Bipolar Disorder: Shelton RC

Keck PE, McIntyre RS, Shelton RC. · Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, OH, USA. · CNS Spectr. · Pubmed #18163039 links to  free full text

Abstract: Although certain aspects of bipolar disorder are well understood, there is a need for more information concerning management of acute bipolar depression, the effect of comorbid conditions, and long-term management of bipolar disorder. The outpatient presenting with bipolar disorder often presents with many of the key problems related to the long-term course of the disorder, including misdiagnosis and treatment non-adherence. Depressive symptoms are also prevalent during the course of bipolar disorder, with studies finding that depression can cause a low-grade "darkness" that longitudinally affects outpatients with bipolar disorder. These variable and persistent depressive symptoms may cause severe functional impairment and increased suicidality. Pharmacologic treatment of bipolar disorder typically includes anti-manic and mood-stabilizing medication. Although some studies find antidepressants have some positive effect, researchers have found that antidepressants, including selective serotonin reuptake inhibitors, when used as monotherapy or in conjunction with mood stabilizers, have little benefit for the treatment of bipolar disorder and may increase the likelihood of a switch into mania, hypomania, or mixed episodes. For long-term outpatient treatment, lamotrigine and lithium are proven to be highly effective. However, clinicians should also stress psychosocial treatment approaches, such as cognitive-behavioral therapy, as a principle of chronic disease management for long-term outpatients. Data on pharmacotherapy and psychosocial treatments are emerging, and clinicians should integrate these two treatment options into the standard of care. This expert roundtable supplement focuses on the treatment and management of the bipolar outpatient at risk for a depressive relapse as well as patients experiencing both acute and long-term symptoms of the disorder. Two case studies are presented to elucidate the best practices for the varying clinical states of bipolar disorder.

Shelton RC, Reddy R. · Vanderbilt University, 1500 21st Avenue, South, Suite 2200, Nashville, TN 37212, USA. · Curr Psychiatry Rep. · Pubmed #18980736 No free full text.

Abstract: Depression is much more common in the life course of people with bipolar disorder than mania or mixed states. Unfortunately, few established treatments are available, and new ones are needed. Modafinil is a novel stimulant approved for treating improving wakefulness in patients with excessive sleepiness associated with narcolepsy, obstructive sleep apnea, and shift-work sleep disorder. Given that bipolar depression is commonly associated with fatigue and somnolence, modafinil is a logical choice. In one recent study of moderate size (n = 85), modafinil was shown to be more effective than placebo in treating bipolar depression. The incidence of cycle induction in this trial was very low (lower than placebo), although isolated case reports of mania, hypomania, or mixed states have been reported. Given the limited options for bipolar depression, modafinil should be considered in patients who have not responded to approved treatments, although more research is needed.

Shelton RC. · Department of Psychiatry, Vanderbilt University Medical Center, Nashville, TN 37212, USA. · Expert Rev Neurother. · Pubmed #16466309 No free full text.

Abstract: Bipolar depression remains one of the most difficult to treat of all mental disorders. Until recently, no treatments, including antidepressants, have consistently shown to be effective in this condition. Olanzapine, an atypical antipsychotic, has been approved by the US Food and Drug Administration for the acute treatment of mania and maintenance prevention of relapse into depression or mania. A clinical trial tested the relative effectiveness of the combination of olanzapine and fluoxetine in bipolar type I depression, against olanzapine alone or placebo. The combination produced a very robust clinical effect acutely and a long-term follow-up study indicated that there was a low rate of induction of mania or mixed states. Therefore, the olanzapine/fluoxetine combination represents a viable alternative for bipolar depression. However, uptake of this combined product in practice has been modest. This is likely to be the result of several factors, including resistance to the use of fixed combination preparations and, more recently, evidence of effectiveness of the atypical quetiapine and the anticonvulsant lamotrigine. Perhaps the greatest resistance to the use of olanzapine alone or in combination has been the problem of weight gain and the attendant risk of type 2 diabetes and the metabolic syndrome. Vigorous management of this problem has been shown to mitigate the potential for weight gain and is required if this combination is to be used. However, many clinicians find management of weight gain in olanzapine treated patients a challenge. In addition, weight, waist circumference, lipids and glucose should be monitored.

Shelton RC. · 1500 21 Avenue, South, Suite 2200, Nashville, TN 37212, USA. · Expert Opin Pharmacother. · Pubmed #12831342 No free full text.

Abstract: Depression can occur either with or without alternation with periods of mania. Depression that alternates with mania (bipolar depression) is a particularly difficult problem in clinical practice. The evidence base of the treatment for this condition is not strong and the choices at best are limited. Furthermore, although there are a number of effective antidepressants for the non-cycling variety ('unipolar' major depression), > 50% of patients experience incomplete response to any given drug. Given the proportion of the population involved, these represent fairly sizeable markets. Studies over the last several years indicate that the combination of the novel antipsychotic olanzapine and the serotonin-selective re-uptake inhibitor (SSRI), fluoxetine, may be effective for both conditions. One trial in 28 patients showed that this combination was an effective treatment, compared to the individual components with unipolar depressed patients who had not responded to two antidepressants of different chemical classes. Two subsequent large-scale attempts at replication have resulted in failed trials. Patients randomly assigned to antidepressant monotherapies showed a good response, indicating that the populations being studied were not actually treatment-resistant; therefore, more research is needed. Alternatively, a recent study showed that monotherapy with olanzapine produced a greater effect than placebo in bipolar depression and the combination of olanzapine and fluoxetine yielded an even more robust response. However, important questions remain, e.g., the issue of comparative effectiveness, that is to say, whether the same result could occur with combinations of other novel antipsychotics and SSRIs. In addition, there remain significant concerns regarding the safety and tolerability of olanzapine in these populations. Essential questions about the potential for substantial weight gain, Type II diabetes and for the development of tardive dyskinesia (a syndrome of permanent, disfiguring abnormal involuntary movements) remain. These problems will have to be vigorously addressed in order to achieve a substantial market penetration for these conditions.

Shelton RC. · Vanderbilt University School of Medicine, Nashville, TN, USA. · J Fam Pract. · Pubmed #12676079 No free full text.

This publication has no abstract.

Shelton RC. · Department of Psychiatry, Vanderbilt University, Nashville, Tenn, USA. · J Clin Psychiatry. · Pubmed #10192406 No free full text.

Abstract: Mood-stabilizing drugs including lithium, anticonvulsants, and antipsychotics have established effects in the management of bipolar disorder, especially in mania. However, these drugs also have been shown to be effective in depressed patients. For example, lithium is well established as an effective augmenting strategy with tricyclic antidepressants in refractory depression. This article will review a variety of effects of mood-stabilizing drugs in bipolar and unipolar depressed patients, which will include acute treatment, prevention of relapse and recurrence, and the management of refractory patients. The effects of antipsychotics (especially atypicals) and new research directions also will be reviewed.

Shelton RC, Stahl SM. · Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN 37212, USA. · J Clin Psychiatry. · Pubmed #15641878 No free full text.

Abstract: BACKGROUND: Bipolar depression is a major clinical problem that remains under-researched. The current study was intended to evaluate the effects of the novel antipsychotic risperidone, the selective serotonin reup-take inhibitor (SSRI) paroxetine, and the combination in patients with bipolar disorder. METHOD: Thirty patients with DSM-IV bipolar (I or II) disorder, depressed phase, who were receiving a stable dose of a mood stabilizer were randomly assigned to 12 weeks of double-blind treatment with risperidone (plus placebo), paroxetine (plus placebo), or the combination of risperidone and paroxetine. Data were gathered from August 1999 to September 2001. RESULTS: All 3 groups experienced significant reductions in depression ratings from baseline to endpoint; there were no significant differences in outcome between groups. There were statistically significant differences in paroxetine dose contrasting paroxetine plus placebo against the combined condition. The switch rate into mania or hypomania was very low, with only 1 patient in the paroxetine plus placebo condition experiencing mild hypomania. CONCLUSION: These results suggest that risperidone, paroxetine, and the combination of risperidone and paroxetine are equally but modestly effective when added to a mood stabilizer in bipolar depression. The paroxetine dose differed between groups, possibly because of drug-drug interactions. Using another SSRI in the combined condition could have produced a more robust effect and should be tested.

Mazei-Robison MS, Couch RS, Shelton RC, Stein MA, Blakely RD. · Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232-8548, USA. · Neuropharmacology. · Pubmed #16171832 No free full text.

Abstract: The activity of the presynaptic dopamine (DA) transporter (DAT) is critical in mediating the magnitude and duration of dopaminergic signaling in the brain. Multiple genetic studies have found an association between attention deficit hyperactivity disorder (ADHD) and a variable number tandem repeat (VNTR) in the 3'-untranslated region (3'VNTR) of the hDAT gene (SLC6A3), however none of these studies examined the hDAT coding region for polymorphisms. Thus, we sought evidence of polymorphisms in hDAT, focusing on the coding region and splice junctions, utilizing genomic DNA from children diagnosed with ADHD. Two separate ADHD cohorts (N=70 and N=42) were screened and sampled for both status of the 3'VNTR and for common/novel genomic variants. We found evidence of increased DAT variation in African-American subjects as well as in predominantely hyperactive-impulsive probands. Cumulatively, multiple hDAT sequence variants were identified, including five novel variants, as well as one nonsynonymous single nucleotide polymorphism (SNP), converting Ala559 to Val (A559V). A559V was identified in two Caucasian male siblings with ADHD and both subjects were homozygous for the ADHD-associated, 10-repeat 3'VNTR allele. Interestingly, the A559V variant was previously identified in a subject with bipolar disorder [. Molecular Psychiatry 5, 275], a psychiatric disorder that has a significant number of overlapping symptoms with ADHD.