Retrospective cohort study evaluating exenatide twice daily and long-acting insulin analogs in a Veterans Health Administration population with type 2 diabetes.

AIM: This was a retrospective cohort study that evaluated the differences in glycated haemoglobin (HbA1c) and body mass index (BMI) in veterans with type 2 diabetes mellitus (T2DM), prescribed exenatide twice daily (BID) versus long-acting insulin analog (LAIA) two years after initiation in the United States (US) veteran population. MATERIALS AND METHODS: Patients were included if they were ≥ 18 years old with T2DM, and initiated exenatide BID or LAIA at the Veterans Health Administration between January 1, 2006 and December 31, 2010. Multivariate models were used to evaluate the changes in HbA1c and BMI between groups, controlling for potential confounders. Logistic regression was used to evaluate the odds of achieving ≥ 0.5% HbA1c reduction based on baseline HbA1c stratifications: low,<7%; moderate, 7% to<9%; and high,≥ 9%. RESULTS: A total of 446 exenatide BID and 51,531 LAIA patients met inclusion/exclusion criteria. On average, exenatide BID patients were significantly older (64 versus 60 years) with a higher BMI (37.8 versus 32.9 kg/m(2)). Baseline HbA1c was 8.2% and 8.8% for exenatide BID and LAIA patients, respectively (P<0.001); otherwise, patients were similar for all other characteristics. Exenatide BID treatment was significantly associated with a 0.32% (95%CI: 0.18-0.47%) greater reduction in HbA1c at two years compared with LAIA. Similar findings were observed for BMI reduction (0.68 kg/m(2); 95%CI: 0.42-0.95 kg/m(2)). Exenatide BID patients with moderate baseline HbA1c had significantly higher odds of achieving ≥ 0.5% HbA1c reduction compared with LAIA patients (OR=1.5; 95%CI: 1.2-2.0). CONCLUSIONS: Veterans treated with exenatide BID had significantly greater reduction in HbA1c and BMI compared with patients treated with LAIA patients two years after initiation.

Is late-onset schizophrenia a subtype of schizophrenia?

OBJECTIVE: To determine whether late-onset schizophrenia (LOS, onset after age 40) should be considered a distinct subtype of schizophrenia. METHOD: Participants included 359 normal comparison subjects (NCs) and 854 schizophrenia out-patients age >40 (110 LOS, 744 early-onset schizophrenia or EOS). Assessments included standardized measures of psychopathology, neurocognition, and functioning. RESULTS: Early-onset schizophrenia and LOS groups differed from NCs on all measures of psychopathology and functioning, and most cognitive tests. Early-onset schizophrenia and LOS groups had similar education, severity of depressive, negative, and deficit symptoms, crystallized knowledge, and auditory working memory, but LOS patients included more women and married individuals, had less severe positive symptoms and general psychopathology, and better processing speed, abstraction, verbal memory, and everyday functioning, and were on lower antipsychotic doses. Most EOS-LOS differences remained significant after adjusting for age, gender, severity of negative or deficit symptoms, and duration of illness. CONCLUSION: Late-onset schizophrenia should be considered a subtype of schizophrenia.

Suicidality in middle aged and older patients with schizophrenia and depressive symptoms: relationship to functioning and Quality of Life.

BACKGROUND: Suicidality is a health concern in patients with schizophrenia. We examined the hypotheses: (1) Middle aged and older patients with schizophrenia, depressive symptoms and suicidality would exhibit worse quality of life and worse everyday functioning, social skills and medication management relative to those without suicidality; (2) higher levels of suicidality would be significantly associated with worse functioning, worse quality of life and older age. METHODS: We examined 146 outpatients with schizophrenia and depression. Patients were at least 40 years old and were diagnosed with schizophrenia or schizoaffective disorder and had two or more depressive symptoms based on DSM-IV criteria for major depression. We assessed suicidality with the Intersept Suicide Scale (ISS) and functioning with the UCSD Performance-based Skills Assessment (UPSA), Social Skills Performance Assessment (SSPA), and Medication Management Ability Assessment (MMAA). Quality of life was assessed with the Heinrichs Quality of Life Scale (QLS). RESULTS: The mean age of patients was 52.4+ 6.9 years. Subjects with suicidality (ISS scores > 0) had lower QLS scores compared to those without suicidality. However, there were no differences in UPSA, SSPA nor MMAA scores between the two groups. In addition, based on Spearman's rho correlational analysis, there were significant associations of QLS scores with ISS scores (r = - 0.236) and with MMAA "total errors" scores (r = 0.174). Logistic regression demonstrated that only QLS scores predicted suicidality. CONCLUSION: Thirty-six percent of our sample had at least mild degrees of suicidality. Lower quality of life appears to be an important predictor of suicidality.

Neurocognitive functioning in dually diagnosed middle aged and elderly patients with alcoholism and schizophrenia.

BACKGROUND: Alcohol abuse and dependence have important clinical implications for managing patients with schizophrenia. Alcoholism in schizophrenia patients can interfere with the course and prognosis of the schizophrenic illness. OBJECTIVE: The purpose of the present study was to compare the cognitive status, symptom profile and quality of life of middle aged and older patients (>44 years old) with schizophrenia and alcohol abuse/dependence vs those without alcohol abuse/dependence. We initially hypothesized that more males in this age group with schizophrenia would exhibit alcoholism. We also examined the characteristics of the 45-54 year age group with those of the > or = 55 year old group and hypothesized that comorbidity with alcohol would be associated with worse cognition and quality of life in later life. METHODS: Data were obtained from a database from the Center for Services and Interventions research at the University of California, San Diego. Patients had diagnoses of schizophrenia or schizoaffective disorder. Data collected included demographic characteristics, cognitive status (tested with the Mattis Dementia Rating Scale learning, the Figural and Story Memory Test of the Wechsler Memory Scale-Revised and the California Verbal Learning Test [CVLT]). In addition, patients had undergone psychopathologic assessment and were screened for quality of life using the Quality of Well Being scale. RESULTS: We demonstrated that the older aged patients with alcoholism had worse scores assessing cognition relative to the same aged group without alcoholism. In addition, they had worse cognitive scores relative to the younger group (45-54 year old) with alcoholism. There was no significant difference with regards to quality of life. In addition, more males than females exhibited alcoholism. CONCLUSION: The results are consistent with the premise that the higher cognitive function in the younger schizophrenia patients with alcoholism appear to mask the effects of alcohol use on cognition at that age. However, for the older group of schizophrenia patients, the effects of alcohol use on neuropsychological functioning appear to be deleterious.

Olanzapine vs haloperidol in geriatric schizophrenia: analysis of data from a double-blind controlled trial.

OBJECTIVES: To compare the six-week clinical response and safety profile of schizophrenia patients, age > or =60 years, receiving olanzapine (OLZ) vs haloperidol (HAL) in a double blind, randomized trial. METHODS: Double-blind data on patients age > or =60 randomized to 5 mg/d OLZ (n=83) or 5 mg/d HAL (n=34) (Week 1) then flexibly dosed to 5-20 mg/d over six weeks, with a 48-week extension for responders, were analyzed post-hoc. Efficacy indices included the PANSS Total and PANSS Psychosis Core Total (PPCT). Safety measures included the Simpson-Angus Scale (SAS), Barnes Akathisia Scale (BAS), Abnormal Involuntary Movement Scale (AIMS), treatment-emergent adverse events, and laboratory values. Mixed model, repeated measures (MMRM) analyses were applied to all continuous data measured at each visit. Continuous data recorded only at phase completion or termination were analyzed with a fixed effect last observation carried forward (LOCF) model. Frequencies of categorical response data were analyzed using Fisher's exact methods. Differences were tested for significance at Week 6 using a two-sided alpha value of 0.05. RESULTS: HAL group (n=34; age range 60-80) received a mean modal dose 9.4 mg/d while OLZ group (n=83; age range 60-86) received a mean modal dose 11.9 mg/d. At Week 6, OLZ was superior to HAL on both the PANSS Total (p=0.015) and PPCT (p=0.043). Considering safety, OLZ was superior to HAL for the SAS and BAS (p<0.001; p<0.001). No spontaneous adverse event occurred more frequently with OLZ than with HAL. In patients never receiving adjunct anticholinergic therapy, no significant differences were present for anticholinergic-like side effects including blurred vision, dry mouth, constipation, or urinary difficulties. CONCLUSIONS: In elderly schizophrenia patients, olanzapine was more efficacious and better tolerated for extrapyramidal signs than was haloperidol. Olanzapine was equivalent to haloperidol for anticholinergic-like side effects when corrected for anticholingergic agents.

Aging and outcome in schizophrenia.

OBJECTIVE: Controversy exists about long-term outcome of schizophrenia, but few studies have compared older out-patients to normal subjects. We sought to examine the relationship of age to clinical features, psychopathology, movement abnormalities, quality of well-being, and everyday functioning in schizophrenia out-patients and normal comparison subjects, and to further characterize these outcomes in elderly schizophrenia out-patients. METHOD: A total of 290 out-patients and 144 comparison subjects, aged 40-85 years, underwent comprehensive assessments. RESULTS: Among patients, aging was associated with decreased psychopathology, even after controlling for duration of illness. There was no accelerated aging-related decline on any measure in the patients. Yet, elderly patients were more impaired than comparison subjects on various measures. CONCLUSION: The course of schizophrenia in late life appears stable, but most elderly patients remain symptomatic and impaired. Our findings dispute notions of either progressive deterioration or marked improvement in aging schizophrenia out-patients.

Relationship of mood disturbance to cigarette smoking status among 252 patients with a current mood disorder.

BACKGROUND: The relationship between cigarette smoking and mood has received increasing attention. This retrospective study evaluated the relationship between mood disturbance and cigarette smoking status among patients with a current mood disorder. The association between level of nicotine dependence and severity of mood disturbance was also evaluated among current smokers. METHOD: Retrospective data for 252 patients (63.5% male, 85.0% white) admitted for treatment of a mood disorder at the San Diego Veteran Affairs Mental Health Clinical Research Center between November 1988 and June 1997 were studied. All current cigarette smokers at admission (N = 126) were matched with nonsmokers (N = 126) on the primary DSM-IV Axis I mood disorder diagnosis, admission status (inpatient or outpatient), gender, age (+/- 5 years), and ethnicity. The Hamilton Rating Scale for Depression (HAM-D), the Beck Depression Inventory, and the Profile of Mood States (POMS) were administered to patients on admission. Conditional logistic regression analysis for matched sets with a backward elimination was used to identify factors independently predictive of current smoking status. RESULTS: A greater number of cups of coffee consumed per day (p = .002), a history of alcoholism (p = .004), and higher POMS fatigue subscale scores (p = .007) were predictive of current smoking status. Among current smokers, the HAM-D terminal insomnia item was positively associated with mean number of cigarettes smoked per day (p = .012). CONCLUSION: Cigarette smoking should be addressed in the treatment of patients with a current mood disorder. Smokers experience greater levels of fatigue than nonsmokers. In addition, higher cigarette consumption levels are associated with mild-to-severe symptoms of terminal insomnia.

Health-related quality-of-life measure enhances acute treatment response prediction in depressed inpatients.

BACKGROUND: Many nonbiological variables are reported to predict treatment response for major depression; however, there is little agreement about which variables are most predictive. METHOD: Inpatient subjects (N = 59) diagnosed with current DSM-IV major depressive disorder completed weekly depressive symptom ratings with the Hamilton Rating Scale for Depression (HAM-D-17) and Beck Depression Inventory (BDI), and weekly health-related quality-of-life (HRQL) ratings with the Quality of Well-Being Scale (QWB). Acute responders were identified by a 50% decrease in HAM-D-17 score from baseline within 4 weeks of medication treatment. Predictor variables were initially chosen from a literature review and then tested for their association with acute treatment response. RESULTS: An initial predictive model including age at first depression, admission BDI score, and melancholia predicted acute treatment response with 69% accuracy and was designated as the benchmark model. Adding the admission QWB index score to the benchmark model did not improve the prediction rate; however, adding the admission QWB subscales for physical and social activity to the benchmark model significantly improved acute treatment response prediction to 86% accuracy (p = .001). CONCLUSION: In addition to being designed for use in cost-effectiveness analyses, the QWB subscales appear to be useful HRQL variables for predicting acute inpatient depression treatment response.

The effects of transdermal nicotine therapy for smoking cessation on depressive symptoms in patients with major depression.

This study examines the effects of transdermal nicotine patches for smoking cessation on depressive and withdrawal symptoms among 38 non-medicated subjects with Major Depressive Disorder. The study was conducted over a 29-day period, which included a 7 day baseline phase, a 14 day treatment phase, and an 8 day placebo phase. During the treatment phase subjects received either active nicotine patches (N = 18) or placebo patches (N = 20) that were administered in a randomized, double-blind fashion. The target quit date (TQD) was day 8. Significantly, more subjects in the placebo group than in the nicotine group resumed smoking following the TQD (50% vs. 22%). There was little evidence for effects of active nicotine patches on measures of mood (HRSD, BDI, POMS) or withdrawal symptoms among subjects that remained abstinent throughout the study (N = 24). Those who resumed smoking had more severe withdrawal symptoms than those who remained abstinent. One patient in the placebo group (n = 20) became more depressed after 2 weeks of abstinence. None of the patients in the nicotine group (n = 18) became more depressed.

Preliminary evidence of an association between increased REM density and poor antidepressant response to partial sleep deprivation.

BACKGROUND: One night of total sleep deprivation or of late-night partial sleep deprivation (PSD) produces a temporary remission in approximately 40-60% of patients with major depressive disorder; however, little is known about polysomnography (PSG) characteristics of responders to these types of sleep deprivation (SD). METHODS: Twenty-three unmedicated unipolar patients (17-item Hamilton Depression Rating Scale (HDRS17) >16) and 14 normal controls underwent 1 night of late-night PSD (awake after 3 a.m.) Subjects underwent baseline PSG and received the HDRS17 at standard times before and after PSD. Clinical response was defined as a reduction of >30% in the modified HDRS17 (omitting sleep and weight loss items) following PSD. RESULTS: The 12 responders and 11 nonresponders did not differ from each other significantly on baseline HDRS17 or PSG variables. The only PSG variable correlating with percent decrease in modified HDRS17 was baseline REM density (Pearson's r=-0.52, n=23, P=0.01.) In other words, the lower the baseline REM density, the more robust the antidepressant response was. LIMITATIONS: Subject numbers are relatively small. CONCLUSIONS: Increased REM density, which reflects the number of rapid eye movements per epoch of REM sleep, may be a physiological marker for severity or poor prognosis in a variety of psychiatric disorders, including relapse in recovering alcoholics, suicidality in schizophrenia, and poor response to PSD or interpersonal psychotherapy in depression.

Polysomnography and depressive symptoms in primary alcoholics with and without a lifetime diagnosis of secondary depression and in patients with primary major depression.

BACKGROUND: There is evidence suggesting that there is: (1) additive polysomnographic effects of alcoholism and depression; and (2) elevated baseline REM density in primary alcoholics with (PASD) and without lifetime history of secondary depression (NPA). METHODS: 23 PASDs, 59 NPAs, and 23 primary major depression patients (PMD) underwent polysomnography. Any drinking within 3 months after a 1-month inpatient alcohol rehabilitation defined relapse. RESULTS: PASDs' polysomnography was more like NPAs than PMDs. Polysomnography reflected 3-month sobriety status more than diagnosis. LIMITATIONS: Not all PASD's met full major depression criteria upon admission. CONCLUSIONS: Alcoholism affected polysomnography more than depression. Elevated admission REM density predicted 3-month relapse in PASDs and NPAs.

Abnormal involuntary movements in neuroleptic-naive children and adolescents.

OBJECTIVE: To determine the prevalence of and identify risk factors for abnormal involuntary movements in a well-characterized community sample of neuroleptic-naive children and adolescents. METHOD: The Abnormal Involuntary Movement Scale (AIMS) was administered to 390 subjects aged 3-17 years who were in foster care. Additional instruments were used to assess intellect and behaviour problems. RESULTS: A total 12.6% of subjects had at least 1 rating of "mild" movements on AIMS; these included 4.1% with at least 2 ratings of "mild" or 2 of "moderate" severity. Significant risk factors for movement disorder were younger age, lower IQ, and more severe behaviour problems. The abnormal movements were usually orofacial, and the affected subjects were generally unaware of these movements. CONCLUSION: The base prevalence of abnormal involuntary movements must be considered in children and adolescents assessed for medication in order to determine the true rate of motor side effects.

Sleep EEG studies during early and late partial sleep deprivation in premenstrual dysphoric disorder and normal control subjects.

In this study of 23 patients with premenstrual dysphoric disorder (PMDD) and 18 normal comparison (NC) subjects, we examined sleep EEG measures during baseline midfollicular (MF) and late luteal (LL) menstrual cycle phases and after early sleep deprivation (ESD), in which subjects slept from 03.00 to 07.00 h, and late sleep deprivation (LSD), in which subjects slept from 21.00 to 01.00 h. Each sleep deprivation night was followed by a night of recovery sleep (ESD-R, LSD-R) (sleep 22.30-06.30 h) and was administered in the late luteal phase of separate menstrual cycles. During baseline studies, sleep EEG measures differed significantly by menstrual cycle phase, but not group. Both PMDD and NC groups showed longer REM latencies and less REM sleep (minutes and percent) during the luteal compared with the follicular menstrual cycle phase. PMDD subjects, however, did not show sleep architecture changes similar to those of patients with major depressive disorders. Sleep quality was better during recovery nights of sleep in PMDD compared with NC subjects. REM sleep measures changed in association with clinical improvement in responders to sleep deprivation. Both early and late sleep deprivation may help to correct underlying circadian rhythm disturbances during sleep in PMDD, although differential sleep changes during ESD vs. LSD did not correlate with clinical response. Further sleep studies addressing additional circadian variables may serve to elucidate mechanisms mediating the therapeutic effects of sleep deprivation in PMDD.

A comparison of descriptive characteristics of male outpatients and inpatients with affective disorders.

Recent studies of patients with affective disorders have found that there are biological differences between inpatients and outpatients. Concerned by these findings, we compared individuals admitted to our inpatient and outpatient affective disorders clinical research center who met criteria for major depression. We hypothesized that inpatients would be more severely ill, more suicidal, more functionally impaired, and have more co-morbid disorders and higher ratings of depression and mood state dysfunction. The demographic profiles, lifetime co-morbid Axis I diagnoses, consumption histories, symptom profiles, global assessment of functioning, and severity of current stressors (Axis IV) were compared and contrasted for the two groups. Inpatients had more severe current psychosocial stressors, lower current levels of functioning, increased lifetime co-morbid Axis I diagnoses, and increased rates of psychiatric hospitalizations, however, they did not have higher depression symptom ratings. In conclusion, inpatients and outpatients differed significantly in the severity of their stressors, coping abilities and history of previous hospitalizations, but not in most demographic variables or their current symptoms of depression.

Increased REM sleep density at admission predicts relapse by three months in primary alcoholics with a lifetime diagnosis of secondary depression.

BACKGROUND: Having previously reported that 3-month relapse was associated with increased admission REM pressure in nondepressed primary alcoholics, we hypothesized that baseline polysomnography would predict outcome in primary alcoholics with a lifetime diagnosis of secondary depression. METHODS: Twenty-one primary alcoholics with secondary depression received polysomnography and the Hamilton Depression Rating Scale during the first and fourth weeks of a 1-month inpatient alcohol treatment program. Exclusion criteria included serious illness, current major alcohol withdrawal symptoms, other Axis I diagnoses, sleep apnea, nocturnal myoclonus, and psychoactive substances within 14 days of polysomnography. Relapse was defined as drinking any alcohol between hospital discharge and 3-month follow-up. RESULTS: Relapsers' total sleep time was reduced, and REM density (reflecting REM sleep ocular activity) was increased significantly throughout admission compared with abstainers. Sleep continuity and Hamilton scores improved by discharge in sober and relapsing alcoholics. Factors derived from admission REM latency, REM percent, and REM density predicted sobriety vs. relapse within 3 months after hospital discharge in 76% of patients. Admission REM density was greater, and total sleep time was less in relapsers than in patients sober at 3 months. CONCLUSIONS: Results suggest that increased REM density and decreased total sleep time at about 2-4 weeks of abstinence predict relapse by 3 months in depressed alcoholics.

Effects of a tryptophan-free amino acid drink challenge on normal human sleep electroencephalogram and mood.

BACKGROUND: Serotonin has been implicated in the regulation of sleep and mood. In animals a tryptophan-free amino acid drink (TFD) challenge has been found to reduce brain serotonin. We hypothesized this TFD would produce alterations in electroencephalographic (EEG) sleep commonly associated with depression, i.e. an enhancement of rapid eye movement (REM) sleep, and adversely affect mood ratings in humans. METHODS: We investigated the effects of a TFD challenge in 11 healthy male subjects on EEG sleep and mood (assessed by Profile of Mood States). All subjects received on separate occasions an experimental drink containing approximately 100 g of an amino acid mixture (100% TFD) and a control drink containing one fourth strength (25% TFD) of the experimental drink 5 hours prior to sleep (6:00 PM). RESULTS: Both drinks significantly decreased plasma tryptophan levels 5 hours postchallenge (11:00 PM). Both drinks significantly decreased REM latency, and the 25% TFD also increased REM time and REM% compared to baseline. No significant changes were found in subjective ratings of depression; however, subjects reported confusion and tension and a decrease in elation, vigor, and friendliness compared with baseline. CONCLUSIONS: These TFD findings further support the involvement of serotonin deficiency in EEG sleep findings commonly seen in depression.

Is there a relationship between delta sleep at night and afternoon cerebral blood flow, assessed by HMPAO-SPECT in depressed patients and normal control subjects? Preliminary data.

We wished to explore the relationships between waking HMPAO uptake and visually scored polysomnography. We hypothesized that HMPAO activity would correlate positively with slow wave sleep measures the same night. Eight unmedicated unipolar patients with current DSM-IV major depression (17-item Hamilton Depression Rating Scale score 21.5+/-2.9) and seven control subjects received polysomnography on 2 consecutive nights. On the afternoon following the adaptation night, subjects received cerebral SPECT, with 15 mCi Tc-99m-HMPAO injected while subjects performed the Continuous Performance Task. Patients and control subjects did not significantly differ on demographic, polysomnographic, and SPECT variables. Slow wave sleep measures correlated positively (Spearman's) with global and regional tracer activity for depressed (n = 8), control (n = 7) and combined groups (n = 15); in other words, the greater the global or regional afternoon HMPAO uptake, the greater the slow wave sleep measures were the same night. In addition, the greater the waking afternoon global or regional HMPAO activity, the faster subjects fell asleep and the less Stage 2% they had. In patients, global and regional HMPAO activity correlated positively with REM density. Positive correlations between waking tracer activity and subsequent slow wave measures are consistent with previous hypotheses linking slow wave sleep with brain energy conservation and restoration. Further study is needed to determine whether these functional relationships differ in depression.

Preliminary longitudinal assessment of quality of life in patients with major depression.

This study examines the longitudinal relationships between a health-related quality of life measure and depressive symptoms in patients with major depression. One hundred eighteen patients with primary major depression and 81 controls were evaluated. The patients were divided into three groups based on Diagnostic Interview Schedule criteria for a major depressive episode at baseline (T1) and 6 months later (T2). Results indicate that the Quality of Well-Being (QWB) measure is sensitive to different levels of depressive symptoms over a 6-month period. The QWB is a health-related quality of life and cost/utility measure that may be useful for pharmacoeconomic analysis. The reduction in quality of life associated with symptoms of depression is comparable to that observed with chronically physically ill patients. As a generic symptom/function measure, the QWB may be very useful in evaluating public health policy.

Ipsapirone, a 5-HT1A agonist, suppresses REM sleep equally in unmedicated depressed patients and normal controls.

To determine whether ipsapirone, a 5-HT1A agonist, differentially suppresses REM sleep in depressed patients compared with normal controls, we administered placebo, ipsapirone 10 mg, or ipsapirone 20 mg in a double-blind, random order before bedtime in 18 unmedicated patients with depression and 16 age-matched, gender-matched normal controls. Compared to placebo, ipsapirone affected REM sleep measures equally in depressed patients and controls as follows: (1) increased REM latency; (2) reduced total REM percent, REM time, and REM density; and (3) delayed the onset of REM sleep. In addition, ipsapirone had similar effects in patients and controls in other sleep measures: (1) reduced total sleep time; (2) delayed sleep onset time; and (3) increased sleep latency, stage 1%, stage 2%, the amount of stage 3 & 4 sleep in the first non-REM period, and wake time after sleep onset. The study does not support the hypothesis that downregulated 5-HT1A receptors mediate the pathophysiology or sleep disturbances of depression, although further studies are needed as these patients did not differ from controls in baseline sleep measures.