Bipolar disorders treatment-refractory

Shock Therapy. Insulin coma treatments were used in the early 1900s but offered no tangible improvement. Electroconvulsive therapy (ECT) arose in the 1930s and 1940s and was the hrst treatment to provide some relief from psychosis. However, its effects are only temporary and it proved too costly for continuous use. ECT continues to have some use for life-threatening catatonia, but it is mainly used to treat refractory depression or bipolar disorder. 

Olanzapine (Zyprexa). The olanzapine molecule is structurally very similar to clozapine and therefore exerts very similar effects on brain receptors. The dose range of olanzapine for treating schizophrenia is from 5 to 30mg/day. Like clozapine, olanzapine appears to treat both positive and negative symptoms. It is also approved for the treatment of the manic phase of bipolar disorder. It has also been shown to augment the antidepressant effects of fluoxetine in refractory patients. 

Despite the widespread use of neuroleptics in maintenance treatment of bipolar disorder, there have not been any systematic studies of their suitability for this role. Through clinical experience it has been widely accepted that neuroleptics are useful adjunctive treatments to lithium and related drugs. Treatment refractory patients frequently respond to atypical antipsychotics such as clozapine or risperidone. Such adverse effects as EPS, cognitive dysfunction and weight gain frequently limit the long-term use of classical neuroleptics. For this reason, the atypical neuroleptics such as olanzapine and risperidone should now be considered as alternatives for maintenance treatment. 

The main indications for atypical antipsychotics are the acute and maintenance treatment of schizophrenic disorders, with an emphasis on the treatment of refractory and chronic disorders. However, because of the lower risk of EPS and in particular of tardive dyskinesia, there is a tendency toward a wider range of indications for some of the atypical neuroleptics. Favorable effects in drug-induced psychoses have been demonstrated for olanzapine. Clozapine seems effective in the treatment and relapse prevention of manic episodes and bipolar disorders, and risperidone has been shown to have good efficacy in conduct disorders and in the pervasive developmental disorders. 

Bipolar disorder, manic prophylaxis of bipolar disorder MDD aggressive behavior, conduct disorder adjunct treatment in refractory MDD... 

Faedda GL, Baldessarini RJ, Tohen M, et al Episode sequence in bipolar disorder and response to lithium treatment. Am J Psychiatry 148 1237-1239, 1991 Falkenburg T, Mohammed AK, Henriksson B, et al Increased expression of brain-derived neurotrophic factor mRNA in rat hippocampus is associated with improved spatial memory and enriched environment. Neurosci Lett 138 153-156, 1992 Fallon BA, Campeas R, Schneier FR, et al Open trial of intravenous clomipramine in five treatment-refractory patients with obsessive-compulsive disorder. J Neuropsychiatry Clin Neurosci 4 70-75, 1992... 

Lithium has been proven effective for acute and prophylactic treatment of both manic and depressive episodes in patients with bipolar illness (American Psychiatric Association 2002). However, patients with rapid-cycling bipolar disorder (i.e., patients who experience four or more mood disorder episodes per year) have been reported to respond less well to lithium treatment (Dunner and Fieve 1974 Prien et al. 1984 Wehr et al. 1988). Lithium is also effective in preventing future depressive episodes in patients with recurrent unipolar depressive disorder (American Psychiatric Association 2002) and as an adjunct to antidepressant therapy in depressed patients whose illness is partially refractory to treatment with antidepressants alone (discussed in Chapter 2). Furthermore, hthium may be useful in maintaining remission of depressive disorders after electroconvulsive therapy (Coppen et al. 1981 Sackeim et al. 2001). Lithium also has been used effectively in some cases of aggression and behavioral dyscontrol. 

Clozapine also has been shown to benefit schizoaffective and bipolar patients with treatment-refractory mania ( 54) patients with Parkinson s disease and those with other neurological disorders with psychoses, such as Huntington s disease. Although clozapine has been shown to be an effective agent in the elderly, its usefulness in this population is limited because of its anticholinergic, sedative, cardiovascular, and potentially toxic effects on the bone marrow ( 55). In a study of 12 elderly female psychotic patients on clozapine (maximal daily dose, 300 mg), for example, five were taken off clozapine because of postural hypotension, one had a nonfatal episode of agranulocytosis, and one had leukopenia ( 56). 

Early reports found clozapine to benefit some affectively disordered patients (e.g., bipolar, schizoaffective) who had previously been treatment-refractory, but improved rapidly and significantly on this agent ( 108, 109, 278). Further, many patients were able to sustain their early gains in psychosocial functioning over a 3-5-year period. The low incidence of EPS and TD also increased interest in potentially new indications for these agents. 

The Depakote form of valproic acid is approved for the acute phase of bipolar disorder. It is also commonly used on a long-term basis, although its prophylactic effects have not been as well established. Valproic acid is now frequently used as a first-line treatment for bipolar disorders, as well as in combination with lithium for patients refractory to lithium monotherapy and especially for patients with rapid cycling and mixed episodes. Oral loading can lead to rapid stabilization, and plasma levels must be monitored to keep drug levels within the therapeutic range. 

Patients with bipolar disorders may benefit from risperidone. This has been observed in an open trial of ten patients with rapid cycling bipolar disorder who were refractory to lithium carbonate, carbamazepine, and valproate eight improved after 6 months of treatment. One patient dropped out through non-adherence to therapy and one because of adverse effects (agitation, anxiety, insomnia, and headache) (5). There was a similar beneficial effect in eight adults with moderate to profound mental retardation (6). Risperidone was associated with a significant reduction in aggression and self-injurious behavior, whereas adverse effects were primarily those of sedation and restlessness. 

Vieta E, Gasto C, Colom F, Martinez A, Otero A, Vallejo J. Treatment of refractory rapid cycling bipolar disorder with risperidone. J Clin Psychopharmacol 1998 18(2) 172 1. 

Some cases of psychosis and bipolar disorder refractory to treatment with other anti psych otics... 

Well accepted for use in schizophrenia and bipolar disorder, including difficult cases Documented utility in treatment-refractory cases, especially at higher doses Documented efficacy as augmenting agent to SSRIs (especially fluoxetine) in nonpsychotic treatment-resistant major depressive disorder Documented efficacy in bipolar depression, especially in combination with fluoxetine... 

Patients with bipolar disorder frequently require multiple medications or changes in therapy. For example, antianxiety agents are helpful in reducing anxiety and agitation, especially in patients who refuse antimanic or antipsychotic agents. Likewise an added antipsychotic is more effective than lithium alone in acute manic episodes that include significant psychomotor activity and delusions or hallucinations. Ongoing treatment with antipsychotics after the manic episode is resolved is often not necessary. However, it is not uncommon for a refractory patient to require a combination of mood stabilizers, an antidepressant, and an antipsychotic. 

Giving lithium, carbamazepine, antipsychotics, or benzodiazepines with valproate may augment its antimanic effects. The addition of valproate to lithium may have synergistic effects in treatment-refractory rapid cycling and mixed states, and the combination has demonstrated efficacy in maintenance therapy for bipolar I disorder. ... 

Gupta S, Masand PS, Frank B et al. Topiramate in bipolar and schizoaffective disorder mood stabilizing properties in treatment refractory patients. XXII Collegium Internationale Neuropsychopharmacologicum Conference, Brussels, Belgium, July 2000. 

A 74-year-old man with treatment-refractory bipolar disorder and multiple medical problems, including chronic renal insufficiency (creatinine clearance 26 ml/minute) secondary to type 2 diabetes and lithium, took psychotropic... 

Lamotrigine is approved for the maintenance treatment of bipolar I disorder. It has been used as monotherapy or add-on therapy for refractory bipolar depression. 

Bass EW, Means A, McMillen B Buspirone impairs performance of a three-choice working memory escape task in rats. Brain Res Bull 28 455-461, 1992 Bastani B, Arora RC, Meltzer HY Serotonin uptake and imipramine binding in the blood platelets of OCD patients. Biol Psychiatry 30 131-139, 1991 Bauer MS, Whybrow PC Rapid cychng bipolar affective disorder, II treatment of refractory rapid cychng with high-dose levothyroxine a prehminary study. Arch Gen Psychiatry 47 435-440, 1990... 

Bauer MS, Whybrow PC. Rapid cycling bipolar affective disorder. II. Treatment of refractory rapid cycling with high-dose levothyroxine a preliminary study. Arch Gen Psychiatry 1990 47 435-440. 

Other interventions used for refractory bipolar depressed patients include atypical antipsychotics, thyroid hormones, stimulants (often used in the treatment of attention-deficit/hyperactivity disorder), and phototherapy. Repetitive transcraneal magnetic stimulation (rTMS) and vagal nerve stimulation (VNS) are techniques currently being researched. 

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