Question: Is this an appropriate treatment regimen for an adolescent with bipolar disorder?

Patient’s list of scheduled Medications:

• Abilify 20 mg orally daily at bedtime for mood stability

• Tenex 1 mg orall four times a day for impulsivity

• Trazadone 100 mg orally at bedtime for sleep/depression

• Neurontin 600 mg orally in the morning and 600 mg orally at bedtime for mood stabilization

INTRODUCTION

Bipolar disorder is a lifelong illness with variable course and requires both nonpharmacologic and pharmacologic treatments for mood stabilization. “Patients with bipolar I disorder experience manic and mixed episodes, and nearly always experience major depressive and hypomanic episodes. Bipolar II disorder is marked by at least one hypomanic episode, at least one major depressive episode, and absence of manic and mixed episodes.”

Neurotransmitters play an integral part in both manic and depressive episodes. An increase in catecholamine activity (Dopamine and Norepinephrine) can cause manic episodes, and a decrease can cause depressive episodes. GABA inhibits norepinephrine and dopamine, therefore its deficiency has been proposed to cause mania. An increase in excitatory glutamate and aspartate may be involved in manic episodes. Also, a decrease in serotonin (5HT) has also been linked to depression. Prominent serotonin receptors include 5HT1A and a vasodilator receptor (5HT2A). Other theories involve hypothalamic pituitary adrenal axis dysregulation. The pathophysiology of bipolar disorder is vast, and this can warrant the need for multiple treatments individualized to a particular patient.

RATIONALE FOR USING EACH DRUG FOR BIPOLAR DISORDER

Abilify is a partial agonist at D2 and 5-HT1A receptors and an antagonist at the 5-HT2A receptors. It is indicated for Bipolar 1 disorder and borderline personality disorder. Tenex stimulates α2 adrenergic receptors. This decreases heart rate and it is non-FDA labeled for Tourette’s syndrome (a physical motor dysfunction). Trazodone selectively inhibits serotonin reuptake at the 5HT2a, and is indicated for depression and insomnia. Neurontin has an unknown mechanism of action, but it is indicated as an anticonvulsant and an analgesic. Use of drugs with different actions can be warranted because the exact cause of bipolar is unknown, and its presentation involves several physical and emotional symptoms.

CLINICAL STUDIES VALIDATING USE OF THESE MEDICATIONS TO TREAT BIPOLAR

Keck et al conducted a 3-week, multicenter, double blind placebo-controlled study of the use of Abilify in patients with acute bipolar mania. 262 bipolar patients with manic or mixed episode were randomly given Abilify or placebo, and hospitalized for 2 weeks. Abilify produced a statistically significant response rate of 40% compared to 19% for placebo. It had a greater efficacy than placebo for treatment of bipolar symptoms.

Tenex has not been widely studied for bipolar treatment. A five case behavioral activation study conducted on children and adolescents suggested that Tenex appears to precipitate secondary mania in children.

A case study was done to investigate plasma concentrations of Trazodone in treatment of depression. Out of 32 cases of unipolar depression, 2 cases moved treatment location, 2 cases did not complete the study, and noncompliance occurred in another 2 cases. A total of 12 males and 14 females were assessed. 150mg/d at bedtime for 3 weeks was the dose given. A montgomer-Aberg Depression Rating scale (MADRS) of 10 or less was considered significant, a p-value less than 0.05 was considered statistically significant. Result was an average MADRS scale of 17, and 9 of the cases were significant. The significant groups had a high plasma concentration of Trazodone (> 714ng/ml). In conclusion, the study suggested that a certain level (700ng/ml) of plasma Trazodone concentration may be needed for therapeutic efficacy.

A preliminary open label study was done to determine the efficacy of neurontin in prevention of bipolar disorder. 8 males and 13 females were assessed for one year with a mean age of about 52 years. Patients had bipolar 1 and 2 with remission of both manic and depressive states. Doses of 300 to 2400 mg/day were administered. 5 patients dropped out of the trial by the 6^th month of treatment. The Brief Psychiatric rating scale (BPRS) was a clinical assessment used, and an ANOVA test was used as statistical analysis. Overall, a significant decrease in mean BPRS score was observed with p < 0.05 showing statistically significant difference. BPRS is not specific to bipolar disorder. Therefore, an improvement in the score may not necessarily be valid in this case. These results are statistically significant and does support the potential benefit in bipolar disorder. The study indicates that neurontin should be reserved for bipolar disorder in which traditional therapies are not indicated.

CONCLUSION

The patient is being treated with nontraditional bipolar medications. Abilify can be administered at bedtime to control episodes of mania. A morning dose of neurontin can also be given to prevent remission through the day. Tenex has not been well evaluated in treatment of bipolar disorder and some evidence even suggests that it can possibly induce mania. Therefore, Tenex should be taken out of the patient’s regimen. Trazodone is indicated for insomnia and can be administered at bedtime for this purpose. Efficacy of Trazodone in depression is based on its plasma therapeutic level. Plasma concentration of Trazodone should be examined, and a concentration greater than 700ng/ml should be ensured for therapeutic efficacy. Overall, the progress of the patient needs to be constantly monitored to ensure efficacy of treatment and patient safety.

References

Dipiro J., Talbert R., Yee G., Matzke., Wells B., Posey M. 8^th edition Pharmacotherapy: A Pathophysiology Approach. Bipolar Disorder. Pg 1191

Ralph Kupka. Rapid Cycling Bipolar Disorder: Epidemiology, Pathogenesis, clinical features, and diagnosis. Pubmed. Wolters Kluwer Health. Aug 27, 2012.

Dipiro J., Talbert R., Yee G., et. Al. 8^th edition Pharmacotherapy: A Pathophysiology Approach. Bipolar Disorder. Pg 1193, 1069

Abilify. In: Drugdex [database on the internet]. Greenwood Village (CO): Thomson Reuters Micromedex; 1974-2012 [cited 29 Sept 2012]

Guanfacine Hydrochloride. In: Drugdex [database on the internet]. Greenwood Village (CO): Thomson Reuters Micromedex; 1974-2012 [cited 29 Sept 2012]

Trazodone. In: Drugdex [database on the internet]. Greenwood Village (CO): Thomson Reuters Micromedex; 1974-2012 [cited 29 Sept 2012]

Neurontin. In: Drugdex [database on the internet]. Greenwood Village (CO): Thomson Reuters Micromedex; 1974-2012 [cited 29 Sept 2012]

Keck, Paul E Jr. Marcus, et al. A placebo-controlled, double-blind study of the efficacy and safety of Aripiprazole in patients with acute bipolar mania. A clinical trial. The American Journal of Psychiatry. 2003; 160(9): 1651-8.

Horrigan J p., Barnhill L J. Guanfacine and secondary mania in children. Journal of Affective Disorders. 1999; 54(3): 309 – 14.

Mihara, Kazuo, Yasui- Furukori, et al. Relationship Between Plasma Concentrations of Trazodone and Its Active Metabolite,
m- Chlorophenylpiperazine, and Its Clinical Effect in Depressed Patients. Therapeutic Monitoring. Lippincott Wikins and Wilkins, Inc. 2002; pp 563-566,ISSN 0163-4356.

Mauri, Massimo C., Laini, Valerio, et al. Gabapentin and The Prophylaxis of Bipolar Disorder in patients intolerant to Lithium. Clinical drug investigation. Adis International. 2001; pp 169 – 174, ISSN 1173 – 2563.