Adjunct modafinil for the short-term treatment of fatigue and sleepiness in patients with major depressive disorder: a preliminary double-blind, placebo-controlled study

BACKGROUND: Fatigue and sleepiness are primary symptoms of depression that may not resolve with antidepressant therapy. Modafinil is a novel agent that has been shown to improve wakefulness and lessen fatigue in a variety of conditions. In this study, we examined the utility of modafinil as an adjunct therapy to treat fatigue and sleepiness in patients with major depression who are partial responders to antidepressants. METHOD: Patients with partial response to anti-depressant therapy given for at least a 6-week period for a current major depressive episode (DSM-IV criteria) were enrolled in this 6-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter study. Patients received once-daily doses (100-400 mg) of modafinil or matching placebo as adjunct treatment to ongoing antidepressant therapy. The effects of modafinil were evaluated using the Hamilton Rating Scale for Depression (HAM-D), the Fatigue Severity Scale (FSS), the Epworth Sleepiness Scale (ESS), the Clinical Global Impression of Change (CGI-C), and the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36). Adverse events were monitored throughout the study. RESULTS: One hundred thirty-six patients were randomized to treatment, with 118 patients (87%) completing the study. Most patients (82%) were fatigued, and one half of patients (51%) were sleepy. Modafinil rapidly improved fatigue and daytime wakefulness, with significantly greater mean improvements from baseline than placebo in fatigue (FSS) scores at week 2 (p < .05) and sleepiness (ESS) scores at week 1 (p < .01); the differences between modafinil and placebo at week 6 were not statistically significant. Assessment of the augmentation effects of modafinil (HAM-D, CGI-C, and SF-36) did not significantly distinguish modafinil from placebo. Modafinil was well tolerated in combination with a variety of antidepressants. CONCLUSION: Modafinil may be a useful adjunct therapy for the short-term management of residual fatigue and sleepiness in patients who are partial responders to antidepressant therapy.     

Double-blind, placebo-controlled study of entacapone in levodopa-treated patients with stable Parkinson disease

BACKGROUND: The catechol O-methyltransferase inhibitor entacapone acts by extending the elimination half-life of levodopa and is currently approved as an adjunct to levodopa for the treatment of patients with Parkinson disease (PD) with motor fluctuations. OBJECTIVE: To determine if the addition of entacapone administration provides benefit to levodopa-treated PD patients who have a stable response to levodopa and do not experience motor complications. DESIGN: Prospective, double-blind, placebo-controlled trial. SETTING: Outpatient multicenter study. PATIENTS: Female and male patients 30 years or older with idiopathic PD receiving stable doses of levodopa or carbidopa with or without other dopaminergic therapies and who did not experience motor fluctuations were eligible for the study. MAIN OUTCOME MEASURES: Parkinsonian function and quality of life. RESULTS: The addition of entacapone did not improve motor scores on the Unified Parkinson's Disease Rating Scale in levodopa-treated PD patients who did not experience motor fluctuations. The mean +/- SE adjusted change between baseline and final treatment visit was -0.9 +/- 0.35 in the entacapone group and -0.8 +/- 0.35 in the placebo group (P = .83). Significant improvement with entacapone treatment was detected in several quality-of-life measures, including the Parkinson Disease Questionnaire 39, the 36-item Short-Form Health Survey, the Parkinson's Symptom Inventory, and investigator and subject Clinical Global Assessments. The drug was well tolerated by patients in this population. CONCLUSIONS: The catechol O-methyltransferase inhibitor entacapone, used as an adjunct to levodopa in PD patients who do not experience motor fluctuations, does not improve Unified Parkinson's Disease Rating Scale motor scores but does improve a variety of quality-of-life measures.     

Benefits of adjunct modafinil in an open-label, pilot study in patients with schizophrenia

Patients with schizophrenia experience cognitive impairments associated with hypofunctioning of the frontal cortex. Modafinil, a novel wake-promoting agent, works through the sleep-wake centers of the brain to activate the cortex. This 4-week, open-label, pilot study evaluated adjunct modafinil in patients with schizophrenia or schizoaffective disorder. Eleven patients received once-daily oral doses of modafinil (100 mg/day, days 1-14; 100 or 200 mg/day, days 15-28) in addition to antipsychotic therapy. Modafinil significantly improved patients' global functioning as assessed by a blinded clinician (week 2, P = 0.026; week 4, P = 0.012) and the investigator (week 3, P = 0.035). Modafinil significantly improved overall clinical condition, with 64% and 82% of patients rated as clinically improved at week 4 by a blinded clinician and the investigator respectively. Eighty-nine percent of patients considered themselves to be clinically improved. Modafinil significantly improved fatigue (P = 0.025, week 3) and tended to improve cognitive functioning scores. Control of positive symptoms was well maintained. Treatment-emergent adverse events included dry mouth (n = 2) and hallucinations (n = 2). One patient discontinued the study because of hallucinations that were considered to be possibly related to inadequate antipsychotic therapy. Although preliminary, these results suggest modafinil may be an effective and well-tolerated adjunct treatment that improves global functioning and clinical condition, and reduces fatigue in patients with schizophrenia or schizoaffective disorder. Additional controlled studies are warranted.     

Incidence and costs of cardiometabolic conditions in patients with schizophrenia treated with antipsychotic medications

To examine the incidence of cardiometabolic conditions and change in care costs for patients with schizophrenia treated with antipsychotic medications, medical and pharmacy claims from the South Carolina Medicaid program were used to compare the incidence rates for five cardiometabolic conditions in 2,231 patients with schizophrenia who were newly prescribed one of seven antipsychotic medications, using a retrospective cohort design spanning three years. Incidence and cumulative prevalence (pre-existing + incident) rates for the five cardiometabolic conditions were: 10%/23.3% for Type II diabetes mellitus, 7%/13.3% for obesity/excessive weight gain, 17%/20.9% for dyslipidemia, 4.5%/7.3% for high blood pressure, and 15.6%/41.8% for hypertension. After being treated with the antipsychotic medications examined, the odds of developing obesity/excessive weight gain, Type II diabetes mellitus, or dyslipidemia were not significantly related to any specific atypical agent compared to haloperidol. Incidence rates for elevated blood pressure and clinically diagnosed hypertension were higher for patients prescribed ziprasidone (Odds Ratio [OR]=2.41, Confidence Intervals [CI]=1.20-4.85; OR=1.83, CI=1.16-2.90, respectively) relative to those prescribed haloperidol. Cost results indicate significant differences over time in medical service and pharmacy costs in the group which developed incident cardiometabolic conditions. Individuals diagnosed with schizophrenia with moderate prevalence and incidence rates for these cardiometabolic conditions demonstrated substantially decreasing medical care costs over the three years examined, perhaps indicating a widening gap in access to needed services for conditions that are known mortality risk factors.     

A review of the effects of modafinil on cognition in schizophrenia

Modafinil, a wake-promoting agent believed to operate via the hypocretin/orexin system, has a similar clinical profile to that of conventional, dopaminergic stimulants but different biochemical and pharmacological properties. There is increasing interest in the use of modafinil to improve cognition in schizophrenia as well as in other disorders such as attention-deficit/hyperactivity disorder. Recent research has focused on enhancing cognition in patients with schizophrenia because of the association between cognitive performance and functional outcome. Initial findings indicate that modafinil may lead to better executive functioning and attentional performance in patients with schizophrenia. The results further suggest that patient characteristics such as overall current cognitive functioning levels, genetic polymorphisms, and medication status may be important mediators for the effectiveness of modafinil, allowing for future treatment to be targeted to those most likely to benefit. Currently, further research is required to address the potential benefits and risks of chronic administration of modafinil to patients with schizophrenia.     

Double-blind placebo-controlled study of milnacipran in hospitalized patients with major depressive disorders

Fifty-eight inpatients with a DSM-III diagnosis of major depressive disorder participated in a 5-week double-blind trial of milnacipran and placebo. Milnacipran was superior to placebo on all measures of depression. The first index of milnacipran superiority was the difference of dropouts due to treatment failure between milnacipran (10.3%) and placebo (55.2%). All patients were evaluated up to day 14. The improvement with milnacipran was statistically significant at day 14. Side effects were identical for milnacipran and placebo.     

A multicenter, placebo-controlled study of modafinil augmentation in partial responders to selective serotonin reuptake inhibitors with persistent fatigue and sleepiness

BACKGROUND: Up to one half of depressed patients have partial or no response to antidepressant monotherapy. This multicenter, placebo-controlled study evaluated the efficacy of modafinil augmentation in major depressive disorder (MDD) patients with fatigue and excessive sleepiness despite selective serotonin reuptake inhibitor (SSRI) monotherapy. METHOD: Patients (18-65 years) with a DSM-IV diagnosis of MDD and partial response to SSRI monotherapy (> or = 8 weeks) at a stable dose for > or = 4 weeks were eligible. Patients had screening/baseline 31-item Hamilton Rating Scale for Depression (HAM-D) scores of 14 to 26, Epworth Sleepiness Scale (ESS) scores > or = 10, and Fatigue Severity Scale (FSS) scores > or = 4. Patients were randomly assigned to augmentation therapy with modafinil 200 mg/day or placebo for 8 weeks. Assessments included the ESS, Clinical Global Impressions-Improvement scale (CGI-I), 31- and 17-item HAM-D, FSS, Brief Fatigue Inventory (BFI), and Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: Of 311 enrolled patients who received > or = 1 dose of study drug, 158 were randomly assigned to modafinil (70% women) and 153 to placebo (72% women); 85% of each treatment group completed the study. At final visit, modafinil significantly improved patients' overall clinical condition compared with placebo on the basis of CGI-I scores (p = .02), and there were trends toward greater mean reductions in ESS, 31- and 17-item HAM-D, and MADRS scores versus placebo. Modafinil significantly reduced BFI scores for worst fatigue at final visit (p < .05 vs. placebo). There were no significant differences between modafinil and placebo at final visit in FSS or BFI total scores. Adverse events significantly more common during modafinil compared with placebo treatment were nausea (9% vs. 2%; p = .01) and feeling jittery (4% vs. 1%; p = .03). CONCLUSION: These findings suggest that modafinil is a well-tolerated and potentially effective augmenting agent for SSRI partial responders with fatigue and sleepiness.     

Normal P50 suppression in schizophrenia patients treated with atypical antipsychotic medications

OBJECTIVE: Patients with schizophrenia have deficits in attention, cognition, and information processing. Measures such as P50 suppression are used to study cognitive and attentional dysfunction among these patients. P50 suppression is an operational measure of sensory gating that can be assessed by averaging electroencephalographic responses to multiple pairs of auditory clicks separated by 500 msec. Normally, the P50 response to the second click is smaller than the response to the first click. Many studies have demonstrated that schizophrenia patients have deficient P50 suppression, meaning that the difference between the first and second clicks is not as large as normal. Atypical antipsychotic medications may have superior clinical efficacy for negative symptoms and cognitive deficits. It is important, therefore, to evaluate the effects of atypical antipsychotic medications on measures such as P50 suppression. METHOD: P50 suppression of 13 patients with schizophrenia receiving clinically effective doses of clozapine, olanzapine, or risperidone (classified as atypical antipsychotic medications) was compared to that of 13 patients receiving conventional antipsychotic medications. RESULTS: The patient groups did not differ on clinical or demographic measures. The patients receiving atypical antipsychotic medications had normal-range P50 suppression (mean=72%). In contrast, the patients receiving typical antipsychotic medications had dramatically lower P50 suppression (mean=27%). CONCLUSIONS: The results support the hypothesis that patients treated with atypical antipsychotic medications have normal P50 measures of sensory gating. Longitudinal within-subjects studies are warranted to clarify the mechanisms mediating this effect.     

The effect of modafinil on cortical excitability in patients with narcolepsy: A randomized,placebo-controlled,crossover study

ObjectiveTo investigate the effect of modafinil on cortical excitability in patients with narcolepsy using transcranial magnetic stimulation (TMS).MethodsNineteen drug-naïve narcolepsy patients with cataplexy (10 males, 9 females, and mean age 28.5 years) and 25 age- and sex-matched healthy controls were recruited. In this double-blind, randomized, crossover study, patients and controls received a single dose of 400 mg modafinil or placebo. Modafinil and placebo administrations were separated by a 2-week washout period. TMS parameters, such as resting motor thresholds (RMT), motor-evoked potential (MEP) amplitudes, cortical silent periods (CSP), short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF), were measured before and 3 h after administering modafinil or placebo. The differences of TMS parameters were statistically tested between patients and controls and between before and after modafinil or placebo administration.ResultsNarcolepsy patients had significantly increased CSP durations compared to controls (independent t-test, P < 0.05), indicating decreased excitability of cortical networks in human narcolepsy. In patients after modafinil administration, MEP amplitudes, SICI, and ICF increased, and CSP duration shortened significantly, meaning enhanced motor excitability, whereas in controls modafinil did not change TMS parameters significantly. Placebo administration did not affect TMS parameters both in patients or controls.ConclusionsNarcolepsy patients with cataplexy showed decreased cortical excitability than normal healthy controls. Single dose modafinil significantly increased motor excitability in narcolepsy patients but had no effect in healthy controls.     

Double-blind, crossover, placebo-controlled trial of bromocriptine in patients with sleep bruxism

This study was designed to assess the effects of bromocriptine, a dopamine D2 receptor agonist, on sleep bruxism. Seven otherwise healthy patients with severe and frequent sleep bruxism participated in this randomized, double-blind, placebo-controlled study. The study used a crossover design that included 2 weeks of active treatment or placebo with a washout period of 1 week. To further evaluate whether bromocriptine influences striatal D2 receptor binding, we used iodine-123-iodobenzamide single photon emission computed tomography (SPECT) under both placebo and bromocriptine regimens. Bromocriptine did not reduce the frequency of episodes of bruxism during sleep (mean +/- SEM, 9.0 +/- 1.0 and 9.6 +/- 1.5 bruxism episodes per hour for placebo and bromocriptine, respectively) or the amplitude of masseter muscle contractions (root mean square values, 48.2 +/- 15.5 microV and 46.9 +/- 12.7 microV for placebo and bromocriptine, respectively). SPECT also failed to reveal that either treatment had any influence on striatal D2 binding (values for total binding in counts/pixel, 1.80 [1.72-1.93] and 1.79 [1.56-1.87] for placebo and bromocriptine, respectively). This study shows that a nightly dose of bromocriptine does not exacerbate or reduce sleep bruxism motor activity.     

Double-blind placebo-controlled trial with flunarizine in therapy-resistant epileptic patients

The anticonvulsant efficacy and side-effect liability of flunarizine (15 mg/day) was investigated in a randomized, double-blind, placebo-controlled, crossover design in 30 outpatients with drug-resistant complex partial seizures. Flunarizine or placebo was added to the preexisting medication and each patient was followed up for 10 months. At the end of the study data from 22 patients were available for evaluation. In patients taking first flunarizine and then placebo, plasma levels of flunarizine were still detectable at the end of the 4 months' placebo phase. In the group of 13 patients starting therapy with placebo, a significant seizure frequency reduction was observed during the flunarizine period in 11 patients, whereas one patient showed no change and seizure frequency increased in another patient. Two patients had a 50% reduction in seizure frequency. Flunarizine was well tolerated and few side effects were noted.     

精神分裂症患者认知异常的事件相关电位研究

目的探讨精神分裂症患者失匹配负波（mismatch negativity,MMN）的特征及药物对MMN的影响。方法对31例精神分裂症患者（研究组）和30名健康被试（对照组）行MMN的检测,并比较首发未用药组与已用药组MMN潜伏期、波幅的差异。结果（1）研究组和对照组Fz,Cz,Pz点均可见较明显MMN波形,精神分裂症组波形欠规则。（2）研究组Fz、Cz、Pz点的MMN潜伏期较对照组差异无统计学意义（t=0．74,0．09,0．63;P〉0．05）;三点波幅降低,较对照组比较差异具有统计学意义（t=5．04,5．83,4．47;P〈0．05）。（3）首发未用药病患组12例和已接受药物治疗的病患组19例,在Fz、Cz、Pz点MMN潜伏期、波幅,差异均未见统计学差异（t=0．59,1．17,1．73,1．88,1．12,0．90;P〉0．05）。结论精神分裂症患者认知功能受损,且MMN是一个稳定的素质性指标,不受药物影响。     

Double-blind, placebo-controlled, fixed dose trial of minaprine in patients with major depression

Minaprine dihydrochloride is a novel psychotropic drug possessing both antidepressant and psycho-stimulant properties. Prior clinical studies have shown minaprine to be as effective as standard antidepressant agents in the treatment of endogenous depression. The present study examined the safety and efficacy of minaprine at four different doses compared to placebo in 190 outpatients with major depression. Overall, minaprine demonstrated a significant antidepressant action compared to placebo, which was most evident at the maximum dose of 400 mg daily. These data, together with a favorable side effects profile, suggest that minaprine may be an effective antidepressant agent for the treatment of major depression.     

Double-blind,placebo-controlled study of L-carnosine supplementation in children with autistic spectrum disorders

L-Carnosine, a dipeptide, can enhance frontal lobe function or be neuroprotective. It can also correlate with gamma-aminobutyric acid (GABA)-homocarnosine interaction, with possible anticonvulsive effects. We investigated 31 children with autistic spectrum disorders in an 8-week, double-blinded study to determine if 800 mg L-carnosine daily would result in observable changes versus placebo. Outcome measures were the Childhood Autism Rating Scale, the Gilliam Autism Rating Scale, the Expressive and Receptive One-Word Picture Vocabulary tests, and Clinical Global Impressions of Change. Children on placebo did not show statistically significant changes. After 8 weeks on L-carnosine, children showed statistically significant improvements on the Gilliam Autism Rating Scale (total score and the Behavior, Socialization, and Communication subscales) and the Receptive One-Word Picture Vocabulary test (all P < .05). Improved trends were noted on other outcome measures. Although the mechanism of action of L-carnosine is not well understood, it may enhance neurologic function, perhaps in the enterorhinal or temporal cortex.     

Effect of psychotropic medications on seizure control in patients with epilepsy

Psychiatric problems are frequently encountered in patients with epilepsy. In an adult clinic population of 2,000 patients, 219 were identified as having been treated with psychotropic medication (PTM). Of these, 59 patients had adequate documentation of seizure frequency 2 months prior to and 2 months during treatment with PTMs. Contrary to many reports, most patients experienced better seizure control on PTM therapy. This demonstrates that most patients will not have an increased frequency of seizures when psychotropic medication is used in low to moderate doses and is introduced slowly.