders. This study aimed to evaluate the efficacy and tolerability of the purinergic agents allopurinol and dipyridamole combined with lithium in bipolar mania. A randomized, placebo-controlled, double-blind study was performed in adult inpatients (N = 180) with a DSM-IV-TR diagnosis of bipolar I disorder, current episode manic with or without psychotic features (rapid cyclers and mixed episodes were not included). No antipsychotic agent was used during the study. Subjects were given fixed oral doses of either allopurinol 600 mg/day (N = 60), dipyridamole 200 mg/day (N = 60), or placebo (N = 60) added to lithium for 4 weeks. Subjects were rated at baseline and days 7, 14, 21, and 28 using the Young Mania Rating Scale (YMRS) as the primary efficacy measure. The study was conducted between September 2003 and September 2006. Allopurinol resulted in greater mean reductions in YMRS scores from baseline to day 21 (p < .001) and day 28 (p = .003) compared with placebo using a linear model analysis (d = 0.32, 95% CI = 0.07 to 0.57). Remission rates were significantly higher for allopurinol compared with dipyridamole and placebo (p = .008). Lithium showed a significant antimanic efficacy even in the placebo group. Decrease in plasma uric acid levels showed a significant positive association with antimanic effects in the allopurinol group (p < .001). Allopurinol is clinically effective and well-tolerated adjunctively with lithium in manic episodes and may represent an alternative approach in the treatment of acute mania, especially for those presenting tolerability and safety issues with antipsychotics. The present results strongly support the involvement of the purinergic system in the pathophysiology and therapeutics of bipolar disorder. Further placebo-controlled studies with allo-purinol compared with standard mood stabilizers in mania and maintenance are warranted. clinicaltrials.gov Identifier: NCT00560079.

Bipolar disorder: candidate drug targets

Current pharmacotherapy for bipolar disorder is generally unsatisfactory for a large number of patients. Even with adequate modern bipolar pharmacological therapies, many afflicted individuals continue to have persistent mood episode relapses, residual symptoms, functional impairment, and psychosocial disability. Creating novel therapeutics for bipolar disorder is urgently needed. Promising drug targets and compounds for bipolar disorder worthy of further study include both systems and intracellular pathways and targets. Specifically, the purinergic system, the dynorphin opioid neuropeptide system, the cholinergic system (muscarinic and nicotinic systems), the melatonin and serotonin [5-hydroxytryptamine receptor 2C] system, the glutamatergic system, and the hypothalamic-pituitary adrenal axis have all been implicated. Intracellular pathways and targets worthy of further study include glycogen synthase kinase-3 protein, protein kinase C, and the arachidonic acid cascade.

Protein Kinase C Inhibition by Tamoxifen Antagonizes Manic-Like Behavior in Rats: Implications for the Development of Novel Therapeutics for Bipolar Disorder

Rationale: In the context of bipolar disorder (BPD) research it was demonstrated that administration of the structurally dissimilar mood stabilizers lithium and valproate produced a striking reduction in protein kinase C (PKC) in rat brain. In a small clinical study, tamoxifen (a PKC inhibitor) had antimanic efficacy. However, both lithium and valproate exert many biochemical changes and attribution of therapeutic relevance to any molecular findings needs to be based on linking them to behavioral effects. Objectives: The present study was designed to explore such relationship by studying the effects of PKC inhibition in amphetamine-induced behavioral animal models of mania and changes in GAP-43. Methods: The effects of two daily tamoxifen (1 mg/kg) i.p. injections on acute or chronic (7 injections) amphetamine (0.5 mg/kg) -induced behaviors and GAP-43 phosphorylation were tested. Results: The study demonstrates that tamoxifen significantly reduced amphetamine-induced hyperactivity in a large open field without affecting spontaneous activity levels and normalized amphetamine-induced increase in visits to the center of an open field (representing risk-taking behavior). Tamoxifen also attenuated amphetamine-induced phosphorylation of GAP-43, a result that is consistent with the behavioral findings. Conclusions: These results support the possibility that PKC signaling may play an important role in the pathophysiology and treatment of BPD. These findings may have direct clinical implications as they offer a new avenue for attempts to develop more specific drugs for the disorder.

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.

Research reports on treatments for bipolar disorder: preliminary assessment of methodological quality

To assess frequencies of types of publications about bipolar disorder (BD) and evaluate methodological quality of treatment studies. We classified 100 randomly selected articles (1998-2002) from five psychiatric journals with highest impact ratings, by topic areas, and assessed methods employed in treatment studies. Topics ranked: treatment (41%; 37% on pharmacotherapy) > biology (31%) > psychopathology (14%) = miscellaneous (14%). Of treatment studies, only 19% of original articles were randomized, 15% were relatively large (n > or = 50) but non-randomized, 65% were small non-randomized, case-series or -reports, and 53% relied on baseline-to-endpoint contrasts without a control group. Patient dropout rates were > or =40% in 43% of prospective studies. Only two reports provided confidence intervals; one included a power analysis, and 53% included no references on study design or statistical methods. Even in highly respected journals, the typical methodological quality of recent reports on therapeutics for BD was unexpectedly limited, and psychopathology and psychotherapies were little studied.