Emerging drugs for bipolar depression: an update.

Review

Emerging drugs for bipolar depression: an update

Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by University of Newcastle on 08/24/14 For personal use only.

Paul A Keedwell† & Allan H Young †

Kings College London, Institute of Psychiatry, Centre for Affective Disorders, De Crespigny Park, London, UK

1.

Background

2.

Medical need

3.

Existing first-line treatments

4.

Market review

5.

Current research goals

6.

Scientific rationale

7.

Competitive environment

8.

Potential development issues

9.

Conclusion

10.

Expert opinion

Introduction: The acute management of bipolar depression presents particular challenges. In most cases, it responds poorly to traditional antidepressants -- chronicity and partial response are commonly observed. In a subset of patients, antidepressants provoke a switch into mania and/or cause rapid cycling over the long term. Areas covered: The evidence supporting emerging and existing pharmacological treatments for bipolar depression, with particular reference to response and remission rates and risk of switching into mania, is reviewed. Novel modes of action and future pharmacological strategies are considered. Expert opinion: Drugs with greater efficacy, tolerability and speed of action are required in the treatment of bipolar depression. Novel antidepressant agents, including NMDA antagonists, GABA-ergics, 5HT-7 and 5HT-2 antagonists and adjunctive dopaminergics, offer promise, perhaps with a low risk of switching. Newer dual-action antidepressants (e.g., milnacipran) may have good efficacy but the risk of switching is not known. More randomized controlled trials and naturalistic studies are required. Keywords: bipolar disorder, depression, psychopharmacology, treatment Expert Opin. Emerging Drugs (2014) 19(1):25-36

1.

Background

Epidemiology of bipolar disorder and the bipolar ‘spectrum’ Bipolar disorder has a lifetime prevalence of 2.1 -- 2.3% and affects the genders roughly equally [1,2]. Psychiatrists increasingly recognize two subtypes of the disorder: bipolar I disorder, characterized by at least one manic episode, has a lifetime prevalence of 0.7 -- 1%, while bipolar II disorder, characterized by at least one hypomanic episode and at least one depressive episode, has a lifetime prevalence of 1.1 -- 1.6%. Individuals with major depressive disorder (MDD) who also have sub-syndromal hypomanic symptoms (i.e., an element of ‘bipolarity’) may have a lifetime prevalence as high as 6.7% [2]. An increased awareness of this extended bipolar ‘spectrum’ results from the development of more sensitive clinical measures, such as the hypomania checklist [3]. Individuals identified as having cyclothymic personality can reasonably be considered a part of this spectrum. 1.1

The presentation and natural history of bipolar disorder Bipolar disorder is a relapsing-remitting condition typically characterized by cycling episodes of elevated (manic or hypomanic) and depressed mood. In contrast, unipolar depression is characterized by recurrent episodes of depression only. Episodes of elevated mood range in severity from mild expansive states with relatively unaffected social and occupational functioning (hypomania) to incapacitating and sometimes psychotic episodes severely affecting judgment and the ability to stay on task and increasing the risk of exploitation due to social and often sexual disinhibition (mania). Manic and hypomanic episodes are frequently characterized by irritable or dysphoric mood rather than euphoric mood. 1.2

10.1517/14728214.2014.872628 © 2014 Informa UK, Ltd. ISSN 1472-8214, e-ISSN 1744-7623 All rights reserved: reproduction in whole or in part not permitted

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P. A. Keedwell & A. H. Young

The outcome of bipolar disorder into old age is poor. Full recovery without further episodes is rare, incomplete remission of depression the rule and suicides frequent [4]. Both increased mortality due to cardiovascular disease and increased risk for dementia have been reported for patients with bipolar disorder, and cognitive dysfunction (overlapping with that observed in unipolar depression and schizophrenia) commonly affects functioning [5]. Depressed individuals who have subthreshold hypomanic symptoms may have a worse prognosis than those with depressive symptoms only, possibly due to the destabilizing effect of antidepressants on the bipolar tendency [6]. Mood stabilizer treatment might be indicated in a sub-population of these individuals. There is some evidence that individuals labeled with cyclothymia respond favorably to mood stabilizers [7]. Bipolar depression: diagnostic challenges While accepting the existence of the bipolar spectrum, in many cases, bipolar depression does not differ phenomenologically from a single major depressive episode or an episode occurring in the context of recurrent depressive disorder (unipolar depression). The core features of both unipolar and bipolar depressive episodes are pervasive sadness or dysphoria, anhedonia (reduced or absent pleasure in formerly enjoyable activities) and anergia. Somatic symptoms (reduced appetite, weight loss, reduced libido and sleep disturbance) and negative cognitions of helplessness, guilt and worthlessness are common, while hopelessness with regard to the future alerts the clinician to the risk of suicide. While it has been proposed that bipolar depression might be more severe than unipolar depression (on average), in practice, this is not a sensitive or specific way of distinguishing the two disorders. Patients may present with a ‘mixed episode’ where depressive symptoms are either present simultaneously with manic symptoms, or alternate rapidly with them from hour to hour. Thus, when patients present with mixed states, recognizing that the depressive symptoms are occurring in the context of bipolar disorder should be more straightforward. However, mixed states might be wrongly perceived as episodes of ‘agitated depression’, where depression presents with marked anxiety, when in truth they are suffering from a combination of dysphoria and manic hyper-excitement [8]. The distinction is important: treating mixed states with antidepressants alone might increase the risk of suicide [8]. The forthcoming DSM-V diagnostic system allows for a ‘with mixed features’ specifier to be applied to bipolar 1, bipolar 2, bipolar disorder ‘not elsewhere defined’ and unipolar depression. To be diagnosed with the ‘with mixed features’ specifier, a person has to meet the full criteria for one mood pole (depression, mania or hypomania) and have three or more symptoms of the other mood pole. Symptoms that are common to both mood poles (mania/hypomania and depression) are not included in the possible criteria for a mixed mood, including: distractibility irritability, insomnia and indecisiveness 1.3

26

Bipolar disorder most commonly comes to the attention of a psychiatrist in the first instance when the patient is suffering from a depressive episode. Mixed episodes are relatively rare. If a careful history is not taken to exclude previous (or current) hypomanic or manic symptoms, an incorrect diagnosis of MDD will be made. In these cases the true diagnosis of bipolar disorder only emerges when a manic episode is triggered acutely by an antidepressant (known as ‘switching’), or if mania emerges later in the natural history of the disorder. It is estimated that 10% or more of individuals diagnosed with MDD will later be diagnosed with bipolar disorder [9]. Even if a careful history is taken, bipolarity might be missed. There is some evidence that bipolar patients preferentially recall depressive episodes over hypomanic episodes and have poor insight regarding upswings, especially if they do not lead to adverse consequences. The differentiation of unipolar and bipolar depression is crucial in order to optimize treatment in the short and long term. 2.

Medical need

The costs of managing bipolar disorder are significant. In a retrospective analysis of over 3000 bipolar patients and randomly selected age and sex matched controls in the US [10], prescription costs for bipolar disorder patients were 18 times higher than those of controls over a year ($582 vs $33 per person), while the cost of medical encounters were four times higher ($16,230,840 vs $4,074,797). Inpatient costs were over $4 million. In the UK the annual NHS cost of bipolar disorder was estimated to be £342 million at 2009/2010 prices [11]. Of the overall direct costs of care, hospitalizations accounted for 60%, outpatient and community mental health 26.7% and medication in primary care 7.4%. A recent study demonstrated that when compared to unipolar depression, bipolar disorder patients were associated with a higher prevalence of receiving government benefits, taking time off work and spending longer periods in hospital, while unipolar patients had more stable work histories than bipolar patients [12]. 3.

Existing first-line treatments

Prophylaxis The gold standard prophylactic treatment for both depressive and manic episodes in bipolar disorder is a mood stabilizer. This is defined as a drug with both antidepressant and antimanic properties. The first-line mood stabilizer of choice is still lithium. It provides the best prophylaxis for bipolar I disorder, in preventing both manic and depressive episodes, although the number needed to treat to prevent an episode is 4. Sodium valproate, valproate semi-sodium and carbamazepine are also commonly prescribed. Of the secondgeneration antipsychotics, there is evidence that quetiapine provides prophylaxis against manic and depressed episodes. 3.1

Expert Opin. Emerging Drugs (2014) 19(1)



Olanzapine may also be helpful but its effectiveness in preventing depressive episodes is questionable based on the trial evidence. Lamotrigine, with its relatively strong antidepressant properties but relatively weak antimanic action, is emerging as the treatment of choice for bipolar II disorder. In classic bipolar I disorder, the ideal mood stabilizer would be equally good at treating and preventing both poles of the illness. However, there is considerable variability in the periodicity and temporal contiguity of episodes. In some cases depression predictably follows a manic episode, with relative stability until the next manic episode. In these individuals prevention of mania is the priority, because in effect control of mania will prevent the consequent switch to depression. However, in the generality of bipolar I individuals seen in clinical practice, depressive episodes can be spontaneous, as opposed to immediately following a manic episode, and are more frequent than periods of elevated mood. In other words, most mood stabilizers do a better job of preventing manic episodes than depressive episodes, necessitating the need for additional antidepressant interventions in the short and long term. Acute management The acute management of bipolar depression remains the most significant treatment challenge in the management of bipolar disorder. Current NICE guidance advocates optimizing the mood stabilizer dose as the first step. Although it is good practice in general to optimize mood stabilizer levels, there is mixed evidence that acute increases in mood stabilizer dose will bring about recovery from bipolar depression. Valproate may bring about some benefit [13-15] but remission rates of 23 -- 46% are arguably of negligible clinical importance. Early studies suggested that up to 80% of patients with bipolar depression responded to acute lithium treatment; and the recent CANMAT and ISBD collaborative update recommends lithium as a first-line acute treatment [16]. However, the EMBOLDEN I study suggests that lithium is no more effective than placebo for bipolar depression [17] so this advice is controversial. Overall the data are more convincing for the effectiveness of lithium during the maintenance phase [18]. Additionally, it might have an antisuicidal effect [19,20]. Lamotrigine is effective in the maintenance phase, with strong evidence for bipolar II disorder [21]. A meta-analysis of lamotrigine trials for acute depression treatment indicated a modest effect over placebo, but the effect became stronger for more severe depression [22]. Adding lamotrigine to lithium was more effective than placebo in patients with bipolar depression [23]. Of the acute treatment options in the management of bipolar depression, antidepressants are the most commonly prescribed. A recent review of over 2000 patients admitted for the treatment of bipolar depression in Germany between 1994 and 2010 observed that over 74% received antidepressants in combination with other drugs [24]. Selective serotonin reuptake inhibitors (SSRIs) were most commonly prescribed, with mirtazapine and venlafaxine being prescribed less frequently (16% each). Combinations of more than one 3.2

antidepressant were sometimes used. Lithium was the most commonly prescribed mood stabilizer (33%), followed by valproic acid (23%). Other commonly prescribed treatments for bipolar depression included quetiapine (15%), lamotrigine (14%) and olanzapine (13%). An increase in secondgeneration antipsychotics was observed over time, a trend we will examine further in our Market Review. In 2010, quetiapine (alone and combined) was the most frequently prescribed drug (39%); aripiprazole was administered in 10%. A randomized placebo-controlled study of imipramine and fluoxetine in the treatment of bipolar disorder reported a response in 86% of the fluoxetine-treated patients, 57% of the imipramine-treated ones and 38% of the placebo-treated ones [25]. Two other studies [26,27] have suggested that fluoxetine is effective in both the acute and the maintenance phase of treatment in bipolar II, and without switching to mania. A small study suggests that after 6 months of fluoxetine monotherapy in bipolar II, 43% of patients and 100% of placebo-treated patients with bipolar disorder type II have relapsed [28]. A placebo-controlled, crossover study [29] also demonstrated good outcomes with SSRI monotherapy in bipolar II compared with placebo, with reduced depressive and hypomanic relapses. However, in the EMBOLDEN II study, where bipolar I and II disorders were included, quetiapine, but not paroxetine, proved beneficial over placebo in managing depressive episodes [30]. The community-based STEP-BD trial also observed that there was no additional benefit to be gained from adjunctive antidepressant treatment as a strategy for managing bipolar depression when bipolar I patients were included [31]. There are three main reasons why existing antidepressant treatments developed for use in MDD can be problematic when prescribed for bipolar depression, either alone or in combination. First, early research demonstrated that, compared to unipolar depression, bipolar depression may be more resistant to treatment with conventional antidepressants than unipolar depression, despite the similar symptomatology. This is consistent with the clinical observation that bipolar depression tends to be more melancholic in nature. A recent meta-analysis of the main clinical trials challenges this clinical consensus, however: response and remission rates were demonstrated to be similar in both unipolar and bipolar patients. Whether or not treatment responsiveness diverges for unipolar and bipolar depression, it is a fact that many patients with bipolar depression are resistant to treatment with antidepressants, with and without mood stabilizers. The second major problem in the management of bipolar depression is the observation that conventional antidepressants can provoke a swing from a depressive episode to a manic one. Earlier studies [32-35] highlighted this problem in up to 30% of patients. There is some evidence that switching to mania or hypomania depends on the antidepressant agent and dose used. Tricyclic antidepressants and venlafaxine may confer a particular risk of switching, while the risk with SSRIs may be considerably lower. A meta-analysis [36] indicated a


27



higher switch rate for venlafaxine in comparison with SSRIs; however, the studies may have included unusually refractory patients. Clinical features may help to guide treatment with antidepressants. Prepubertal onset and strong family history may increase the risk [36-38]. A recent review suggests that individuals with a history of severe mania, severe and prolonged depression and/or rapid cycling are particularly at risk [31]. However, more research is needed. Evidence reviewed above suggests that SSRIs confer a low risk of switching in bipolar II disorder. Switching rates may not be reduced significantly by the concomitant use of a mood stabilizer. In a modestly powered study of antidepressants prescribed for a breakthrough depression in bipolar disorder patients (type not specified), who were already taking mood stabilizers, 14 and 30% switched during acute and maintenance phases, respectively [39]. However, there is a possible bias toward treatment refractoriness. When the effect of antidepressant type was analyzed in a larger follow-up study, there was a significantly increased risk of switches into hypomania or mania in participants treated with venlafaxine compared with bupropion or sertraline [40]. The economic consequences of treating an undetected bipolar disorder with antidepressants is demonstrated by a US study conducted in 2008 [31]. In the 12 months following initiation of antidepressant treatment unrecognized bipolar patients incurred significantly greater mean monthly medical costs (1179 US dollars) than correctly diagnosed bipolar patients (801 US dollars) and non-bipolar patients (585 US dollars). Finally, the poor control of recurrent depressive episodes by first-line mood stabilizers over time inevitably leads to the chronic prescribing of antidepressants with the intention of achieving better prophylaxis. This carries a significant risk of destabilizing the illness and provoking a rapid cycling disorder (four or more episodes in a year). For these reasons, expert consensus on the treatment of bipolar depression by the International Society for Bipolar Disorders Task Force [41] concludes that the risk-benefit ratio for antidepressant treatment is questionable. The authors suggest that antidepressants could be considered in an individual with bipolar depression provided that there had been a good therapeutic response in the past, but not if there were mixed features present or if there had been a history of rapid cycling. Existing antidepressants should not be prescribed in bipolar I disorder without antimanic cover. These considerations have led to the use of drugs developed for other indications -- particularly atypical antipsychotics -- in the management of bipolar depression. In a placebo controlled study of bipolar depression, 600 and 300 mg/day of quetiapine produced response rates of 58.2 and 57.6%, respectively, versus 36.1% for placebo, while remission rates were 52.9% in the groups taking 600 and 300 mg/day of quetiapine versus 28.4% for placebo. Quetiapine significantly improved the Montgomery-A˚sberg 28

Depression Rating Scale (MADRS) items corresponding to the core symptoms of depression. Treatment-emergent mania rates were low and similar for the quetiapine and placebo groups (3.2 vs 3.9%, respectively) [42,43]. Similar low switching rates were observed in a study of quetiapine and lithium monotherapy (EMBOLDEN I), where lithium did not separate from placebo [17], and in EMBOLDEN II, which was also positive for quetiapine and negative for paroxetine [30]. Quetiapine’s remission rates were as high as 70% but there is no convincing evidence that a higher dose of 600 mg is more effective than 300 mg. In a recent review of four randomized controlled trials (RCTs) of quetiapine monotherapy in bipolar II depression [44] quetiapine monotherapy demonstrated significant efficacy compared with placebo and was generally well tolerated [44]. In a modest (n = 86) trial of olanzapine monotherapy the remission rates were much less impressive (32.8 vs 24.5% for placebo) but improved in combination with fluoxetine (48.8%) [45]. Rates of treatment-emergent mania did not differ from placebo. Adding olanzapine to lithium or valproate improves general outcomes in bipolar I [46,47], but the data for depression are unconvincing compared to mania prophylaxis. The combination of olanzapine and mood stabilizer might reduce suicidal behavior [48,49]. The evidence base for risperidone and newer atypicals such as ziprasadone, asenapine and paliperidone is limited and more work is needed. Lamotrigine might have a place in the acute treatment of bipolar depression when used as an adjunct to lithium: in a multicenter trial of 124 bipolar I and II patients with depression, significantly more patients responded to lamotrigine than to placebo on the MADRS over 8 weeks. Augmentation strategies include thyroid hormones and neutriceuticals (e.g., omega-3 fatty acids) but the evidence base is limited. Non-pharmacological approaches, including cognitive behavioural therapy (CBT), psychoeducation, rTMS, vagus nerve stimulation and sleep deprivation might improve the efficacy of drug treatments or offer alternatives. Electroconvulsive therapy (ECT) is an effective treatment for unipolar and bipolar depression, with slightly better remission rates for the latter [50]. The evidence to date suggests that it is efficacious for both phases of the bipolar illness. In other words, it is effective both as acute treatment for bipolar depression and as a mood stabilizer if continued during any switch to mania [51]. On the negative side it is less and less acceptable to patients, especially in view of the growing evidence of its deleterious effects on autobiographical memories. In practice, therefore, its application will be limited to more refractory patients. 4.

Market review

Some of the emerging drugs already reviewed for the treatment of unipolar depression [52] may prove to be helpful in bipolar depression, but separate trials will be needed of their




use in this context due to the specific challenges of treating bipolar depression. It is not yet known if new SSRIs (e.g., vilazodone) and serotonin and noradrenaline reuptake inhibitors (SNRIs), emerging ‘triple action’ antidepressants and drugs acting on nonmonoamine targets including corticotrophin, melatonin, opioid, glutamate, cholinergic, sigma and neurokinin receptors will be effective while also having a relatively low risk of switching/rapid cycling. It would be cause for concern if those drugs which are most effective in treating bipolar depression acutely might also be more likely to provoke a switch. There is no evidence to suggest that this is the case for existing antidepressants, but if evidence did emerge, this could represent a significant challenge in the marketing of new generation antidepressants for this indication. However, it is important to confirm, more generally, which features of an individual’s illness confer an increased risk of switching. Trials might stratify, or determine post-hoc, if the features identified thus far (early onset, strong family history, severe and prolonged episodes and rapid cycling), do indeed lead to differential rates of response and switching. It is likely that bipolar II individuals would have a smaller risk of switching than bipolar I individuals, while a history of rapid cycling might rule out acute treatment with an antidepressant. Second-generation antipsychotics with antidepressant properties are not known to cause switching and may be particularly effective in the management of mixed states. This might in part explain the almost threefold increase in the use of second-generation antipsychotics for treatment of bipolar disorder observed in the US (from 18% in 1998 to 49% in 2009). At the same time, the use of mood stabilizers and first-generation antipsychotics has declined substantially. A significant but smaller increase has also been observed in the UK between 1995 and 2009 in the primary care setting with prescribing increasing by 16% for olanzapine and by 10% for quetiapine [53]. In the STEP-BD trial there is evidence that individuals with an increased burden of bipolar depression are likely to be prescribed more complex polypharmacy (four or more drugs) [54]. Notably, individuals were more likely to receive atypical antipsychotic medication among these drugs. Bipolar depression had a stronger association with polypharmacy than previous psychosis, rapid cycling or previous hospitalizations. The authors conclude that ‘complex regimens are especially common in patients with substantial depressive illness burden and suicidality, for whom simpler drug regimens may fail to produce acceptable levels of response.’ 5.

Current research goals

The main research goal is to conduct randomized trials of novel drugs in the acute treatment of i) bipolar depression with typical depressive features and ii) mixed episodes, compared with placebo, or treatment as usual. Emerging drugs

should demonstrate: Increased efficacy over existing antidepressant and antipsychotic treatments; a minimal risk of switching to mania. In addition, more work needs to be done to determine the clinical indicators of high risk of switching to mania during antidepressant treatment, and trials should be stratified accordingly. Treatments could then be tailored to clinical profiles.

6.

Scientific rationale

Conventional antidepressants are thought to work predominantly by increasing the availability of the monoamines in the synaptic cleft, and subsequent, delayed alterations to presynaptic function, although their mode of action is still not established beyond doubt. The potential for existing antidepressants to destabilize bipolar disorders and their poor remission rates for bipolar depression necessitate a different pharmacological approach. It has been observed for some time that some atypical antipsychotics which have a significant action on serotonin receptors also have antidepressant qualities. In addition, most antipsychotics are effective in the management of acute mania, primarily as result of D2 receptor blockade. Thus, such compounds are of particular interest in the acute treatment of bipolar depression due to the low likelihood of them provoking a manic episode and destabilizing the illness over time. Dopamine agonists may provide some additional relief in tandem with a mood stabilizer or conventional antidepressant in non-treatment responsive cases. The rationale is that they provide improved cognitive abilities, the major determinant of poor functioning in acutely depressed individuals. The interest in dopaminergic agents is also consistent with the central role of dopamine in the processing of reward and pleasure. Reduced reward sensitivity and amotivation are core features of depression which would theoretically be reversed by dopamine potentiation: dopaminergic projections from the ventral tegmentum through the striatum to the medial prefrontal cortex are responsible for reward processing. Agonists under consideration have a low affinity for D2 receptors; D2 agonism could precipitate mania. Preclinical and clinical neuroimaging studies implicate abnormal GABA and glutamate receptor function in mood relevant cortico-striatal-limbic networks in depressed individuals. MRS studies suggest that glutamate levels are reduced in depression, while others report reduced GABA concentrations. Treatment approaches have included GABA agonists and NMDA antagonists, which may increase AMPA neuron activity. AMPA and glycine agonists are also emerging. Finally, there is a body of research investigating thyroid hormone replacement for this specific indication, and augmentation with omega-3-fatty acids. It has long been known that thyroid disorders exacerbate bipolar disorder. Furthermore, there is some evidence to support a neuroprotective


29

30

Sunovion

Gedeon Richter

Generic

Lurasidone

Cariprazine

Ketamine

Johnson & Johnson

Paliperidone

Otsuka

Pierre Fabre

Milnacipran Dalcipran

Aripiprazole Abilify

Takeda

Company

Ramelteon

Drug name

Acute treatment of bipolar depression (I and II) as monotherapy or adjunct to mood stabilizers Acute treatment of bipolar depression (type unspecified). Originally developed as an atypical antipsychotic A small case series of acute treatment of bipolar II depression. Many more studies of its use in treatment-resistant depression. Cohorts may have contained some bipolar patients

Prevention of mood symptom recurrence in bipolar I disorder. Might improve depressive phase of schizo-affective disorder

Acute treatment of bipolar depression (type unspecified)

Sublingual tablets (8 mg) to augment mood stabilizers (lithium or valproate) in acute bipolar I depression

Bipolar depression indication

Table 1. Emerging drugs for bipolar depression.


Treatment-resistant depression

Depression, bipolar

Schizophrenia Psychosis, bipolar Depression, major depressive disorder Autism Tourette’s syndrome Alzheimer’s disease Addiction, alcohol Post-traumatic stress disorder Attention deficit hyperactivity disorder Schizophrenia

Insomnia Psychosis, bipolar Migraine prophylaxis Apnoea Sleep disorder, unspecified Alzheimer’s disease Depression, unspecified Fibromyalgia Vulvodynia Depression, major depressive disorder Schizophrenia Autism Psychosis, bipolar Insomnia

Additional indications

Phase II

Phase II

Phase II

Phase II and III

Phase III

Phase II

Recruiting to Phase III; due for completion in November 2013

Stage of development


NMDA antagonist. May have a dopaminergic action

D2/D3 antagonist

High affinity at D2, 5HT-2A and 5HT-7 receptors (antagonism)

Partial dopamine D2 agonist

Full 5HT-2 and partial dopamine D2 antagonist. It also has high affinity for the 5HT-7 receptor

Serotonin and norepinephrine uptake inhibitor

ML-1-selective melatonin receptor agonist: ML-1A and ML-1B (MT1/MT2) receptors

Mechanism of action


Phase II

Parkinson’s disease, restless legs syndrome GlaxoSmithKline and others (generic) Ropinirole (ReQuip)

As for pramipexole

Generic preparations available Pramipexole

Adjunct to mood stabilizers in bipolar depression

Phase II

D2/D3 agonist with preferential binding affinity to D3 receptors Similar to pramipexole. Highest affinity at D2 receptors

Phase II

Narcolepsy Apnoea Circadian rhythm sleep disorder Binge eating disorder Schizophrenia Cancer fatigue Parkinson’s disease, restless legs syndrome Teva Armodafinil (R)modafinil

Adjunctive therapy to improve cognition in bipolar I depression

Binds to the a-2-d (alpha2-delta) subunit of the voltage-dependent calcium channel Inhibits the dopamine transporter (DAT), preventing reuptake. May have other actions. Has a longer mode of action than the racemic drug Phase II Epilepsy, neuropathic pain, generalized anxiety disorder Acute management of bipolar depression Pfizer Pregabalin (Lyrica)

Stage of development Additional indications Bipolar depression indication Company Drug name

Table 1. Emerging drugs for bipolar depression (continued).


Mechanism of action


role of fatty acids. However, neither of these approaches offers an acute treatment for bipolar depression. 7.

Competitive environment

Emerging treatments for bipolar depression are summarized in Table 1. Melatonin receptor agonist Ramelteon is an ML-1-selective melatonin receptor agonist, developed by Takeda, for promoting sleep in the treatment of sleep disorders. A proof of concept Phase II study of its safety and efficacy in acute bipolar depression (bipolar I patients) is under way in the US. It is in a randomized, double-blind, placebo-controlled trial (TAK-375SL_201) which will evaluate the efficacy and safety of sublingual once daily tablets over an 8-week period in 300 patients with bipolar I disorder who are on lithium and/or valproate [55]. A randomized, double-blind, placebo-controlled, Phase III study (TAK-375SL_301) is also under way in 279 adult subjects with bipolar depression, whose acute response will be measured over a 6-week period. This is a multicenter trial which includes Bulgaria, the Czech Republic, Germany, Montenegro, Romania, Russia, Serbia, Spain, Ukraine, the UK and the US [56]. 7.1

New generation antipsychotics (5HT-2 and 5HT-7 antagonism, D3 antagonism, partial D2 agonism)

7.2

Two major trials sponsored by Sunovion Pharmaceuticals recently demonstrated significant efficacy of the atypical lurasidone in the treatment of bipolar depression, either as augmentor of mood stabilizer treatment (Program to Evaluate Antidepressant Impact of Lurasidone (PREVAIL) 1), or as a monotherapy (PREVAIL 2). Although the results have not yet been published, the drug received FDA approval for the treatment of bipolar depression as adjunct or monotherapy in the US in July 2013; it has not yet received a license in the EU. In the latter study, significantly greater reductions in MADRS and CGI-bipolar depression severity ratings were seen after 6 weeks of treatment with lurasidone compared with placebo, and significant improvements versus placebo were observed on the Sheehan Disability Scale and the Quality of Life, Enjoyment and Satisfaction Questionnaire. Doses in the range 20 -- 60 mg and 80 -- 120 mg were similarly effective. Discontinuation rates did not differ from placebo. Changes in weight, glucose and lipids were minimal. Experience of lurasidone treatment in schizophrenia suggests that it has a good safety and tolerability profile: it appears to be relatively weight neutral and does not cause a metabolic syndrome. Lurasidone blocks serotonin 5HT-7 receptors, which might explain its antidepressant effects. This relative newcomer could be a realistic contender to quetiapine in the management of bipolar depression, although further trials


31



are required to determine if it is more efficacious and/or better tolerated. Paliperidone is a follow-up compound to risperidone, developed for the treatment of schizophrenia. It is a full 5HT-2 and partial dopamine D2 antagonist. A randomized, double-blind, placebo-controlled Phase III trial (CR010825) in 768 bipolar I disorder patients was completed in the US in 2012. It evaluated the prevention of mood symptoms recurrence, including depression, in patients who had responded to paliperidone ER during an acute manic or mixed episode. Paliperidone ER 3 -- 12 mg/day was compared to olanzapine 5 -- 20 mg/day over a 15-week period and then until recurrence. Time to recurrence of any mood symptoms was significantly longer with paliperidone ER than placebo. However, the difference was significant for preventing recurrence of manic, but not depressive, symptoms [57]. More promisingly, in a randomized, double-blind, 6-week Phase III trial of the drug in 311 patients experiencing an acute episode of schizoaffective disorder, those patients with prominent depressive symptoms experienced a significant improvement in Hamilton depression ratings compared to placebo [58]. Cariprazine is an orally active D2/D3 receptor antagonist under development as an atypical antipsychotic. A doubleblind, placebo-controlled Phase II dose-response trial (RGH-MD-56) evaluated the safety and efficacy of cariprazine 0.75 -- 3 mg/day in 600 patients with bipolar depression in Canada and the US [59]. An 8-week, double-blind, placebocontrolled Phase II exploratory study (RGH-MD-52) of cariprazine 0.25 -- 0.75 mg/day or 1.5 -- 3 mg/day p.o. in 233 bipolar depression patients in the US is complete. The primary endpoint was a change from baseline to 8 weeks in the MADRS total score compared to placebo treatment. Preliminary top-line results showed that the overall difference between the drug-treated and placebo-treated patients was not statistically significant, but evidence of a clinically relevant treatment effect in the high-dose arm was observed. Tolerability results were ‘favorable’: 9% of patients discontinued the study due to adverse events in the high dose study arm [60]. Aripiprazole, a partial D2 and 5HT-1A agonist and 5HT-2A antagonist, was developed as a neuroleptic and has been used extensively for the treatment of psychosis and mania. However, bipolar depression would be a new indication. Two previous trials of 15 mg and 30 mg doses in the acute treatment of bipolar depression found no significant effect on the MADRS outcome measure compared to placebo over 8 weeks. A Phase II trial conducted by Bristol Myers Squibb in conjunction with Osaka demonstrated some efficacy in 362 adults with bipolar depression who had failed to respond to one or more antidepressants. The addition of aripiprazole (2 -- 20 mg/day for 6 weeks) produced a reduction in MADRS total score of -8.8, compared with -5.8 with placebo. Discontinuation rates were 3.3 and 2.3%, respectively (Press release, BMS, 21 May 2007). A multicenter, randomized, double-blind, placebo-controlled study (CN138-149) of aripiprazole 5 -- 30 mg/day p.o. tablet over 8 weeks in 32

the treatment of 420 patients with bipolar I disorder with a major depressive episode in India and the US was withdrawn [61] but it is in Phase III trials in the US for bipolar depression. Dopamine agonists Dopaminergic agents, including bupropion, pramipexole, modafinil and armodafinil, could be useful in the treatment of bipolar depression either as monotherapy or as an add-on therapy [62]. Pramipexole is a D2/D3 agonist with preferential binding affinity to D3 receptors. It was developed for use in Parkinson’s disease at doses ranging from 0.375 to 4.5 mg/day. The optimal dose for depression has yet to be established but there have been two double-blind, placebo-controlled trials of pramipexole as adjunct to mood stabilizers in bipolar depression [62,63]. They demonstrated that the addition of pramipexole resulted in significant improvement in bipolar depression, although the sample size was small (n = 43). Ropinirole (ReQuip) is a D2 agonist that has similarities to pramipexole. It has been reported in case reports to be useful in the treatment of bipolar depression [64,65]. One placebo-controlled study is currently ongoing in Israel [66]. Armodafinil is a single (R) isomer form of modafinil. A double-blind, placebo-controlled, parallel-group, fixeddosage Phase III study (C10953/3072) to evaluate the efficacy and safety of armodafinil 150 and 200 mg/day as adjunctive therapy in 400 adults with major depression associated with bipolar I disorder was carried out in Argentina, Australia, Bulgaria, Canada, France, Poland, S Africa, Spain, Ukraine and the US and was completed in January 2013 [67]. Results showed that armodafinil 150 mg/day did not meet its primary endpoint of efficacy compared with placebo as adjunct therapy to mood stabilizers and/or atypical antipsychotics. 7.3

Serotonin and noradrenaline reuptake inhibitors Milnacipran is a serotonin and norepinephrine uptake inhibitor with antidepressant activity, developed by Pierre Fabre. In a Phase II trial of (n = 132) patients with major depression and bipolar disorder, both milnacipran and imipramine 50 -- 150 mg/day produced comparable improvements in depressive symptoms over a 4-week period, but milnacipran showed an earlier onset of clinical effect with 38.7% of patients responding in 1 week (vs 18.8% for imipramine) (20th CINP (Melbourne), 1996, Abs P-4-11). The third SNRI to be approved by the US FDA for use in MDD, desvenlafaxine, is the primary active metabolite of the most widely prescribed SNRI, venlafaxine [24]. This might prove to be effective in bipolar depression but might be contraindicated in individuals with a high risk of switching. 7.4

Glutamatergic drugs Ketamine is an NMDA antagonist which is thought to potentiate AMPA glutamate and could be effective for bipolar depression as an intravenous infusion or as an intramuscular 7.5




preparation. A small case series suggested that intramuscular ketamine might be useful in bipolar II depression [68]. Ketamine appears to be safe at therapeutic levels, even with repeat doses. AMPA and glycine agonists are also emerging, which may have similarly speedy modes of action. GLYX-13, an NMDA receptor glycine-site functional partial agonist, induces antidepressant-like effects similar to those seen with ketamine, but without acute dissociative effects [69]. Trials in bipolar depression have not been undertaken. Memantine is another NMDA antagonist with limited data to suggest effectiveness in treatment-resistant bipolar depression. It might also improve cognitive performance. GABA-ergic drugs A small open-label trial of pregabalin, an analogue of GABA, suggests efficacy in the acute management of bipolar depression [70], in addition to an antimanic effect. 7.6

Other drugs Several other agents have potential to help people with bipolar depression. Bifeprunox is a partial agonist at the dopamine D2 receptors and the serotonin 5HT-1A receptors. It has been studied in Phase II in 380 subjects receiving 20 -- 40 mg/day, but data have not been reported [71]. A Phase II trial of GSK1014802, a sodium channel antagonist, in bipolar depression is complete but the results have not been published [72]. Riluzole is a sodium channel antagonist that is approved by the FDA for amyotrophic lateral sclerosis. In a small openlabel trial [73], responses were seen in 66% after 5 weeks of treatment at a dose of 200 mg/day. However, high costs of treatment make larger trials unlikely. Many trials for bipolar depression have limitations. RCTs generally include milder, less comorbid cases of the kind not seen in general practice. Also, response and remission rates in mixed states are not always analyzed separately. 7.7

8.

Potential development issues

The major problems facing the development of new antidepressant treatments for bipolar disorder overlap with those facing the development of antidepressants for major depression. These include the lack of valid animal models and heterogeneity as outlined in a recent review [52]. Efficacy, tolerability and speed of action continue to present challenges. However, bipolar depression represents a niche market for emerging antipsychotic, dopaminergic, glutamatergic and gabaergic drugs and for the new application of existing atypical antipsychotics. Adjuvant therapies will also have a place in treatment refractory cases. 9.

Conclusion

unique management challenges: how to effectively manage stubborn treatment resistance without provoking mania or destabilizing the illness over the medium term. There is much potential for trials of new antidepressants and atypical neuroleptics, and drugs with unique modes of action in this context. 10.

Expert opinion

The best management of bipolar disorder is still prevention in many cases, with adequate control of manic episodes. However, we know that most bipolar individuals have poor control over their depressive episodes, many of which are treatment resistant. Bipolar depression can present as a mixed state, which probably requires a different approach to treatment when compared with a more typical depressive episode. Accepting the limitations of published trials to date, exciting new pharmacological approaches for the treatment of bipolar depression are emerging. However, RCTs do not provide sufficient evidence alone, because the participants do not necessarily reflect the reality of bipolar patients seen in clinical practice. Naturalistic trials, such as STEP-BD, are also required. Specialist tertiary and quaternary clinics should continue to examine non-pharmacological approaches to management. Combinations of medications with different modes of action might prove to be more effective and less likely to cause switching than monotherapies. More attention must be paid to the clinical risk factors for antidepressant switching and clinical predictors of poor response. While quetiapine currently has the lead in the treatment of bipolar depression, followed closely by olanzapine in combination with fluoxetine, newer drugs might promise greater efficacy, tolerability and speed of action. Perhaps the most exciting drugs with potential for development are NMDA antagonists and AMPA agonists, combined with existing mono-amine focused treatments in some cases. Small studies suggest that ketamine is effective in bipolar depression and has short time to onset of clinical improvement. However, there is insufficient data to quantify the risk of switching. GLYX-13 seems as effective but better tolerated. Drugs targeted on the glycine receptor may have a promising future. Dopamine agonists such as pramipexole might also confer benefits as adjunctive treatments. Newer SNRIs like desvenlafaxine might have a place for patients deemed to have a lower risk of switching. The evidence that the SNRI milnacipran brought about a speedy recovery in bipolar depression is encouraging. In all cases of emerging treatments for bipolar depression, efficacy must be weighed against the risk of switching and destabilization of the illness in the medium to long term.

Declaration of interest

While first-line treatments of unipolar depression are dominated by generic off-line preparations, bipolar depression has

The authors state no conflict of interest and have received no payment in preparation of this manuscript.


33


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Affiliation

Paul A Keedwell†1,2 MB ChB MRCPsych PhD & Allan H Young3 MB ChB MPhil PhD FRCPsych FRCPC † Author for correspondence 1 Visiting Researcher, Neuroscience and Mental Health Research Institute, Hadyn Ellis Building, Maindy Road, Cardiff CF24 4HQ, UK 2 Institute of Psychiatry, Kings College London, Centre for Affective Disorders, De Crespigny Park, London SE5 8AF, UK Tel: +44 7788448891; E-mail: [email protected] 3 Professor in Mood Disorders, Institute of Psychiatry, Kings College London, Centre for Affective Disorders, De Crespigny Park, London SE5 8AF, UK

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