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This article is a review of the various treatments that are currently available, in particular in France, for the treatment of bipolar disorders. This article specifically addresses the use of novel antipsychotic agents as alternative therapy to a lithium therapy and/or the use of conventional antipsychotics. The prevalence of bipolar disorder over a lifetime is around 1% of the general population. Bipolar disorder consists of alternating depressive and manic episodes. It mainly affects younger subjects, and is often associated with alcohol and drug addictions. There are two main subtypes of bipolar disorder. According to the DSM IV-R, type 1 of bipolar disorder is characterised when at least one manic episode (or a mixed episode) has been diagnosed. Type 2 of bipolar disorder is related to patients enduring recurrent depressive episodes but no manic episode. Type 2 affects women more frequently as opposed to type 1 affecting individuals of both sexes. Manic-depressive disorder (or cyclo-thymic disorder) appears in relation to patients who has never suffered manic episode, mixed episode or severe depressive episode but have undergone numerous periods with some symptoms of depression and hypomanic symptoms over a two-year period during which any asymptomatic periods last no longer than two months. The average age of the person going through a first episode (often a depressive one) is 20 years-old. Untreated bipolar patients may endure more than ten manic or depressive episodes. Finally, in relation to 10 to 20% of patients, the bipolar disorder will turn into a fast cycle form, either spontaneously or as a result of certain medical treatments. Psychiatrists are now able to initiate various treating strategies which are most likely to be effective as a result of the identification of clinical subtypes of the bipolar disorder. Lithium therapy has been effectively and acutely used for patients with pure or elated mania and its prophylaxis. However, lithium medication may worsen depressive symptoms when used for a long term maintenance therapy. Additionally, mixed mania, rapid cycling type patients and bipolar disorder associated with substance abuse do not respond well to lithium therapy. In addition to the lithium therapy or in place of a lithium therapy, one can report the frequent use of antipsychotic agents in respect of patients with bipolar disorder during both the acute and maintenance phases of treatment. Antipsychotic agents have been used for almost forty years and may be used in combination with a lithium therapy. Conventional antipsychotics are effective but they may induce late dyskinesia, weight gain, sedation, sexual dysfunction and depression. These adverse side effects often lead to non compliance in particular in circumstances where antipsychotic agents are combined with a lithium therapy. A number of alternative somatic treatment approaches have been reported for patients who do not respond well or who are intolerant to lithium therapy. As such, valproate has received regulatory approval for the acute treatment of mania and carbamazepine has been indicated for this condition in a number of countries. Divalproex (Depakote) has recently obtained the authorization to market in France and may be prescribed for manic states or hypomanic states that do not tolerate lithium therapy or for which lithium therapy is contraindicated. A number of other anticonvulsants (lamotrigine, gabapentin and topiramate) are currently being tested. Because of the side effects of the conventional antipsychotic agents, atypical antipsychotic agents are currently on trial and appear to be of interest in the treatment of bipolar disorders. Currently, a number of prospective studies are available with clozapine, risperidone and olanzapine in the treatment of bipolar disorder. Most are short-term studies. Recent randomised, double-blind, placebo-controlled studies have shown clozapine, risperidone and olanzapine to be effective with antimanic and antidepressive effects, both as monotherapy and as add-on maintenance therapy with lithium or valproate. They also have a favorable side effect profile and a positive effect on overall functioning. Similarly, valproate combined with antipsychotics provides greater improvement in mania than antipsychotic medication alone and results in lower dosage of the antipsychotic medication. There is currently no double-blind study regarding the use of clozapine for bipolar disorders. However, based on the results of a number of open-label studies, clozapine appears to be effective in relation to schizo-affective and bipolar patients including those with rapid cycling or those who respond inadequately to mood stabilizers, carbamazepine, valproate or conventional antipsychotics. Clozapine seems to be more appropriate for bipolar and schizo-affective patients than schizophrenics. In particular, studies show that patients with manic and mixed-psychotic state of illness are better responders than patients with major depressive syndromes. Four open studies suggest the efficacy of clozapine in the maintenance treatment of bipolar disorder and three prospective, open-label studies show the efficacy of clozapine in the manic state of the illness. However, the number of patients in the studies was not important and these studies are not controlled. Clozapine has also adverse side affects, one of which consisting of a major risk of agranulocytosis and, potentially, death. In addition, clozapine has been shown to produce significant weight gain and sialorrhea as well as significant anticholinergic effects. As a result, clozapine should not be prescribed in the first place. As opposed to clozapine, there are open-label reports and controlled studies in respect of risperidone and olanzapine. Two recent double-blind studies of acute mania found olanzapine to be more effective than placebo. Based on these two studies, olanzapine has recently been approved for the indication of mania. The effects of olanzapine and divalproex in the treatment of mania have also been compared in a large randomized clinical trial. The olanzapine treatment group had significantly greater mean improvement of mania ratings and a significantly greater proportion of patients achieving protocol-defined remission. Significantly more weight gain and cases of dry mouth, increased appetite and somnolence were reported with olanzapine while more cases of nausea were reported with divalproex. The comparison of olanzapine with lithium for the treatment of mania has also been the subject of a double-blind randomized controlled trial. That study shows no differences between the two drugs. While these studies support the idea that olanzapine has direct acute anti-manic effects, a number of authors are of the opinion that olanzapine may have specific prophylactic mood-stabilizing properties. Olanzapine would appear to be effective in the maintenance treatment, as it exhibited both antimanic and antidepressant effects. Systematic trials have shown that risperidone may be effective and safe in the treatment of acute mania, as an add-on therapy with lithium or valproate (open studies and two controlled double-blind studies) and as monotherapy (open studies). In an open, multi-center, 6-month study, risperidone seems to be effective and safe as long-term adjunctive therapy in treatment-resistant bipolar and schizo-affective disorders, with no exacerbation of manic symptoms. Risperidone had few adverse side effects (and where there were any, they were mostly mild), mostly consisting of APS and weight gain. A naturalistic comparison of clozapine, risperidone and olanzapine in the treatment of bipolar disorder suggests that the efficacy and tolerability of the three treatments are similar. One major differentiation factor of these drugs appears to be weight gain, particularly between olanzapine and risperidone. However, this may partially be caused by the use of mood-stabilizing agents. Bipolar and schizo-affective patients now require combination therapy approach because of the cyclic nature of these disorders. Many studies report the combination of mood-stabilizing agents with conventional antipsychotics and atypical antipsychotics. Combination therapies produce a number of adverse side effects. Atypical antipsychotics (other than clozapine) are now rated as first-line agents for adjunctive treatment of mania because they produce less adverse side effects. Atypical antipsychotics are also rated as first-line agents for combined treatment of psychotic depression and they are strongly preferred when an antipsychotic is required for long-term maintenance.
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PMID:[Antipsychotics in bipolar disorders]. 1562 46

The frequency, phenomenology, and risk factors of hallucinations and delusions were investigated in 64 consecutive inpatients with Parkinson's disease. Fifty patients were admitted to our hospital with symptoms related to Parkinson's disease: psychiatric problems 27 (psychosis 22; anxiety 2; depression 2; mania 1): motor symptoms, 20 (wearing-off 5; akinesia 4; freezing 4; postural instability 4; dyskinesia 2; tremor 2; dystonia 1), and sensory symptoms, 3. Fourteen patients were admitted with other medical problems (pneumonia 4; cerebral infarction 3; bone fracture 3; lumbago 2; seizure 1; cat bite 1). Totally 49 patients had psychiatric problems. Psychosis was present in 43 patients, dementia in 10, depression in 8, mania in 1, anxiety in 10, agitation in 6, stereotypy in 2, and hypersexuality in 2. Of the 43 patients with psychoses, 40 presented with visual hallucinations, 18 with auditory hallucinations, and 23 with delusions. To determine what the clinical correlates with the severity of psychosis were, we divided the patients into 3 groups: the severe group, 22 patients admitted because of psychotic symptoms; the mild group, 21 patients admitted because of problems other than psychosis but presenting psychotic symptoms; and the control group, 21 patients who had no psychotic symptoms. Incidences of auditory hallucinations and delusions were higher in the severe group as compared to the mild group. Patients in the severe group had higher Hoehn-Yahr stages, lower Mini-Mental State Examination scores, decreased H/M ratios of cardiac 123I-MIBG uptake, and lower frequencies of background activity on electroencephalograms. There were no differences in age at admission, age at onset of Parkinson's disease, duration of illness, amounts of levodopa and dopamine agonists received, Hamilton's depression rating scores, and brain MR findings, including atrophy and ischemic changes. Emergence of psychotic symptoms in parkinsonian patients appears to be clearly associated with impaired cognitive function. Therefore, it may be associated with the disease process itself. Terms such as dopaminomimetic or levodopa-induced psychosis may not be appropriate when describing psychosis in Parkinson's disease.
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PMID:[Psychoses in patients with Parkinson's disease; their frequency, phenomenology, and clinical correlates]. 1571 92

Aged people are frequently the victims of iatrogenic diseases, especially adverse effects of drugs since they are affected by many age-related diseases and are given many drugs. Geriatric medicine in Japan has a bitter history of having produced many victims by adverse effects of cerebral vasodilators and cerebral stimulants; they included parkinsonism and depression induced by flunarizine and cinnarizine, and Reye-like encephalopathy induced by calcium hopantenate. Parkinsonism induced by sulpiride, tiapride, metoclopramide or atypical anti-psychotics, dyskinesia induced by anti-parkinsonian drugs or anti-psychotics, and psychotic symptoms induced by anti-parkinsonian drugs, anti-cholinergic drugs, anti-depressants or histamine H2 antagonists are still very common. Wernicke encephalopathy caused by intravenous glucose infusion without thiamine, central pontine myelinolysis by too rapid correction of hyponatremia are important though infrequent. Iatrogenic Creutzfeldt-Jakob disease by dura grafts is a warning against the easy use of medical materials produced with human organs or blood. Iatrogenic diseases are preventable, and geriatricians have to pay attention to the information on adverse effects of drugs and medical materials and carefully observe the early signs of iatrogenic diseases.
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PMID:[Iatrogenic neurological disorders in old people: a review]. 1573 50

The treatment of Parkinson's disease (PD) with l-DOPA leads to involuntary movements (dyskinesias). This 6-month observational study in three European countries in PD patients with various degrees of motor complications examined the effects of dyskinesias on the quality of life (QoL) of patients and health care costs. Retrospective and prospective health economic data were collected, and QoL of patients was measured using the Short Form-36 (SF-36) and the PD Quality of Life (PDQL) Scale. Regression analysis was used to estimate the adjusted effects of dyskinesias on QoL and costs, whilst accounting for the potentially confounding effects of disease progression, motor fluctuations and country. Increasing dyskinesia scores on either the Unified PD Rating Scale or the Goetz Dyskinesia Rating Scale were associated with significant reductions in QoL scores on the SF-36 and PDQL Scale. Increasing dyskinesia severity was also associated with increased depression scores on the Montgomery-Asberg Depression Rating Scale along with significant increases in health care costs. The effects of dyskinesia on QoL, depression and costs decreased but remained significant after adjustment for the confounding effects of disease progression and motor fluctuations. In conclusion, dyskinesias may adversely affect QoL and increase health care costs in patients with PD. Future studies should evaluate the potentially beneficial effects in terms of QoL and health care costs of strategies to delay the onset of, or the treatment of, dyskinesias.
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PMID:Effects of dyskinesias in Parkinson's disease on quality of life and health-related costs: a prospective European study. 1632 89

In addition to treating the motor symptoms of Parkinson's disease, the dopamine agonist pramipexole has shown an antidepressant effect. The trials, however, included patients with motor complications, raising the question of whether the antidepressant benefit represented only a treatment-related motor improvement. To address this issue, we have conducted a 14-week randomized trial comparing pramipexole with an established antidepressant in patients without motor complications. At seven Italian centers, 67 Parkinsonian outpatients with major depression but no history of motor fluctuations and/or dyskinesia received open-label pramipexole (at 1.5 to 4.5 mg/day) or sertraline (at 50 mg/day). In both groups, the Hamilton Depression Rating Scale (HAM-D) score decreased throughout 12 weeks of treatment, but in the pramipexole group the proportion of patients who recovered, as defined by a final HAM-D score </= 8,was significantly higher, at 60.6% versus 27.3% (p = 0.006). Patients' self-ratings improved in both groups. All adverse events were mild or moderate, but five patients (14.7%) withdrew from the sertraline group. Despite the absence of motor complications, the pramipexole recipients showed improvement on the Unified Parkinson's Disease Rating Scale (UPDRS) motor subscore. We conclude that dopamine agonists may be an alternative to antidepressants in Parkinson's disease.
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PMID:Pramipexole versus sertraline in the treatment of depression in Parkinson's disease: a national multicenter parallel-group randomized study. 1660 68

We studied 109 consecutive patients who were unselected for freezing of gait (FOG), anxiety, depression, or panic attacks. All patients completed a panic assessment, the Hamilton Anxiety Scale and the Hamilton Depression Scale. Patients were divided into those with FOG or no FOG based on their answer to the FOG question on the Activities of Daily Living part of the UPDRS. Patients with FOG were more disabled, had more "wearing off", dyskinesia, leg dystonia, and postural instability. They were also more anxious and more likely to panic. FOG, in many patients, is increased by anxiety and panic.
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PMID:Are freezing of gait (FOG) and panic related? 1679 96

Deep brain stimulation (DBS) has the unique characteristic to very precisely target brain structures being part of functional brain circuits in order to reversibly modulate their function. It is an established adjunctive treatment of advanced Parkinson's disease and has virtually replaced ablative techniques in this indication. Several cases have been published relating effectiveness in neuroleptics-induced tardive dyskinesia. It is also investigated as a potential treatment of mood disorders. We report on the case of a 62 years old female suffering from a treatment refractory major depressive episode with comorbid neuroleptic-induced tardive dyskinesia. She was implanted a deep brain stimulation treatment system bilaterally in the globus pallidus internus and stimulated for 18 months. As well the dyskinesia as also the symptoms of depression improved substantially as measured by the Hamilton Rating Scale of Depression (HRSD) score and the Burke-Fahn-Marsden-Dystonia-Rating-Scale (BFMDRS) score. Scores dropped for HRSD from 26 at baseline preoperatively to 13 after 18 months; and for BFMDRS from 27 to 17.5. This case illustrates the potential of deep brain stimulation as a technique to be investigated in the treatment of severe and disabling psychiatric and movement disorders. DBS at different intracerebral targets being actually investigated for major depression might have similar antidepressant properties because they interact with the same cortico-basal ganglia-thalamocortical network found to be dysfunctional in major depression.
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PMID:Mood improvement after deep brain stimulation of the internal globus pallidus for tardive dyskinesia in a patient suffering from major depression. 1696 13

Weight loss is frequent in patients with Parkinson's disease (PD). Reduced energy intake and/or increased energy expenditure have been postulated as the cause. Dysphagia, anorexia, and gastrointestinal dysfunction may be possible causes of reduced energy intake; whereas, rigidity, tremor, and levodopa-induced dyskinesia may increase energy expenditure. Levodopa may enhance glucose metabolism resulting in enhanced energy expenditure. Depression, anti-parkinsonian drugs, and medical complications such as pneumonia and malignancies also may facilitate weight loss in PD. Combinations of various degrees of these factors, especially in advanced PD, may produce weight loss. Such weight loss is associated with malnutrition which may precipitate infection and decubitis; accelerate motor, behavioral, and autonomic impairment; consequently spoiling one's quality of life. Attention must be paid as well to motor symptoms to prevent or reverse weight loss in PD patients.
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PMID:Weight loss in Parkinson's disease. 1713 Dec 27

There is a high frequency of dyshidrosis in Parkinson's disease. Daily use of an antiparkinsonian drug does not affect sweating. Mental sweating relates to the contraction period and seriousness. However, hyperthermic sweating does not necessarily relate to the contraction period or seriousness. Abnormalities in mental sweating are not necessarily correlated with cardiovascular autonomic disturbances. As the autonomic disturbance becomes more advanced, dyshidrosis becomes more common. Hyperhidrosis may develop with dyskinesia. Hyperhidrosis may be improved by the temporally administration of levodopa. Dyshidrosis might be caused by a centrally-acting abnormality during its early stage. However, postganglional abnormalities as well as central changes may increase as the disease progresses. The presence of dyshidrosis affects the QOL and depression in patients with Parkinson's disease. The only therapy for hyperhydrotic sweating disorders is the administration of levodopa or dopaminagonist. Additional studies including therapy for sweating disorders are necessary.
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PMID:Sweating dysfunctions in Parkinson's disease. 1713 Dec 28

Parkinson's disease is a common neurodegenerative disorder that can cause significant disability and decreased quality of life. The cardinal physical signs of the disease are distal resting tremor, rigidity, bradykinesia, and asymmetric onset. Levodopa is the primary treatment for Parkinson's disease; however, its long-term use is limited by motor complications and drug-induced dyskinesia. Dopamine agonists are options for initial treatment and have been shown to delay the onset of motor complications. However, dopamine agonists are inferior to levodopa in controlling motor symptoms. After levodopa-related motor complications develop in advanced Parkinson's disease, it is beneficial to initiate adjuvant therapy with dopamine agonists, catechol O-methyltransferase inhibitors, or monoamine oxidase-B inhibitors. Deep brain stimulation of the subthalamic nucleus has been shown to ameliorate symptoms in patients with advanced disease. Depression, dementia, and psychosis are common psychiatric problems associated with Parkinson's disease. Psychosis is usually drug induced and can be managed initially by reducing antiparkinsonian medications. The judicious use of psychoactive agents may be necessary. Consultation with a subspecialist is often required.
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PMID:Parkinson's disease: diagnosis and treatment. 1955 11


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