dextromethorphan and Mood-Disorders

Major depressive disorder (MDD) is one of the leading causes of disability worldwide. However, many patients do not achieve an adequate clinical improvement with pharmacotherapies targeting monoamine receptors, and the onset of therapeutic benefit typically lags by 4-6 weeks. There is a significant need for mechanistically novel treatments with more rapid efficacy. Combinations of dextromethorphan, an oral N-methyl-D-aspartate (NMDA) receptor antagonist, can potentially fill this gap.. US Clinical Trials registration was systematically searched for studies examining the effects of dextromethorphan in mood disorders. Results were gathered via a PubMed search, adding also press releases, and poster presentations. Two case reports and eight clinical trials were identified for the treatment of MDD or treatment resistant depression (TRD); we also reviewed additional studies in bipolar disorder.. Clinical studies show that the combinations of dextromethorphan with quinidine or bupropion have been effective in decreasing depressive symptomatology in MDD. However, dextromethorphan studies in adults with TRD or with bipolar depression have shown mixed results. The combination of dextromethorphan and bupropion is a well-tolerated, safe, and efficacious treatment option for adults with MDD. Additional studies analyzing the effects of dextromethorphan and bupropion for TRD and bipolar depression are needed.

Topics: Adult; Bipolar Disorder; Bupropion; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant; Dextromethorphan; Humans; Mood Disorders

Fixed-dose dextromethorphan/quinidine capsules (Nuedexta(®)) utilize quinidine to inhibit the metabolism of dextromethorphan, enabling high plasma dextromethorphan concentrations to be reached without using a larger dose of the drug. The drug combination is the first treatment to be approved for pseudobulbar affect (PBA), a condition of contextually inappropriate/exaggerated emotional expression that often occurs in adults with neurological damage conditions, such as amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, traumatic brain injury, Alzheimer's disease or Parkinson's disease. Dextromethorphan/quinidine at the recommended dosages of 20/10 or 30/10 mg twice daily reduced the rate of PBA episodes and improved PBA severity in a 12-week, double-blind, placebo-controlled trial in adults with ALS or MS (STAR), with further improvements in the severity of the condition observed in a 12-week open-label extension phase. Dextromethorphan/quinidine 20/10 mg twice daily also improved PBA secondary to dementia in a cohort of a 12-week noncomparative trial (PRISM II). The drug combination was generally well tolerated in these studies, with no particular safety or tolerability concerns. Although longer-term efficacy and tolerability data for dextromethorphan/quinidine 20/10 or 30/10 mg twice daily would be beneficial, current evidence indicates that it is a useful option in the treatment of adults with PBA.

Topics: Adult; Dextromethorphan; Drug Combinations; Humans; Mood Disorders; Nervous System Diseases; Quinidine

Pseudobulbar affect is characterized by uncontrollable, inappropriate laughing and/or crying that is either unrelated or out of proportion to the emotions felt by the patient and occurs in patients with neurological disorders, such as amyotrophic lateral sclerosis (ALS), multiple sclerosis or traumatic brain injury. Dextromethorphan/quinidine is indicated in the US for the treatment of pseudobulbar affect. Dextromethorphan, when its metabolism is inhibited by the coadministration of quinidine, has been shown to have a positive effect on the symptoms of pseudobulbar affect. Dextromethorphan/quinidine 20 mg/10 mg twice daily was associated with a significantly greater decrease in the rate of pseudobulbar affect episodes per day (primary endpoint) than placebo in the 12-week, randomized, double-blind, placebo-controlled, multicentre STAR trial (Safety, Tolerability, And efficacy Results trial of AVP-923 in PBA [pseudobulbar affect]) involving patients with pseudobulbar affect and ALS or multiple sclerosis. Moreover, the mean change from baseline in Center for Neurologic Study-Lability Scale score at 12 weeks was significantly greater among recipients of dextromethorphan/quinidine 20 mg/10 mg twice daily than those receiving placebo. Dextromethorphan/quinidine 20 mg/10 mg twice daily was generally well tolerated. The drug has been shown to cause dosage-dependent corrected QT interval (QTc) prolongation; however, in the STAR trial, dextromethorphan/quinidine 20 mg/10 mg twice daily appeared to be well tolerated with regard to QTc prolongation.

Topics: Amyotrophic Lateral Sclerosis; Crying; Dextromethorphan; Drug Combinations; Emotions; Female; Humans; Laughter; Male; Mood Disorders; Multiple Sclerosis; Quinidine

Arising in settings of CNS insult, pseudobulbar affect (PBA) consists of uncontrollable episodes of crying or laughter incongruent to the patient's mood. The syndrome has been described by a plethora of names, including pathological laughing and crying, emotional lability, emotionalism and emotional incontinence, which hampers efforts to survey published assessments of pharmacological intervention. Still, until quite recently, all treatment has unavoidably been off-label, chiefly involving antidepressants. Using PBA and other syndrome names as search terms, a PubMed search for English-language case reports and therapeutic trials involving at least five patients identified 22 such publications from 1980 through to 2010. Among the seven randomized, double-blind, antidepressant studies with placebo control, two trials assessed 106 and 123 subjects, respectively. However, the other five assessed only 12-28 subjects, and only one of these seven trials (with 28 subjects) measured change in syndrome severity using a validated scale. The three randomized, double-blind studies of dextromethorphan plus quinidine assessed 129, 150 and 326 subjects. Among these studies, two were placebo-controlled and all three used a validated severity scale. Across all placebo-controlled trials, response to active treatment - either an antidepressant or dextromethorphan/quinidine - has in general been significantly greater than response to placebo, but placebo response has sometimes been substantial, suggesting caution in interpreting uncontrolled findings. In October 2010, dextromethorphan/quinidine received approval from the US FDA as first-in-class PBA pharmacotherapy. Advocates of a continuing role for antidepressants, notably selective serotonin reuptake inhibitors, can point to numerous positive case reports and trials, the potential benefit of attempting to treat PBA and concomitant depression without using multiple drugs, and the ever-present need to tailor treatment to the individual patient.

Topics: Antidepressive Agents; Crying; Dextromethorphan; Drug Combinations; Humans; Laughter; Mood Disorders; Off-Label Use; Quinidine

AVANIR Pharmaceuticals Inc, under license from Irisys Research & Development, is developing AVP-923 (Zenvia, Neurodex) for the treatment of pseudobulbar affect (PBA; in collaboration with Medison Pharma Ltd) and neuropathic pain associated with diabetic peripheral neuropathy. PBA, the main indication of AVP-923, is a neurological disorder characterized by uncontrollable and unpredictable episodes of laughing and/or crying. AVP-923 consists of a combination of the NMDA antagonist/sigma1 receptor agonist dextromethorphan hydrobromide (DM) and the cytochrome P450 2D6 (CYP2D6) enzyme inhibitor quinidine sulfate (Q). DM has been under investigation for several years as a neuroprotective agent in stroke, neurosurgery and amyotrophic lateral sclerosis (ALS); however, it is rapidly metabolized by CYP2D6, reducing the drug's bioavailability at neuronal targets. The inclusion of Q inhibits the rapid first-pass metabolism of DM to increase systemic concentrations of the drug in the plasma and, in theory, increase the potential efficacy. The initial clinical data for AVP-923 in the treatment of PBA demonstrated the combination was effective, but exhibited significant side effects. Of particular concern to the FDA were increased QTc intervals reported in patients dosed with a 30-/30-mg dose of DM/Q. A subsequent phase III clinical trial assessing a lower dose of AVP-923 (20 or 30 mg DM/10 mg Q) for the treatment of PBA in patients with ALS or multiple sclerosis was implemented by AVANIR and demonstrated a favorable safety profile of AVP-923 while maintaining efficacy. Pending approval of the data from the FDA, AVP-923 would be the first FDA-approved treatment for PBA.

Topics: Animals; Clinical Trials as Topic; Dextromethorphan; Diabetic Neuropathies; Drug Combinations; Humans; Mood Disorders; Quinidine

Pseudobulbar affect (PBA), a condition involving involuntary and uncontrollable episodes of crying and/or laughing, occurs frequently in patients with a variety of neurological disorders, including amyotrophic lateral sclerosis (ALS), stroke, traumatic brain injury, dementia including Alzheimer's disease, and multiple sclerosis (MS). Although PBA results in considerable distress for patients and caretakers, it is underrecognized and undertreated. Agents used to treat psychiatric disorders--particularly tricyclic antidepressants and selective serotonin reuptake inhibitors--are useful in alleviating PBA, but act on diffuse neural networks rather than targeting those involved in emotional motor expression. As a result of their nonspecific activity, these agents are associated with a range of unwanted effects that preclude many patients from using them. Dextromethorphan, a common cough suppressant, specifically targets sigma(1) receptors concentrated in the brainstem and cerebellum, thus providing the possibility of targeting regions implicated in emotional expression. When administered in a fixed combination with quinidine, dextromethorphan is effective in treating PBA in patients with ALS, and preliminary results suggest that this therapy also is effective in treating MS-related PBA.

Topics: Adrenergic alpha-Antagonists; Dextromethorphan; Emotions; Excitatory Amino Acid Antagonists; Humans; Mood Disorders; Multiple Sclerosis; Quinidine

Dextromethorphan (DM) is among the most widely used, non-narcotic antitussives, with a predictable safety profile. In 1981, a non-opioid, high-affinity brain recognition site for DM was discovered, and since then a unique neuropharmacological profile has emerged for this 'old' drug , suggesting novel applications. However, an extensive body of research for DM alone in treating various neurological conditions has been inconsistent. This may be largely due to its rapid first-pass metabolism. DM is currently being reintroduced as the active ingredient in a novel combination product in which low-dose quinidine is added to inhibit its breakdown, elevating blood levels of DM and increasing its likelihood of reaching neuronal targets . This has opened new possibilities for therapeutic use; the best evidence at present being for neurological disorders affecting emotional control.

Topics: Affective Symptoms; Biological Availability; Dextromethorphan; Drug Therapy, Combination; Humans; Mood Disorders; Quinidine

Pseudobulbar affect (PBA) is an affective disinhibition syndrome associated with various neuropathologies, which is characterized by involuntary and inappropriate outbursts of laughter and/or crying. The PBA syndrome can be socially and occupationally disabling, and it is largely unrecognized in clinical settings. Validated instruments to distinguish PBA from other disorders of affective regulation exist and could be used to improve recognition of the disorder. There is no pharmacological therapy with a Food and Drug Administration indication for PBA, although antidepressants and dopaminergic agents have been reported to show varying levels of treatment success. Recent evidence suggests that treatment with a fixed combination of dextromethorphan and the cytochrome P450 2D6 enzyme inhibitor, quinidine, can improve PBA. This review describes the clinical and neuropathological features of PBA, and presents an overview of current and future treatment approaches.

Topics: Analgesics, Non-Narcotic; Cytochrome P-450 CYP2D6 Inhibitors; Dextromethorphan; Drug Therapy, Combination; Humans; Mood Disorders; Pseudobulbar Palsy; Quinidine

The functional role of sigma receptors in the central nervous system has been investigated extensively. Sigma1-receptors have been shown to play an important role in antidepressive effects since selective sigma1-receptor agonists, as well as typical antidepressants, reduced the immobility time in the forced swimming and tail suspension tests. The reduction of immobility by sigma1-receptor agonists is antagonized by NE-100, a sigma1-receptor antagonist. It has been suggested that sigma receptors are involved in anxiety since Lu 28-179, a sigma2-receptor agonist, has anxiolytic properties in rodents. In addition to the depressive animal model, phenytoin-sensitive sigma1-receptor agonists such as (+)-SKF-10,047 and dextromethorphan attenuate the conditioned fear stress (CFS) response (which is not influenced by typical anxiolytics and antidepressants) in rodents, the attenuating effects being mediated through phenytoin-sensitive sigma1 receptors, which are closely connected to the mesolimbic dopaminergic systems. Furthermore, neurosteroids such as dehydroepiandrosterone sulfate also attenuate the CFS response, the effect being mediated via sigma1 receptors. These findings suggest that sigma receptors are involved in stress-induced pathophysiological changes such as depression and anxiety and that phenytoin-sensitive sigma1-receptor ligands are useful for the treatment of affective disorders, particularly those considered to be treatment-resistant.

Topics: Animals; Dehydroepiandrosterone; Dextromethorphan; Humans; Ligands; Mood Disorders; Neuropeptide Y; Phenazocine; Receptors, sigma; Sigma-1 Receptor; Stress, Physiological

Reports of rapid-onset but short-duration antidepressant effects in patients with treatment-resistant mood disorders after intravenous administration of ketamine have prompted efforts to find an agent with ketamine's properties that can be administered orally in repeated doses in order to sustain that action. One candidate for this dextromethorphan, and here the pharmacologic mechanism of action is compared and contrasted with that of ketamine.

Topics: Dextromethorphan; Drug Combinations; Excitatory Amino Acid Antagonists; Humans; Ketamine; Mood Disorders; Quinidine

Topics: Antidepressive Agents; Dextromethorphan; Drug Interactions; Humans; Mood Disorders; Pseudobulbar Palsy; Quinidine; Randomized Controlled Trials as Topic