Challenges with bipolar disorder drug discovery

KEYWORDS:

• Drug discovery
• bipolar disorder
• treatment targets
• pathophysiological pathways
• cognitive deficits

1. Introduction

Bipolar disorder (BD) is a chronic and potentially disabling mental disease characterized by episodes of mania or hypomania (BD type I and II, respectively) and episodes of depressed mood. Many difficulties arise in treating BD because of its episodic, recurrent nature, high levels of heterogeneity, and frequent psychiatric and medical comorbidities. [1]

Although, several pharmacological compounds are validated as effective for BD, [2] the real-world outcomes of current standard treatments are rather unsatisfactory. Many BD patients under treatment suffer from chronic, residual mood symptoms, frequent polarity shifts, [3,4] cognitive impairment, [5] and poor community function. [6] Polypharmacy (use of multiple drugs of same or different pharmacological class) is common clinical practice in patients with BD, although it does not seem to reduce chronicity of the illness and improve functioning. [7] Moreover, side effects of the drugs currently used in the management of BD can cause serious long-term health issues for patients, such as the development of metabolic and cardiovascular diseases. [8] Finally, poor treatment adherence, with adherence rates as low as 35%, increases the difficulty of patient management in BD. [9]

These facts highlight the need for developing new, targeted, effective, and safe treatments that will enrich the pharmaceutical armamentarium for full remission of symptoms and better stabilization of BD patients. Furthermore, new drugs for the treatment of BD may also be useful for a broader spectrum of mental disorders with subthreshold bipolarity, such as major depression with subsyndromal hypomanic symptoms or borderline personality disorder.

2. Current limitations and future perspectives in drug development for BD

With the exception of lithium, all commonly used treatments for BD – mainly anticonvulsants or antipsychotics – were originally developed as a treatment for other diseases. Limited knowledge of the main disease mechanisms has hindered drug development in BD so far. New drugs for BD have been produced as minor variations of older ones whereas no new class of psychotropic drugs has been developed for several decades. However, during the last decade, significant progress in our knowledge of underlying pathophysiological pathways implicated in BD has been achieved, mainly through research on molecular targets of lithium and other mood stabilizers. [10] Thus, besides ‘traditional’ targets, a great number of compounds acting on novel therapeutics targets are currently under early investigation. [8,11] A recent review of phase I, II clinical trials and animal studies detected a large number of compounds under early investigation for the treatment of BD but a rather small number of studies with promising results. [12]

Hard evidence of efficacy was not found for any of the compounds investigated in recent phase II clinical trials for BD maintenance treatment. Trials of compounds with neuroprotective and/or neurotrophic properties, such as omega-3 fatty acids and cytidine, did not reveal positive results. Regarding the efficacy of NMDA receptors inhibitors, trials with memantine were negative so far, whereas there is preliminary positive evidence for dextromethorphan. [13] Studies on the therapeutic benefit of modulating circadian rhythms in both preclinical models (CK01, inhibitor of the casein kinase 1 (CK1) ε/δ, which is believed to be involved in the modulation of the molecular clock) and clinical trials (ramelteon, agonist of melatonergic MT1 and MT2 receptors) have yielded encouraging results. [12,14] Other novel drugs targeting intra- and extracellular pathways involved in the pathogenesis of BD are currently investigated in ongoing clinical trials. [12] The amino-acid taurine exhibited an ability to change depression-related signaling cascades in preclinical studies and probably prevents glutamate-induced neuronal excitotoxicity. Antibodies to digoxin are used against endogenous digitalis-like compounds that have been implicated in the pathogenesis of mood disorders through neurotoxic effects. Finally, scyllo-inositol is believed to have mood stabilizing properties through regulation of neuronal phospho-inositol signaling.

Regarding the methodology of clinical trials for maintenance treatment of BD, the major concerns are how the required time period for long-term prophylaxis is defined and how efficacy of each intervention is evaluated. Measuring levels of functioning or residual symptom severity (mania or depression) does not ensure long-term prevention. It may be preferable to use as primary outcome measures days to relapse (for any major mood episode) or the number of participants who will finally relapse and determine appropriate long-term follow up for a potential prophylactic treatment to be considered adequate.

Preclinical research has mainly focused on specific intracellular pathways involved in therapeutic targets of lithium and other mood-stabilizing drugs, such as glycogen synthase kinase 3 (GSK-3) and phospho-inositol pathway, as well as epigenetic-based targets, specifically histone deacetylase (HDAC). [12] Lithium inhibits GSK-3 and GSK-3 inhibition was found to be associated with antimanic-like and antidepressant-like efficacy in animal models. High selective compounds, such as TAT-KLCpCDK peptide [15] and GSK-3β – compound 3a, [16] which were produced for the manipulation of the GSK-3-signaling cascade, have shown antimanic, antidepressant, and neuroprotective properties in recent preclinical studies. Ebselen, possibly acting as an inositol monophosphatase (IMPase) inhibitor, has exhibited lithium-like effects in both depression and mania preclinical models. [17] Two selective HDAC inhibitors, compound 60 (Cpd-60) [18] and sodium butyrate, [19] demonstrated reversal of depressive-like and manic-like behaviors in animal studies, and these behavioral changes were related with gene expression alteration, as confirmed by increased histone acetylation. Another interesting hypothesis based on preclinical data suggests that arachidonic acid (AA) cascade may be a candidate pathway for developing BD treatments. Lithium and other mood stabilizers reduce turnover and downstream metabolism of AA, which has important second messenger actions in brain affecting neurotransmission, neuroinflammation, and other functions suggested to be disturbed in BD. [20]

Many compounds acting in novel therapeutic targets have been recently under early investigation for the treatment of BD episodes. In phase II clinical trials for manic episode treatment, pentazocine, a kappa-opioid receptor agonist and mixed mu agonist, was safe and efficacious although its effectiveness was found equal to low-dose lorazepam. [21] Randomized controlled trials have provided increasing evidence on the antimanic properties of tamoxifen, the only known centrally active protein kinase C (PKC) inhibitor available for use, encouraging further research on the role of PKC in the pathophysiology and therapeutics of BD. [22] Results about the possible antimanic effect of memantine and the COX-2 selective nonsteroidal anti-inflammatory drug, celecoxib, are expected. Two melatonin agonists, agomelatin and ramelteon, are expected to proceed to late trial evaluation as adjunctive treatment for bipolar depression. Ionotropic glutamate receptors currently represent the most promising targets for developing novel antidepressant drugs and glutamatergic system in general may have an important role in the pathophysiology and treatment of BD. [23] Results of randomized controlled trials suggest that ketamine has a rapid antidepressant effect, but there is not enough evidence yet to draw conclusions on the efficacy of other glutamate modulators (e.g. memantine, cytidine, riluzole) in bipolar depression. [23,24] There is also preliminary evidence on the efficacy of N-acetylcysteine, a glutathione precursor with neuroprotective effects which also affects glutamatergic neurotransmission, [25] whereas other mitochondrial enhancers, acetyl-L-carnitine and α-lipoic acid were not superior to placebo as an add-on treatment. [26]

Although the treatment of cognitive dysfunction in BD has only recently been recognized as an important unmet need, many agents have been already tested with mixed results. [27] Two compounds under early investigation were found promising, erythropoietin with implicating neurotrophic properties and mifepristone, a progesterone antagonist and a glucocorticoid receptor antagonist with neuro-anti-inflammatory action. [12]

3. Conclusion

Current standard treatments for BD are far from optimal for many patients. The various shortcomings in the management of BD, that is, poor long-term functional outcome, high rates of residual symptoms, and high comorbidity, highlight the urgent need for more research to develop targeted, effective, and safer treatments. Despite progress in the discovery of novel candidate therapeutics targets, only a limited number of new compounds have demonstrated promising results in clinical trials so far. Improvement in methodological quality of preclinical and clinical trials and further translational research on the molecular and cellular mechanisms underlying BD should be warranted.

4. Expert opinion

Even if new anticonvulsant and antipsychotic drugs may enhance treatment options, the ‘traditional’ therapeutic targets show limited promise for BD maintenance and mania treatment. On the other hand, among the novel compounds investigated so far, only a few were found to be efficacious in bipolar depression and mania while none has shown clearly positive effect in maintenance treatment as yet. While results about the efficacy of many novel compounds under investigation are awaited, the findings from animal studies indicate several molecular pathways as promising therapeutic targets. However, target-based discovery of safe compounds is a major concern [17] because many of these targets (e.g. GSK-3b, IMPase, HDACs) are widely distributed in peripheral organs and their molecular manipulation would potentially induce several adverse effects. [23] Deeper insight into pathophysiological mechanisms of BD, such as neural regulations and cascade of intracellular processes, will allow the identification of new potential therapeutic approaches in the future.

However, in future attempts to develop new drugs for BD, a number of methodological difficulties should be addressed. Although animal studies may provide a better understanding of the neurobiology of mood disorders and are critical for the future of drug discovery in BD, [8] there is a lack of reliable and specific preclinical models for BD. It is doubtful whether the currently used behavioral phenotypes of mania or depression reflect BD. In clinical trials, attention should be given in multiple study-design issues regarding intervention (monotherapy or add-on treatment), inclusion criteria (e.g. baseline symptom severity), duration of follow-up, sample sizes, and outcome measures. Moreover, due to the heterogeneity of BD, a number of stratification issues may be crucial for drug discovery (e.g. possible influence of gender, stage of the disease, and comorbidity on the therapeutic response). [28–30] These potential biases should be systematically examined, since they might result in inconsistent findings or a missed opportunity to discover useful drugs.

In the future, predictive enrichment strategies (i.e. choosing patients likely to respond to treatment) could be also useful in BD drug discovery. The identification of biomarkers of response would facilitate the use of enriched samples in proof-of-concept trials. This research strategy could allow the identification of particular subgroups of patients based on their biological profile and clinical dimensions that may benefit from a new drug or a new class of drugs, in line with the aims of personalized medicine and the paradigm shift in psychiatric research underscored by the new research domain criteria approach. [23] To aid such research, one pathway of particular interest is the use of validated – neuroimaging, EEG, or other – measures of target engagement in future proof-of-concept trials. Furthermore, biomarkers validated in clinical trials offer support to preclinical research in the same area (back-translation) that can identify new molecular control points and new chemical ligands that can modulate them.

Cognitive impairment in BD is a recently identified challenge in BD treatment. Cognitive deficits have significant negative impact on BD patients’ functioning and currently used drugs do not have any notable procognitive effects. Moreover, our knowledge of specific mechanisms underlying cognitive deficits is scarce and the number of existing cognitive enhancers to be tested is limited. Therefore, improving cognition in BD is an important unmet need and more studies are warranted to develop novel, targeted drugs. Compounds with neurotrophic or neuro-anti-inflammatory action seem to be a promising option. It is also highly possible that different medication classes may improve different domains of cognitive function.

Financial and competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.