Botulinum Toxin Type A for Pain in Advanced Parkinson's Disease.

Background and Objective Pain is a frequent symptom in Parkinson's disease (PD), and the therapeutic alternatives are scarce. The goal of this trial was to measure the effects of botulinum toxin type A (BTXA) in the treatment of limb pain in advanced PD. Methods A randomized double-blind crossover versus placebo study of BTXA for limb pain in advanced Parkinson's disease was conducted. Subjects received individualized BTXA/placebo dosing per pain distribution in limbs. The primary outcome was a measure of change in global pain on a numeric rating scale (NRS) at 4 and 12 weeks postinjection and on a visual analogue scale 12 weeks after treatment. Secondary outcomes included the percentage of responders, physician-rated clinical global impressions, MDS-UPDRS and PDQ-39 scores, and adverse events. Results A total of 12 subjects completed the trial. Treatment with BTXA (average dose=241.66 U) produced a significant reduction in NRS score 4 weeks after the injections (-1.75 points, range from -3 to 7, p=0.033). However, there was no significant difference compared to placebo (p=0.70). Participants with dystonic pain showed a greater reduction in NRS score after 4 weeks when treated with BTXA (2.66 points vs. 0.75 for placebo). There were no significant differences for any of the secondary outcomes or significant adverse events. Conclusions Targeted BTXA injections were safe in patients with limb pain and advanced PD; however, the present study failed to show a significant effect when compared to placebo. Further studies may be focused on evaluating the effect of BTXA particularly in dystonic pain.

Botulinum Toxin Use in Refractory Pain and Other Symptoms in Parkinsonism.

BACKGROUND: Parkinson's disease (PD) and other parkinsonian syndromes are chronic, progressive neurodegenerative diseases. With advancing disease, both motor and non-motor symptoms represent a considerable burden and symptom relief and quality of life improvement become the main goal of treatment. Botulinum toxins (BTX) are an effective treatment modality for many neurological conditions. METHODS: To understand the potential usefulness of BTX in this population, we performed a retrospective chart review of all patients with a clinical diagnosis of idiopathic PD and atypical parkinsonism who received treatment with BTX injections in our center from 1995 to 2014 for a variety of symptoms. Response to BTX was assessed using a subjective Clinical Global Impression. RESULTS: Records of 160 patients were reviewed. Probable idiopathic PD was the diagnosis in 117 patients (73.1%). The main indication for BTX treatment was pain (50.6% of cases). Other indications were the treatment of functional impairment resulting from dystonia (26.25%), sialorrhea (18.75%), freezing of gait, and camptocormia. Considering pain as indication, 81% of all patients with PD reported benefits after the first BTX injections. This benefit was maintained after the last recorded visit without significant difference in outcome compared with the first injection (p=0.067). Similar results were observed in patients with atypical parkinsonism. CONCLUSIONS: Our results confirm the safety and efficacy of different uses of BTX in the symptomatic treatment of patients with parkinsonism even in advanced stages of the disease, and suggest BTX treatment could have a safe and useful role in the treatment of pain in this population.

The relationship between childhood abuse and suicidality in adult bipolar disorder.

This study evaluates the effect of childhood sexual and physical abuse on suicidality in adults with bipolar disorder. We conducted a retrospective chart review of adult outpatients (N= 381) with DSM-IV-TR-defined bipolar disorder seeking evaluation and treatment at an academic specialty research program (i.e., Mood Disorders Pharmacology Unit, University Health Network, University of Toronto) between October 2002 and November 2005. Eighteen percent (n = 68) of adult patients with bipolar disorder had a recorded history of childhood abuse (p = 0.009). Sixty-three percent (n = 43) of bipolar patients with a history of childhood abuse reported lifetime suicidality (chi2 = 6.885, df= 1, p = 0.009). Logistic regression analysis indicated that Childhood abuse was a significant predictor of lifetime suicidality in adult bipolar patients (OR = 2.05, CI = 1.19-3.510). Childhood abuse is associated with suicidal ideation and suicide attempts in adults with bipolar disorder. Anamnestic inquiry regarding childhood maltreatment is salient to risk assessment, illness management planning, preventative strategies, and treatment interventions in bipolar disorder.

Comparing features of bipolar disorder to major depressive disorder in a tertiary mood disorders clinic.

BACKGROUND: We sought to describe features that distinguish individuals with bipolar disorder from major depressive disorder. METHODS: A retrospective chart review of adult outpatients (N = 1000) seeking evaluation and treatment was conducted at the Mood Disorders Psychopharmacology Unit (MDPU), University Health Network, University of Toronto between October 2002 and November 2005 was conducted. Sociodemographic parameters, illness-characteristics and therapeutic interventions were evaluated and compared. RESULTS: The MDPU referring diagnosis were major depressive disorder (52%), bipolar disorder (29%), and unspecified (19%). Of all individuals with a non-bipolar entry diagnosis (n = 699), 23% (n = 159) were subsequently diagnosed with bipolar disorder (p < 0.001); the majority of whom (n = 117, 74%) received a non-bipolar I disorder diagnosis [e.g. bipolar II disorder (n = 71); bipolar NOS disorder (n = 46) (p < 0.001)]. Higher rates of unemployment/disability, previous depressive episodes, psychiatric hospitalization, comorbid hypertension, and lifetime substance use disorders, as well as an earlier age of illness-onset were more frequently endorsed by individuals with a diagnosis of bipolar disorder. Fifteen percent of individuals who were newly-diagnosed with bipolar disorder reported a history of antidepressant-associated mania. CONCLUSIONS: The majority of individuals with a newly-diagnosed bipolar disorder at this tertiary center have a non-bipolar I disorder (i.e., bipolar spectrum). Several indices of illness severity differentiate individuals with bipolar disorder from major depressive disorder.

Calculated bioavailable testosterone levels and depression in middle-aged men.

BACKGROUND: The association between circulating total testosterone (TT) levels and depressive symptoms remains unclear. We sought to determine the relationship between physiologically active bioavailable testosterone (BT) and depressive symptoms in middle-aged men with and without major depressive disorder (MDD). METHODS: We assessed and compared calculated BT levels in two groups of middle-aged men (40-65 years): untreated subjects meeting DSM-IV-TR-defined criteria for a major depressive episode as part of major depressive disorder (N=44) and a matched non-depressed control group (N=50). RESULTS: Depressed men had lower mean BT levels (3.51+/-1.69 vs. 4.69+/-2.04 nmol/L; p=0.008) and TT levels (11.94+/-4.63 vs. 17.64+/-1.02 nmol/L; p<0.001) when compared to the control group. Biochemical hypogonadism (i.e., BT level< or =2.4 nmol/L or TT level< or =12.14 nmol/L) was also more prevalent in depressed men vs. non-depressed controls (34% vs. 6%, p<0.001; 61% vs. 14%, p<0.001, respectively). CONCLUSIONS: Changes in physiologically active BT concentration may be a vulnerability factor for depressive symptoms in middle-aged depressed men.

Improving outcomes in depression: a focus on somatic symptoms.

BACKGROUND: It is hypothesized that somatic symptom alleviation is a significant predictor of overall outcome in depressed primary care patients. METHODS: Depressed primary care patients (N=205) meeting DSM-IV-TR criteria received open-label antidepressant therapy. The primary symptom measurement tool used was the 17-item Hamilton Depression Rating Scale (HAMD-17), with the Montgomery-Asberg Depression Rating Scale (MADRS) and the Clinical Global Impression Improvement/Severity (CGI-I/S) used as secondary measures. As proxies for somatic symptoms, 8 items from the HAMD-17 (HAMD-S) and 3 items from the MADRS (MADRS-S) that measure somatic symptoms were identified and extracted. RESULTS: There was a significant correlation between improvement on the HAMD-S score and overall reduction on the MADRS total score (r=.766, P<.001), response (r=.594, P<.001), and remission (r=.552, P<.001). Improvement on the MADRS-S also correlated with overall HAMD-17 improvement (r=.782, P<.001), along with response (r=.649, P<.001) and remission (r=.539, P<.001) rates. Both the HAMD-S and the MADRS-S correlated with global improvement as measured by the CGI-I/S (P<.001). CONCLUSIONS: A reciprocal interaction between somatic symptoms and other depressive-symptom domains is implied by this analysis. Clinicians are encouraged to identify, track, and target the somatic symptoms of depressive illnesses.

Measuring the severity of depression and remission in primary care: validation of the HAMD-7 scale.

BACKGROUND: Symptomatic remission is the optimal outcome in depression. A brief, validated tool for symptom measurement that can indicate when remission has occurred in mental health and primary care settings is unavailable. We evaluated a 7-item abbreviated version (HAMD-7) of the 17-item Hamilton Depression Rating Scale (HAMD-17) in a randomized controlled clinical trial of patients with major depressive disorder being cared for in primary care settings. METHODS: We enrolled 454 patients across 47 primary care settings who met DSM-IV-TR criteria for a major depressive disorder. Of these, 410 patients requiring antidepressant medication were randomized to have their symptoms rated with either HAMD-7 (n = 205) or HAMD-17 (n = 205) as the primary measurement tool. The primary outcome was the proportion of patients who achieved a-priori defined responses to 8 weeks of therapy using each instrument. RESULTS: Of the 205 participants per group, 67% of those evaluated with HAMD-7 were classified as having responded to therapy (defined as a > or = 50% reduction from the pretreatment score), compared with 74% of those evaluated with HAMD-17 (p = 0.43). The difference between the groups' changes in scores from baseline (pretreatment) to endpoint was significant (p < 0.001), without a main effect of group (p = 0.84) or group-by-time (p = 0.83) interaction. The HAMD-7 test was brief to administer (e.g., 3-4 min for 85% of the primary care physicians evaluated), which facilitated the efficient and structured evaluation of salient depressive symptoms. INTERPRETATION: The abbreviated HAMD-7 depression scale is equivalent to the HAMD-17 in assessing remission in patients with a major depressive disorder undergoing drug therapy.

Valproate, bipolar disorder and polycystic ovarian syndrome.

BACKGROUND: Persons with bipolar disorder are often overweight and cluster risk factors for cardiovascular disease. Some antibipolar agents adversely impact upon weight and the lipid milieu. Recent data suggest that valproic acid, a commonly prescribed mood stabilizer, may be associated with polycystic ovarian syndrome (PCOS). This adverse event has not been systematically studied in bipolar disorder. METHOD: Thirty-eight female subjects, aged 18-50 years, meeting DSM-IV criteria for bipolar I or II disorder, in any phase of illness were evaluated. Eighteen females received valproate (sodium valproate and valproic acid) and 20 females received lithium. Patients completed questions regarding their menstrual, reproductive and medical histories. During the follicular phase they were assessed for weight, body mass index (BMI kg/m2), and changes in the reproductive endocrine milieu that included morning estradiol, progesterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), sex-hormone binding globulin (SHBG), androstenedione, dehydroepiandrosterone-sulfate (DHEAS), testosterone, free testosterone, prolactin and thyroid-stimulating hormone (TSH). The blood was also analyzed for fasting metabolic parameters which included total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), insulin, glycosylated hemoglobin (HbA1C), insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding-protein 1 (IGFBP-1), fasting blood glucose and morning leptin. RESULTS: Nine (50%) of the valproate-treated females had menstrual abnormalities versus three (15%) of the lithium-treated females (p < 0.05). Valproate-treated females had significantly higher levels of follicular phase androgen concentrations than lithium-treated females (p < 0.05). Nine (50%) of females who were overweight (BMI > or = 25 kg/m2) and with a history of menstrual irregularities also exhibited laboratory evidence of hyperandrogenism (p < 0.05). Persons receiving valproate exhibited significant increases in fasting biochemical parameters suggestive of an adverse metabolic syndrome (p < 0.05). Leptin levels were significantly elevated in the valproate-treated females (p < 0.05). CONCLUSIONS: In this pilot, open-label cross-sectional study, valproate-treated females exhibited higher rates of menstrual abnormalities and biochemical evidence of both hyperandrogenism and adverse metabolic parameters when compared with lithium-treated females. These preliminary data suggest that valproate may, in some predisposed females, adversely impact upon the reproductive endocrine milieu and result in aspects of the metabolic syndrome.

Treating bipolar disorder. Evidence-based guidelines for family medicine.

OBJECTIVE: To provide an evidence-based summary of medications commonly used for bipolar disorders and a practical approach to managing bipolar disorders in the office. QUALITY OF EVIDENCE: Articles from 1990 to 2003 were selected from MEDLINE using the key words "bipolar disorder," "antiepileptics," "antipsychotics," "antidepressants," and "mood stabilizers." Good-quality evidence for many of these treatments comes from randomized trials. Lithium, divalproex, carbamazepine, lamotrigine, oxcarbazepine, and some novel antipsychotics all have level I evidence for treating various aspects of the disorder. MAIN MESSAGE: Treatment of bipolar disorder involves three therapeutic domains: acute mania, acute depression, and maintenance. Lithium has been a mainstay of treatment for some time, but antiepileptic drugs like divalproex, carbamazepine, and lamotrigine, along with novel antipsychotic drugs like olanzapine, risperidone, and quetiapine, alone or in combination, are increasingly being used successfully to treat acute mania and to maintain mood stability. CONCLUSION: Bipolar disorder is more common in family practice than previously believed. Drug treatments for this complex disorder have evolved rapidly over the past decade, radically changing its management. Treatment now tends to be very successful.

What to do if an initial antidepressant fails?

OBJECTIVE: To provide family physicians with practical ways of managing depressed patients responding insufficiently to initial antidepressant treatment. QUALITY OF EVIDENCE: A search of MEDLINE and relevant bibliographies showed most studies could be categorized as level III evidence. Few well controlled studies (eg, level I evidence) specify treatment of next choice in rigorously defined treatment-refractory depression (TRD). MAIN MESSAGE: Failure to achieve and sustain full symptom remission affects relatively few treated depressed patients. Most chronically depressed people are not absolutely resistant but are relatively resistant to treatment; they fail to achieve the goals of treatment because of improper diagnosis or insufficient treatment application. The literature on TRD has largely focused on medication strategies; fewer studies investigated psychosocial approaches. The best established augmentation strategies are lithium salts and triidothyronine (T3). Combination antidepressants have become clinical psychiatrists' preferred treatment, despite limited evidence. Electroconvulsive therapy (ECT) remains a feasible option for TRD, but response rates are poor among people with TRD. High relapse rates after ECT remain a serious and common clinical dilemma. CONCLUSION: Family physicians should familiarize themselves with some new strategies to modify inadequate response to initial antidepressant treatment.

Antipsychotic-induced weight gain: bipolar disorder and leptin.

Novel antipsychotics impart substantial weight gain. Persons with bipolar disorder are frequently treated with these and other agents known to impart substantial weight gain. We sought to describe the influence of adjunctive risperidone and olanzapine on body weight, body mass index (BMI, kg/m2) and serum leptin levels over a prospective observation period of 6 months. Throughout the 6-month investigation, significant increases from baseline to end point in weight were noted with both agents; with significantly greater weight gain with olanzapine (t(10) = 2.761, P = 0.023; t(9) = 4.783, P = 0.001). Leptin levels were highly correlated with increases in weight and were significantly elevated from baseline at 4 months (r = 0.658, P < 0.05). Significant increases in weight and body mass index were apparent at 3 months (P < 0.05). The temporal association between weight increase and leptin changes does not support the notion that leptin is a primary promoter of antipsychotic-induced weight gain; however, a secondary perpetuating role cannot be ruled out.

The antidepressant effects of risperidone and olanzapine in bipolar disorder.

OBJECTIVE: To describe the antidepressant effectiveness of olanzapine and risperidone and compare their tolerability when employed adjunctively in bipolar I/II disorder. METHOD: In an observational study, twenty-one ambulatory subjects with DSM-IV defined bipolar I/II disorder, in any phase of the illness, openly received adjunctive risperidone or olanzapine. The primary efficacy parameters were the Hamilton Depression Rating Scale (HDRS-17) and the Maier and Philips Severity Subscale. Secondary efficacy parameters included the Young Mania Rating Scale (YMRS) along with the Clinical Global Impressions Scale (CGI). Response was defined as a significant change from baseline to endpoint in the total mean HDRS-17 score. The primary tolerability parameters were the Abnormal Involuntary Movement Scale (AIMS) along with changes in weight and body mass index (BMI-kg/m2). Patients were evaluated prospectively with repeated monthly assessments for up to 6 months. RESULTS: Eleven patients openly received risperidone; 10 received olanzapine adjunctive to either lithium or divalproex. Total mean HDRS-17 scores significantly decreased from baseline to endpoint in both groups (p=0.001), with the mean HDRS-17 total scores falling from 17(SD=3.2) to 5(SD=1.5) by 6 months in the risperidone-treated group and from 18 (SD=1.9) to 7 (SD=2.0) in the olanzapine-treated group. Differences between the risperidone-treated group and the olanzapine-treated group were not significant at 6 months (p=0.754). The mean doses of study medication were 2.88 (SD=1.6) mg/day for the risperidone-treated group and 12.69 (SD=2.3) mg/day for the olanzapine-treated group. Both risperidone and olanzapine were generally well tolerated. No patients developed tardive dyskinesia. Significant weight gain was experienced by patients in both groups [mean weight gain at endpoint was 5.9 kg in risperidone (p=0.023) and 11.3 kg in olanzapine (p=0.001)]. There was a significant difference in weight gain between the risperidone-treated group and the olanzapine-treated group (p=0.001). CONCLUSIONS: These pilot data, from the first prospective comparison study of risperidone and olanzapine in bipolar disorder, suggest that adjunctive administration of either agent may reduce depressive symptom severity. No subjects receiving risperidone or olanzapine developed tardive dyskinesia. Both compounds imparted substantial weight gain with significantly more weight gain accrual with olanzapine. As this was an observational study, the antidepressant effect and tolerability profile of these compounds requires validation via double-blind placebo controlled investigations.

Topiramate versus bupropion SR when added to mood stabilizer therapy for the depressive phase of bipolar disorder: a preliminary single-blind study.

OBJECTIVE: Antiepileptic drugs (AEDs) are commonly employed in the treatment of bipolar disorder. The efficacy and tolerability of topiramate, a novel anticonvulsant, and bupropion SR when added to mood stabilizer therapy were compared under single-blind conditions (rater-blinded) in patients meeting DSM-IV criteria for bipolar I/II depression. METHODS: A total of 36 out-patients with Hamilton Depression Rating Scale (HDRS-17) scores > or = 16 were randomized to receive escalating doses of either topiramate (50-300 mg/day) or bupropion SR (100-400 mg/day) for 8 weeks. Data were analyzed on an intent-to-treat basis using the last observation carried forward method. RESULTS: The percentage of patients meeting a priori response criteria (> or = 50% decrease from baseline in mean HDRS-17 total score) was significant for both topiramate (56%) and bupropion SR (59%) [t(17) = 2.542, p = 0.04 and t(17) = 2.661, p = 0.03, respectively]. Baseline demographic and clinical parameters were comparable between the two treatment groups. The mean doses of study medication were 176 mg/day (SD = 102 mg/day) for the topiramate-treated group and 250 mg/day (SD = 133 mg/day) for the bupropion SR-treated group. A significant and comparable reduction in depressive symptoms was observed from baseline to endpoint following topiramate and bupropion SR treatment, according to a > or = 50% reduction in the HDRS-17. Total mean HDRS-17 scores significantly decreased from baseline to endpoint in both groups (p = 0.001), however, differences between the topiramate-treated group and the bupropion SR-treated group were not significant [t(36) = 1.754, p = 0.097]. Both topiramate and bupropion SR were generally well tolerated. Thirteen patients discontinued the study: 2 because of lack of efficacy, 1 due to withdrawal of consent and 10 following side-effects (six in the topiramate and four in the bupropion SR-treated group). There were no cases of affective switch in either arm. Weight loss was experienced by patients in both groups (mean weight loss at endpoint was 1.2 kg in bupropion SR and 5.8 kg in topiramate) [t(17) = 2.325, p = 0.061 and t(17) = 2.481, p = 0.043, respectively]. CONCLUSIONS: These preliminary data suggest that adjunctive topiramate may reduce depressive symptom severity in acute bipolar depression. The antidepressant efficacy of this compound requires confirmation via double-blind placebo controlled investigation.