Emerging Trends: Novel Molecular Targets and Moving Beyond Acute Symptoms in Bipolar Depression

Eduard Vieta, PhD

Department of Psychiatry, the Bipolar Disorders Program, and the Clinical Institute of Neuroscience, University of Barcelona, Barcelona, Spain

The main unmet need in the management of bipolar disorder is the lack of available optimal treatment options for bipolar depression. Currently, antidepressants, antipsychotics, and mood stabilizers are commonly prescribed for this condition. New agents are needed that improve remission rates and prevent new episodes, have fewer side effects than existing treatments, and are effective on the core symptoms of bipolar disorder, as well as on cognition, functioning, and physical health. Ideally, these new agents will prevent the high mortality rates associated with cardiovascular disease and suicide in bipolar disorder and promote treatment adherence through greater tolerability. Researchers are currently investigating a number of novel treatment targets, particularly the glutamatergic system, among others, in an attempt to develop a drug that will address these unmet needs in the management of bipolar disorder.

Current Treatments for Bipolar Disorder

Antidepressants. A decade ago, antidepressant monotherapy was the most commonly prescribed treatment for bipolar disorder,1 despite insufficient evidence of efficacy for this condition. The ISBD recently convened an international task force of experts to develop consensus recommendations on using this class of agents for bipolar disorder;2 they determined that antidepressant use should be restricted in most patients.

Evidence suggests that clinical practice might be catching up somewhat with expert recommendations. The WAVE-bd study3 (N = 2,896) found that, in parts of Europe and South America, antipsychotics were the most commonly prescribed agents for all phases of bipolar I disorder and for hypomanic phases of bipolar II disorder. However, antidepressants were used nearly as often as antipsychotics for the depressive phase of bipolar I disorder, and they continued to be the most frequently prescribed drugs for depressive and euthymic phases of bipolar II disorder.4 For antidepressant use to further decrease, new treatments for bipolar depression may need to become available.

Antipsychotics. The evidence base for the efficacy of some antipsychotics in bipolar disorder is much stronger than that for antidepressants.5 The mechanisms by which antipsychotics derive their efficacy are not fully understood, but several neurotransmitter systems appear to be involved.6,7 As a class, antipsychotics can antagonize dopamine receptors and multiple serotonin receptors, and they have other varying actions at serotonin receptors as well, including partial agonism of 5-HT1A and antagonism of 5-HT2C and 5-HT7 receptors. Some of the action at serotonin receptors actually modulates dopamine outflow in the prefrontal cortex rather than affecting serotonin, and this dopaminergic mechanism is believed to contribute to the therapeutic effect in bipolar depression (AV 1).7,8

AV 1. Potential Mechanisms of Action of Atypical Antipsychotics Effective for Bipolar Depression (00:46)

Data from Yatham et al7 and Ishibashi et al8

The atypical antipsychotics aripiprazole and ziprasidone have shown some efficacy for bipolar depression early in treatment, but after 6 weeks, only quetiapine, lurasidone, and the olanzapine/fluoxetine combination, the only FDA-approved agents for the treatment of bipolar depression, have been shown to have benefit.5 To find out more on approved treatments for bipolar depression, read “Acute and Maintenance Treatments for Bipolar Depression.”

Mood stabilizers. The WAVE-bd study4 also showed that mood stabilizers, including lithium, valproic acid, carbamazepine, and lamotrigine, are commonly used to treat depressive episodes in bipolar disorder. Note that these drugs are not FDA-approved for acute depressive episodes, and the evidence base for their use in bipolar depression is limited.

The therapeutic effect of mood stabilizers is believed to be related to their ability to affect glutamate.9 Glutamate is the main excitatory neurotransmitter in the brain, is involved in most aspects of learning and behavior, and is necessary for neural plasticity. Impairments of the glutamatergic system are believed to be involved in the pathophysiology of mood disorders, and excess glutamate has been found to have a neurotoxic effect (AV 2).9,10 Lithium and valproate decrease excessive glutamate by modifying the expression of the vesicular glutamate transporter, glutamate presynaptic release, and glutamate intake through postsynaptic receptors. Lamotrigine and carbamazepine inhibit glutamate release.9,11

AV 2. Glutamate Neurotransmission (00:48)

From Sanacora et al9 and Krystal et al10

Novel Treatments

Research into novel agents that will more safely and effectively treat bipolar depression is ongoing. The mechanisms of action of some of these treatments are similar to those of existing agents, like dopamine agonism and glutamate regulation, but others are quite different.

Glutamatergic modulators. Glutamatergic modulators include ketamine, lanicemine, N-acetyl cisteine, and riluzole. Ketamine increases glutamate release while simultaneously blocking NMDA receptors. The extra glutamate then favors AMPA receptors over NMDA receptors, which has been found to exert a rapid antidepressant effect.9 A drawback of ketamine is that it is typically administered by infusion. Two studies12,13 found that patients with bipolar depression who received an adjunctive intravenous infusion of ketamine experienced significant improvement in depressive symptoms within 40 minutes, per MADRS scores. However, these effects were relatively short-lived, remaining significant for only 3 days. The most common adverse event was dissociative symptoms.

Lanicemine is another glutamate modulator that has a similar mechanism of action to ketamine, but, unlike ketamine, it is a low-trapping NMDA antagonist, which reduces the risk of psychotomimetic side effects associated with ketamine. A study14 of patients with treatment-resistant depression who received intravenous lanicemine found significant improvement in their depressive symptoms 80 minutes after the infusion, but these effects only lasted 110 minutes per MADRS scores and 2 days per HDRS scores. No dissociative or psychotomimetic symptoms were reported.


N-acetyl cysteine is a derivative of cysteine, which is the precursor of the antioxidant glutathione. Treatment with N-acetyl cysteine has been found to increase glutathione levels in the brain, which may exert a neuroprotective effect against neurotransmitter defects, such as glutamatergic hypofunction.15 One study15 found that patients with bipolar disorder receiving adjunctive N-acetyl cysteine experienced significant improvement in depressive symptoms (P = .002) over 24 weeks relative to placebo, and no significant differences in adverse events were observed between groups.

Riluzole, which is an FDA-approved treatment for amyotrophic lateral sclerosis, is an anticonvulsant and neuroprotective agent that modulates the glutamatergic system by inhibiting the release and enhancing reuptake of glutamate.9 Riluzole also stimulates brain-derived neurotrophic factor and enhances AMPA receptor plasticity.16 In a small study,17 patients with bipolar disorder experiencing an acute depressive episode were treated with riluzole added to lithium. The study found that riluzole treatment was associated with significant improvement in depressive symptoms (P = .0007), with no incidence of serious adverse events.

Dopamine agonists and psychostimulants. The role of dopamine is gaining attention in the pathophysiology and treatment of bipolar disorder. The motor symptoms of bipolar disorder, which can range from virtual catatonia to hyperactivity as well as the anhedonia/loss of motivation that are typical of bipolar depression, point to dysfunction of the dopaminergic system.18

Pramipexole is a D2/D3 receptor agonist approved for the treatment of Parkinson’s disease.18 Pramipexole preferentially binds to D3 receptors, which may contribute to its safety and efficacy in depression. Further, pramipexole is thought to have neurotrophic properties, which may be beneficial for treating the impairments of cellular plasticity that are now understood to be associated with severe mood disorders. A study18 found that bipolar II disorder patients in a depressive episode receiving pramipexole in addition to a mood stabilizer experienced significantly greater improvement in depressive symptoms compared with those receiving a mood stabilizer plus placebo (P = .03). Pramipexole was well tolerated and was not found to confer a risk of switching into mania or hypomania. Another small study19 of adjunctive pramipexole showed efficacy for bipolar depression, although 1 patient did develop hypomania. Lisdexamfetamine is another dopamine agonist that is being investigated for bipolar depression, but trials are still ongoing.

Modafinil and armodafinil are stimulant-like drugs that are approved for treating excessive sleepiness associated with several disorders. Although these drugs act similarly to stimulants, they have a more selective mechanism of action and less abuse potential.20 Modafinil and armodafinil are thought to act as dopamine reuptake inhibitors.21 Frye and colleagues20 found that patients with bipolar II depression receiving adjunctive modafinil experienced greater improvement in depressive symptoms as measured by IDS scores relative to placebo (P = .038). Incidence of side effects and treatment-emergent mania were similar between groups. Similarly, Calabrese et al22 found that adjunctive armodafinil was significantly more effective than placebo for reducing IDS scores (P = .044) in patients with bipolar I disorder who were experiencing a depressive episode. The most common side effects with armodafinil were headache, diarrhea, and insomnia, but no increase in the incidence of mania was observed. Subsequent studies of armodafinil in bipolar depression did not provide compelling evidence of efficacy, so the manufacturer is not pursuing an indication.

Other agents. Several other agents with differing mechanisms of action are being investigated for bipolar depression, but research is ongoing and evidence of their efficacy is still needed. For example, the protein kinase C inhibitor tamoxifen has been tested only in bipolar mania, and SB216763, a glycogen synthase kinase-3 inhibitor, is still in the preclinical stages of research. Ramelteon is a melatonin agonist that has shown some benefit in reducing depressive symptoms in bipolar I patients.23 Inositol, a carbohydrate found in foods and in the body, is a precursor of the phosphatidylinositol second messenger system, which is involved in neurotransmission at several receptors. Inositol has been found to be depleted in the CSF of patients with bipolar and unipolar depression, and treatment with adjunctive inositol has been studied in patients with bipolar depression but results were mixed.24

AV 3. Educating a Patient About Current and Future Treatment Options for Bipolar Depression (03:54)

Conclusions and Considerations for Selecting Maintenance Treatment

Bipolar disorder is a lifelong condition, and careful selection of maintenance treatment is therefore critical. The goals of maintenance treatment should be to prevent relapses and recurrences while ensuring that the treatment is tolerable over the long term (AV 3). Unfortunately, one meta-analysis25 found a limited number of options for maintenance treatment and a paucity of evidence on which to base long-term treatment recommendations for patients with an index episode of bipolar depression. This finding underscores the need for new and better treatments for bipolar depression that are effective not only for acute episodes but also for long-term treatment. The efforts currently underway investigating novel therapeutic targets, such as dopaminergic and glutamatergic pathways, may hold the most promise for finding new treatments. Hopefully, clinicians can move away from traditional antidepressants and antipsychotics, due to insufficient efficacy and adverse effects, and move toward novel compounds that are safer and more effective in both acute and long-term treatment.

Clinical Points

  • Avoid using antidepressants in most patients with bipolar disorder
  • Understand the role of agents with dopaminergic or glutamatergic mechanisms in the treatment of bipolar depression
  • Stay abreast of research results to select treatments with established efficacy for both the acute and maintenance phases of the illness

Drug Names

acetyl cystene (Acedote and others), aripiprazole (Abilify), armodafinil (Nuvigil and others), carbamazepine (Tegretol, Epitol, and others), ketamine (Ketalar and others), lamotrigine (Lamictal and others), lisdexamfetamine (Vyvanse), lithium (Lithobid and others), lurasidone (Latuda), modafinil (Provigil and others), olanzapine (Zyprexa and others), olanzapine/fluoxetine (Symbyax), pramipexole (Mirapex and others), quetiapine (Seroquel and others), ramelteon (Rozerem), riluzole (Rilutek and others), tamoxifen (Soltamox and others), valproic acid (Depakene and others), ziprasidone (Geodon and others)


5-HT = serotonin, AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, CSF = cerebrospinal fluid, FDA = US Food and Drug Administration, HDRS = Hamilton Depression Rating Scale, IDS = Inventory of Depressive Symptoms, ISBD = International Society for Bipolar Disorders, MADRS = Montgomery-Asberg Depression Rating Scale, NMDA = N-methyl-d-aspartate, WAVE-bd = Wide AmbispectiVE study of the clinical management and burden of Bipolar Disorder


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