Daytime Sedation Research Articles

Managing insomnia in Elderly patients: Evidence-based treatment approaches

Elderly patients (EP) often have Chronic Sleep (CS). Although elders are among the categories with the highest need for therapy, these EP are often seen as challenging to treat. This study offers a thorough the studies on the therapy of persistent insomnia in EP with an emphasis on Evidence-Based (EB) therapeutic strategies. Meta-Analyses (MA), EB evaluations of therapy modalities, randomized controlled trials of Non-Pharmacologic (NP) treatment, and the features and treatment of insomnia were all criteria for selecting publications. MA, EB on solid, and studies including pertinent new data were given preference. When NP gets closer, the field is on their side. Among the medications used to treat insomnia include sedating antidepressants, barbiturates, OTC, prescription, and chloral hydrate antihistamines, as well as OTC and OTC nutritional supplements and cognitive behavioral therapy (CBT). SH drugs, including Benzodiazepine (BZD), Non-Benzodiazepine (NB), and melatonin agonists. NP therapies for insomnia in people of all ages have a large body of research supporting their efficacy and durability, yet still need to be addressed. With a few notable exceptions, the bulk of pharmacological trials found was of short length and did not just include EP as participants. The Non-benzodiazepine Sedative Hypnotics (NSH) proved to have minor, if any, substantial therapeutic benefits in effectiveness or tolerability in EP compared to BZD. Melatonin agonists are among the newer medicines with unique mechanisms of accomplishment and better security profiles that show promise for treating Chronic Insomnia (CI) in EP. There is no strong evidence base for the long-term use of sedative hypnotics (SH) to treat insomnia, and this practice has historically been discouraged because of concerns about possible adverse effects such as cognitive impairment, daytime sedation, motor incoordination, and an increased risk of falls and car accidents. The most effective management technique for senior people with CI will need more study to establish the extended-term consequences of therapy.

The Utility of Betahistine Dihydrochloride, a Structural Analog of Histamine, in Clozapine-associated Daytime Sedation: A Case Series

The Utility of Betahistine Dihydrochloride, a Structural Analog of Histamine, in Clozapine-associated Daytime Sedation: A Case Series

Daridorexant, an Orexin Receptor Antagonist for the Management of Insomnia.

Insomnia is a common sleep disorder that is diagnosed primarily by patients' subjective reported symptoms. Daridorexant is a new dual orexin receptor antagonist that was recently approved by Food and Drug Administration for insomnia characterized by difficulty falling asleep and/or maintaining sleep. The orexin neuropeptide signaling system plays a role in wakefulness, and blocking the wake-promoting neuropeptides results in diminished wake signaling, thus exerting a sedative effect using an entirely different mechanism of action than the classical sleep promoting agents. The drug has quick onset of action, high volume of distribution, and high protein binding. Pharmacokinetics and pharmacodynamic parameters were similar in patients of different sex and age and were not significantly affected by race, body size, or mild-to-moderate kidney impairment. Dose limitation to 25 mg in moderate liver impairment and no use in severe liver impairment are recommended. The drug undergoes hepatic CYP3A4 metabolism; thus, caution with strong CYP3A4 inhibitors and inducers is warranted. The drug was approved based on phase 3 trials involving study 1 and study 2. Study 1 noted daridorexant at doses of 25 and 50 mg demonstrated a statistically significant improvement in wake time after sleep onset, latency to persistent sleep, and self-reported total sleep time against placebo at months 1 and 3. Similarly in study 2, compared with placebo, the 25 mg dose demonstrated statistically significant improvement in wake time after sleep onset, latency to persistent sleep, and self-reported total sleep time at months 1 and 3. Treatment-emergent adverse events were similar for daridorexant and placebo, with nasopharyngitis and headache most frequently reported. Daridorexant is a novel agent with demonstrated efficacy in sleep onset and maintenance and decrease in daytime sedation. Preliminary results from a 1-year extension study note similar incidences of mild-to-moderate side effects as noted in previous trials. Further studies are needed to establish its place in the pharmacological treatment of insomnia.

The effects of acupuncture on psychological symptoms in patients with insomnia: study protocol for a randomized controlled trial

BackgroundInsomnia is a common sleep-related condition that includes dissatisfaction with sleep quality, difficulty in initiating or maintaining sleep, and early morning waking. Insomnia can affect daytime functioning by causing fatigue, depression, and anxiety. Medications are the most common method for the management of insomnia but can cause adverse effects, including psychological and physical dependence, residual daytime sedation, and cognitive impairment. Acupuncture is a common traditional Chinese therapy. It has been used in the treatment of insomnia, depression, and anxiety in China. However, there are no high-quality studies focusing on acupuncture for insomnia, especially for depression and anxiety due to insomnia. Therefore, we have designed a randomized controlled trial (RCT) involving a placebo control to ensure blinding of participants to investigate the effects of acupuncture on insomnia in improving sleep quality and psychosocial symptoms.MethodsWe have designed a single-center, parallel-group, single-blinded RCT. A total of 252 participants who meet the eligibility criteria will be randomly allocated into a manual acupuncture group or sham acupuncture group in a 1:1 ratio. All participants will receive 24 sessions of acupuncture (30 min per session, three sessions per week for 8 weeks). Participants will be assessed using the Pittsburgh Sleep Quality Index score, self-assessment anxiety scale, self-assessment depression scale, and Medical Outcomes Study 36-Item Short-Form Health Survey at baseline and 8 weeks. All analyses will be based on an intention-to-treat principle. The results will be published in an international peer-reviewed journal.DiscussionThe results of this study are expected to clarify the effects of acupuncture on sleep quality and psychosocial symptoms in patients with insomnia. This will contribute to the clinical practice of acupuncture in the management of insomnia.Trial registrationChinese Clinical Trail Registry ChiCTR2100049172. Registered on 24 July 2021.

The efficacy and safety of zolpidem and zopiclone to treat insomnia in Alzheimer's disease: a randomized, triple-blind, placebo-controlled trial.

No prior studies have evaluated the efficacy and safety of zolpidem and zopiclone to treat insomnia of demented patients. This randomized, triple-blind, placebo-controlled clinical trial used these drugs to treat patients with probable, late onset Alzheimer's dementia (AD) (DSM V and NINCDS-ADRDA criteria) exhibiting insomnia (DSM V criteria and nocturnal NPI scores ≥ 2). Actigraphic records were performed for 7 days at baseline and for 14 days during the treatment period in 62 patients aged 80.5 years in average and randomized at a 1:1:1 ratio for administration of zolpidem 10 mg/day, zopiclone 7.5 mg/day or placebo. Primary endpoint was the main nocturnal sleep duration (MNSD), whereas secondary outcomes were the proportion of the night time slept, awake time after sleep onset (WASO), nocturnal awakenings, total daytime sleep time and daytime naps. Cognitive and functional domains were tested before and after drug/placebo use. Three participants under zopiclone use had intervention interrupted due to intense daytime sedation and worsened agitation with wandering. Zopiclone produced an 81 min increase in MNSD (95% confidence interval (CI): -0.8, 163.2), a 26 min reduction in WASO (95% CI: -56.2, 4.8) and a 2-episode decrease in awakening per night (95% CI: -4.0, 0.4) in average compared to placebo. Zolpidem yielded no significant difference in MNSD despite a significant 22 min reduction in WASO (95% CI: -52.5, 8.3) and a reduction of 1 awakening each night (95% CI: -3.4, 1.2) in relation to placebo. There was a 1-point reduction in mean performance in the symbols search test among zolpidem users (95% CI: -4.1, 1.5) and an almost eight-point reduction in average scores in the digit-symbol coding test among zopiclone users (95% CI: -21.7, 6.2). In summary, short-term use of zolpidem or zopiclone by older insomniacs with AD appears to be clinically helpful, even though safety and tolerance remain issues to be personalized in healthcare settings and further investigated in subsequent trials. This trial was registered in ClinicalTrials.gov Identifier: NCT03075241.

Selective Serotonin Reuptake Inhibitors for the Treatment of Depression in Adults with Down Syndrome: A Preliminary Retrospective Chart Review Study.

Background: Depression is a common psychiatric comorbidity in individuals with Down syndrome (DS), particularly adults, with an estimated lifetime prevalence of at least 10%. The current literature on the treatment of depression in adults with DS is limited to case series published more than two decades ago, prior to the widespread use of modern antidepressant medications such as selective serotonin reuptake inhibitors (SSRIs). The purpose of this retrospective chart review study was to examine the effectiveness, tolerability, and safety of SSRIs for depression in adults with DS. Methods: Medical records of 11 adults with DS and depression were reviewed. Assignment of scores for severity (S) of symptoms of depression and improvement (I) of symptoms with treatment with an SSRI was made retrospectively using the Clinical Global Impression Scale (CGI). Demographic and clinical characteristics of the study population, SSRI name, dose, and duration of treatment; and adverse effects were also recorded. Results: All 11 patients (7 male, 4 female; mean age = 27.2 years, range 18–46 years) completed a 12-week treatment course with an SSRI. The median duration of time after initiation of the SSRI covered by record review was 2.1 years, with a range of 24 weeks to 6.7 years. Nine of the 11 patients (82%; 95% CI 52%, 95%) were judged responders to SSRIs based on a rating of “much improved” or “very much improved” on the CGI-I after 12 weeks of treatment (median time of follow-up was 14.4 weeks, with a range of 12.0–33.0 weeks). Adverse effects occurred in four patients (36%). The most common adverse effects were daytime sedation and anger. Conclusions: In this preliminary retrospective study, the majority of patients responded to a 12-week course of SSRI treatment and some tolerated long-term use. Controlled studies are needed to further assess the efficacy, tolerability, and safety of SSRIs for the treatment of depression in adults with DS.

P12.08 Efficacy of trazodone slow release in insomnia associated with high-dose steroid therapy in neuro-oncological patients

Abstract BACKGROUND Insomnia linked to therapeutical intake of intravenous (IV) megadoses of steroid (Mgds, 8–16 mg) is a common side effect in neuro-oncology patients. Hypno-inducing drugs (IP) and Benzodiazepines (BDZ) can provoke drug interference and daytime sedation. Trazodone (Trz) is an atypical antidepressant with poor liver metabolism; it has moderate histamine-1 (H1) receptor antagonism and possesses some anxiolytic and hypnotic properties. We tested the use of the Trz retard (RP) formulation as a hypnotic drug in patients undergoing a therapeutic regimen with IV Mgds. To evaluate anxiety and side effects. MATERIAL AND METHODS 10 patients (6 females and 4 males) admitted to the Neuro-oncology Department of the Neurological Institute “Carlo Besta” treated with Mgds IV. The average age was 55 years and the mean HAM-A score was 25. Instruments included the Hamilton Anxiety Scale (HAM-A), the Clinical Global Impression (CGI), and the Pittsburgh Sleep Quality Index (PSQI). Trz RP was administered at a dosage of 25-50-75 mg/day in the evening. RESULTS All 10 patients reported improved hypnotic profiles within the third day of Trz RP administration. Four patients improved on the first day. Reduction of the HAM-A score was found on the third day. No adverse events (epilepsy, daytime sedation, incontinence) were observed in 3 weeks. CONCLUSIONS Trz RP proved to have a swift beneficial effect on sleep and anxiety without side effects in the short term. Trz may be preferred to IP and BDZ in patients receiving IV Mgds, considering the lack of daytime sedation and the reduced pharmacological inference. Larger samples will enable future research to better describe the characteristics and the indication of Trz.

Study to Evaluate Safety and Daytime Sedation in Subjects With Parkinson's Disease With Neuropsychiatric Symptoms Treated With Pimavanserin or Low-Dose Quetiapine

Study to Evaluate Safety and Daytime Sedation in Subjects With Parkinson's Disease With Neuropsychiatric Symptoms Treated With Pimavanserin or Low-Dose Quetiapine

Pharmacodynamic and pharmacokinetic profile of SM‐1, a triple‐drug combination to increase total sleep time

The primary objective was to characterize the pharmacokinetics and pharmacodynamics of SM-1 after administration of a single oral dose to healthy volunteers in a placebo-controlled double-blind trial of daytime sedation. Secondary objectives were to determine the onset, duration, and offset of the sedative effects using subjective and objective measures of sedation. Safety and tolerability of SM-1 were also investigated. Males and females 18-45 years of age received SM-1, a combination drug product comprised of diphenhydramine, zolpidem (delayed release), and lorazepam (delayed release). The pharmacokinetic profile of each drug was determined from blood samples. Sedative effects were assessed by visual analog scale, digit symbol substitution test, memory test, and quantitative electroencephalography. Similar number and severity of adverse events were observed following administration of SM-1 and placebo. Onset of sedation, as determined by subjective, performance, and electroencephalography measures, occurred 0.5-1 hr postdose, lasting about 7-7.5 hr. Plasma concentration curves for the two delayed-release components were altered compared with published data for unmodified drugs. Exposure values obtained with the combination product were in good agreement with published values of the drugs given individually. SM-1 was well tolerated and has pharmacologic activity starting within an hour of ingestion, lasting approximately 7-8 hr. Sedative activity was seen with subjective, psychomotor, and electroencephalography assays.

Levetiracetam for prophylactic treatment of pediatric migraine: A randomized double-blind placebo-controlled trial.

Few drugs are available for migraine prophylaxis in children. Levetiracetam is a broad-spectrum anti-seizure drug that has been suggested to be effective in reducing adult migraine episodes. We assessed the safety and efficacy of levetiracetam in the prevention of pediatric migraine. A randomized double-blind placebo-controlled trial was performed. Eligible participants were aged 4-17 years old with at least four migrainous episodes monthly or had severe disabling or intolerable episodes. Primary endpoints were the mean changes in monthly frequency and intensity of headaches from the baseline phase to the last month of the double-blind phase. Safety endpoint was the adverse effects reported. Sixty-one participants (31 taking levetiracetam and 30 taking placebo) completed the study. All had a significant reduction in frequency and intensity of episodes that was significantly greater in the levetiracetam arm. Sixty eight percent of individuals in the treatment group reported more than 50% reduction of episodes at the end of the trial compared with 30% in the placebo group (p-value: 0.007). Irritability, day-time sedation, and mild tic were reported. Levetiracetam may be useful in migraine prevention and may decrease migraine episodes and severity. The study is prospectively registered with Iranian Registry of Clinical Trials; IRCT.ir, number IRCT2017021632603N1.

Zolpidem and Gender: Are Women Really At Risk?

In 2013 the Food and Drug Administration (FDA) claimed the existence of new data showing women to be at risk for excessive daytime sedation and impaired driving proficiency following bedtime doses of zolpidem. The putative explanation was the reduced metabolic clearance of zolpidem and higher morning blood concentrations in women compared to men. The FDA acted to reduce the recommended dosage for women down to 50% of the dose for men. No other regulatory agency worldwide has taken similar action. Gender effects on zolpidem pharmacokinetics, pharmacodynamics, adverse effects, clinical efficacy, and driving performance were evaluated through a further analysis of data from a previous study, together with a literature review. Women had on average 35% lower apparent clearance of zolpidem than men (236 vs 364 mL/min, P < 0.001). This difference was not explained by body weight. In some laboratory studies, women had greater functional impairment than men taking the same dose, but in all studies active drug was not distinguishable from placebo at 8 hours after oral dosage. On-the-road driving studies likewise showed no evidence of driving impairment in men or women at 8 hours after 10 mg of oral immediate-release zolpidem. No clinical trial demonstrated a gender-related difference in clinical efficacy or adverse reactions, and there was no evidence of a particular risk to women. Dosage reduction in women is not supported by available scientific evidence, and may in fact lead to underdosing and the consequent hazard of inadequately treated insomnia.

Deprescribing benzodiazepine receptor agonists taken for insomnia: a review and key messages from practice guidelines.

Long‑term benzodiazepine receptor agonist (BZRA) use for insomnia is common and highly prevalent in adults in all care settings. Evidence syntheses suggest that the therapeutic benefits of benzodiazepines for insomnia are marginal and very short term. On the harm side, BZRAs are associated with daytime sedation and confusion. Long‑term use increases the risk of falls, fractures, cognitive impairment, and motor vehicle accidents. An evidence‑based clinical practice guideline has been developed to assist with deprescribing BZRAs. This review highlights the rationale for deprescribing BZRAs used for insomnia and summarizes key messages for clinicians from the new BZRA deprescribing guideline and their supporting evidence.

A randomized control trail on the effectiveness of (Tricyclic antidepressant) Amitriptyline 10 mg bedtime in patients suffering from Meniere’s disease

&lt;p class="abstract"&gt;&lt;strong&gt;Background:&lt;/strong&gt; Meniere’s disease is one of the most common causes of chronic recurrent vertigo in general population. Meniere’s disease is closely associated with migraine and migrainous vertigo/ vestibular migraine. Amitriptyline has been classically used in management of Vestibular migraine. This randomized control trail examines the effectiveness of (Tricyclic antidepressant) Amitriptyline 10mg bedtime in patients suffering from Meniere’s disease using a Randomized control trial. This was a randomized, double-blinded, placebo-controlled trial, cross over type with a power of 80% at 5% significance level.&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Methods:&lt;/strong&gt; One hundred five patients with definite Meniere’s disease were randomized and assigned to either placebo or trial arm. Trial arm were given Amitriptyline 10 mg bedtime and placebo arm were given a generic Vitamin B-complex tablet. Visual analogue score and standard questionnaires were used to assess the improvements in vertigo, imbalance, dizziness and disease-specific quality of life before and after use of Amitriptyline vs. placebo for period of 10 days each. &lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Results:&lt;/strong&gt; Amitriptyline 10mg at bedtime (10mg H.S), produces significant improvement in the vertigo in patients suffering from Meniere’s disease compared to placebo. Chronic imbalance and hearing levels are not affected by the use of the above drug regime. Daytime sedation and weight gain are the most troublesome adverse effects of Amitriptyline at 10mg per day dose. No other serious adverse effects were observed in this research.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions:&lt;/strong&gt; Low dose bedtime Amitriptyline 10mg appears to be safe and produces improvement in vertigo and disease-specific quality of life in Meniere’s disease patients. &lt;/p&gt;

The Effect of Daily Sedation-Weaning Application on Morbidity and Mortality in Intensive Care Unit Patients.

Background/aimsSedation is one of the most important components of intensive care unit (ICU) in patients who are mechanically ventilated at intensive care conditions. As a result of sedation and analgesia in the intensive care unit, the patient is to be awakened a comfortable and easy process. The aim of the study is to demonstrate the effects of day-time sedation interruptions in intensive care patients.Material and methodsWe made a retrospective review of 100 patients who were monitored, mechanically ventilated and treated at our intensive care unit between January 2008 and January 2013. Patients were divided into two groups, including Group P (continuous infusion of sedative agent) and Group D (daily sedation interruptions - daily recovery).Demographics, mechanical ventilation time, stay at intensive care unit, hospitalization period, time of first weaning, success of weaning, ventilator-related pneumonia (VRP), total doses of drugs, re-intubation frequency, Acute Physiology and Chronic Health Evaluation II (APACHE II), Sequential Organ Failure Assessment (SOFA) scores and mortality rates of patients were compared. Ramsay Sedation Score (RSS) was used to evaluate the level of sedation. Considering that ideal sedation level is "3" with RSS, RSS < 3 is considered as mild sedation, while RSS > 3 is considered as deep sedation.ResultsThere was no difference between demographics of patients. Mechanical ventilation period was significantly longer in Group P than Group D (p < 0.001). When stay at ICU unit was considered, ICU stay was significantly longer in Group P than Group D (p < 0.001). No statistically significant difference was found between two groups with respect to hospitalization period. In inter-group comparison, time to start first weaning was significantly late in Group P than Group D (p < 0.05). There was no difference between groups in terms of frequency of success of weaning and mortality rate (p > 0.05). In inter-group comparison the frequency of reintubation viewed in Group D was significantly less than in Group P (p < 0.05). Considering development of VRP, it was significantly more common in Group P in comparison with Group D (p < 0.05). No statistically significant difference was found between groups in terms of doses of sedative agents (p > 0.05). Considering doses of opioid analgesics, the total dose of fentanyl was significantly higher in Group P than Group D (p = 0.04), while no difference was found for doses of morphine (p > 0.05). Again, no statistical difference was found in doses of muscle relaxant agents (p > 0.05).ConclusionIt was observed that the sedation technique with daily interruption is superior to continuous infusion of sedatives. Accordingly, we believe that daily weaning will make positive contributions to patients who are mechanically ventilated at intensive care unit.

Clinical Practice Guideline on Management of Sleep Disorders in the Elderly.

Clinical Practice Guideline on Management of Sleep Disorders in the Elderly.

Risk Factors for Obstructive Sleep Apnea Are Prevalent in People with Psychosis and Correlate with Impaired Social Functioning and Poor Physical Health.

Obstructive sleep apnea (OSA) in the general community is associated with obesity, smoking, alcohol, and sedative medication use and contributes to depressed mood, daytime sedation, and sudden cardiovascular deaths. Poor cardiovascular health, impaired social functioning, and negative and cognitive symptoms are also among the common clinical features of psychotic disorders. People with psychosis have higher rates of sleep disturbance; however, OSA has not been extensively investigated in this population. This study aimed to determine the prevalence of OSA and general sleep disruption symptoms in a representative Australian sample of people with psychosis. We investigated the prevalence of potential risk factors for OSA, including obesity, psychotropic medications, and substance abuse in this population. Finally, we evaluated associations between symptoms of OSA, symptoms of general sleep disruption, and various clinical features in people with psychosis. Participants took part in the Second National Australian Survey of Psychosis, a population-based survey of Australians with a psychotic disorder aged 18-64 years. Symptoms associated with OSA (snoring and breathing pauses during sleep) in the past year were assessed using questions from the University of Maryland Medical Centre Questionnaire and symptoms associated with general sleep disruption in the past week using the Assessment of Quality of Life Questionnaire. Data collected included psychiatric diagnosis and symptoms, education, employment, medications, smoking status, physical activity, drug and alcohol use, and cognitive function. Physical health measures included body mass index, waist circumference, blood pressure, fasting blood glucose, and lipids. Snoring was reported by 41.9%; 7% stating they frequently stopped breathing (pauses) during sleep. Univariate logistic regressions show OSA symptoms (pauses and snoring) were associated with older age, female gender, lower levels of social participation or employment, cardiovascular risk factors, sedentary lifestyle, and poorer quality of life, while symptoms of general sleep disruption were more likely in people with depressive symptoms. Australians with psychosis have high levels of sleep disturbance, including OSA. OSA symptoms were associated with cardiovascular disease risk factors, reduced social participation and employment, and poorer quality of life. Whether correction of OSA can improve these factors in people with psychosis remains to be determined.

Mirtazapine for Symptomatic Relief on a Psychiatric Consultation Service: A Case Series

With a complex pharmacologic profile, mirtazapine may promote sleep, stimulate appetite, improve nausea, and reduce pain. Some practitioners working on the Mayo Clinic inpatient psychiatric consultation/liaison service have recommended mirtazapine in medically ill patients with or without formal psychiatric comorbidity to target these symptoms. To assess the success of this practice, we conducted a retrospective chart review covering a 4.5-year period. For patients recommended to start mirtazapine, global improvement in specific symptoms and suspected side effects were recorded. During the study period, 528 medically ill patients started mirtazapine following a recommendation from the psychiatric consultation service. In total, 475 patients were provided mirtazapine to specifically target sleep, nausea, pain, or appetite. There was documented improvement in these symptoms for 37.7%, 37.0%, 36.4%, and 23.5% of the patients, respectively. These rates of improvement are conservative for the 229 patients without documented response, i.e., 48% of the patients who were given the medication for a somatic symptom were counted as having no improvement. Commonly documented adverse effects were daytime sedation (5.3%), worsening mental status (2.3%), and nightmares (1%). Despite the limitations of this retrospective, qualitative study, these data confirm that mirtazapine is generally well tolerated and can provide at least short-term relief of certain symptoms in medically ill patients. Controlled trials are needed to assess these benefits more systematically, and it is not clear how long mirtazapine should be used for these symptoms.

High-Dose Benzodiazepines May Increase Risk of Death in Schizophrenia Patients

Back to table of contents Previous article Next article Clinical and Research NewsFull AccessHigh-Dose Benzodiazepines May Increase Risk of Death in Schizophrenia PatientsMark MoranMark MoranSearch for more papers by this authorPublished Online:4 Feb 2016https://doi.org/10.1176/appi.pn.2016.1b14AbstractUse of antipsychotics or antidepressants was associated with overall mortality rates 15 to 40 percent lower compared with no use of these medications.Chronic, high-dose use of benzodiazepines among patients with schizophrenia appears to be associated with a markedly higher overall mortality rate than is seen in patients with schizophrenia who have not been exposed to benzodiazepines, according to a report in AJP in Advance (December 7, 2015).The report also found a lower overall mortality rate among patients with schizophrenia who received antipsychotics and/or antidepressants.“The results indicate that any amount of antipsychotic and antidepressant usage is associated with overall mortality rates 15 percent to 40 percent lower compared with no use of these medications,” wrote study authors Jari Tiihonen, M.D., Ph.D., and colleagues at the Karolinska Institutet in Stockholm. “In contrast, benzodiazepine exposure revealed a clear dose-response curve for mortality, where high exposure was associated with a 70 percent higher risk of death compared with no use.”The authors prospectively compared all-cause and cause-specific mortality in individuals aged 16 to 65 who had been diagnosed with schizophrenia (N=21,492) in Sweden. All-cause and cause-specific mortality rates were calculated as a function of cumulative low, moderate, and high exposure to antipsychotics, antidepressants, and benzodiazepines from 2006 through 2010. The cohort participants were identified from two nationwide Swedish health care registers.Compared with 214,670 age- and gender-matched persons from the general population, the mortality of the cohort with schizophrenia was 4.8-fold higher. The most common specific cause of death was cardiovascular disease (32.7 percent), followed by neoplasms (16.5 percent), respiratory diseases (11.0 percent), and suicide (9.5 percent). Any degree of exposure to antipsychotics or antidepressants was associated with a lower overall mortality compared with no use. The opposite was observed for benzodiazepines, and high exposure was associated with a 74 percent higher risk of death compared with no use. “The association between benzodiazepine exposure and mortality may be explained by several mechanisms,” the authors noted. “Although long-term benzodiazepine use may be a marker for more severe illness and coexisting substance abuse, it is also plausible to assume that prescribing of high doses for long periods may lead to tolerance and dose escalation. This could result in fatal interactions with concurrent use of alcohol and illicit drugs, and worsening of polysubstance dependence may result in a less healthy lifestyle in general. In addition, high-dose benzodiazepine use may also contribute to daytime sedation and proneness to accidents.”Although adverse events associated with antipsychotics have received considerable attention, the study authors emphasized that their findings suggest that patients on high doses of benzodiazepines should be monitored closely.“It is important to realize that although monitoring of patients with moderate- or high-dose antipsychotic treatment is relevant, it is essential to focus the preventive interventions on those patients who have an even higher risk of death, that is, patients not using antipsychotics and patients using high doses of benzodiazepines,” they wrote. AJP Editor Robert Freedman, M.D., cautioned that the study is not necessarily an indictment of benzodiazepines and noted that high-dose use among people with schizophrenia appears to be more common in Sweden than in the United States. “Dr. Tiihonen and colleagues fulfill the maxim that great epidemiologists raise more questions than they answer,” he told Psychiatric News. “As the authors of the study point out, regular benzodiazepine use in addition to antipsychotics likely indexes a more severely ill group of patients. “The message for clinicians is that use of benzodiazepines to avoid the toxicity of antipsychotics seems to have its own problematic consequences,” Freedman continued. “A second message is that Tiihonen and colleagues found that antidepressant use decreases mortality and should be considered as a beneficial therapeutic addition for schizophrenia.” This research was supported by Karolinska Institutet, Niuvanniemi Hospital in Kuopio, Finland, and the Sigrid Juselius Foundation. ■“Mortality and Cumulative Exposure to Antipsychotics, Antidepressants, and Benzodiazepines in Patients With Schizophrenia: An Observational Follow-Up Study” can be accessed here. ISSUES NewArchived

An updated clozapine treatment guide against clozaphobic attitudes

In recent years, clozapine-related publications are gradually increasing. Despite all the new generation of antipsychotics, one-third of patients with scizophrenia are still treatment-resistant. Clozapine is a unique and gold standard antipsychotics with FDA approval for treatment-resistant schizophrenia cases following failure with antipsyhotics from two separate groups with sufficient doses for at least six weeks duration and also preventing suicidal behavior in patients with schizophrenia and schizoaffective disorder. While at least 30% of schizophrenia patients are treatment- resistant and suicide rate is 5%; clozapine, both in Turkey and around the world, is used 10–15 times less in 2–10% of patients. This is not easy to explain rationally like in phobias. Although this cannot be exactly labeled as phobia or clozaphobia, labeling it as a clozaphobic attitude might be appropriate. In our opinion, claiming that prescription of clozapine less than required by the psychiatrists in Turkey due to this clozaphobic attitude is an important public health problem would not be an exaggeration. In addition to clozaphobic attitude, one of the major reasons underlying this attitude is clinicians’ lack of adequate awareness and experience in managing the potential serious adverse events. Clozapine causes major adverse events such as agranulocytosis, myocarditis/ cardiomyopathy, and epileptic seizures along with side effects such as weight gain, constipation, metabolic syndrome which might compromise patient’s health. In addition, daytime sedation, urinary incontinence at night, and hipersalivation can adveresly affect the quality of life of patients. Blood count monitoring for 18 weeks is another reason for reluctant use of clozapine. All these side effects and challenges can be overcome with specific approaches. The FDA promoted a rational use of clozapine with REMS (Risk Evaluation and Mitigation Strategy) program. In this review, updated information about clozapine have been outlined and clinicians were aimed to be informed by the pharmacoeconomics advantages of clozapine and how to overcome the potential adverse events in clozapine use.

Changes in First Postoperative Night Bispectral Index After Daytime Sedation Induced by Dexmedetomidine or Midazolam Under Regional Anesthesia: A Randomized Controlled Trial

Background and ObjectivesSupplementation of spinal anesthesia with various sedatives is a standard protocol to alleviate patient anxiety associated with the surgical procedure. We hypothesized that, compared with dexmedetomidine, midazolam might...