Lars Tanum

The effect of variable cigarette consumption on the interaction with clozapine and olanzapine

ObjectiveCigarette smoking has been shown in several studies to induce the metabolism of the cytochrome P4501A2 (CYP1A2) substrates clozapine and olanzapine. The aim of the present study was to investigate the dose-dependent effect of cigarette smoking on serum concentrations of these drugs in a naturalistic setting.MethodsIn 73 schizophrenic patients recruited from psychiatric nursing homes, patient characteristics, smoking habits, drug dosing and serum concentrations of clozapine (n=33) and olanzapine (n=40) were registered. Concentration to dose (C/D) ratios of clozapine and olanzapine in non-smokers and subgroups of smokers were compared.ResultsFifty-nine patients (80%) were smokers and these were stratified into the following groups according to smoking habits: 1–6 (n=0), 7–12 (n=13), 13–19 (n=18) and ≥20 (n=28) cigarettes daily. While the mean ratio was twice as high in non-smokers compared to smokers for both drugs (p<0.01), the C/D ratios of clozapine and olanzapine were not significantly different between the subgroups of smokers (p >0.15). Absolute serum concentrations were also higher in non-smokers compared to smokers: 50% for clozapine (p=0.058) and 67% for olanzapine (p<0.01).ConclusionA daily consumption of 7–12 cigarettes is probably sufficient for maximum induction of clozapine and olanzapine metabolism. A 50% lower starting dose of both drugs in non-smokers seems rational to avoid side effects.

Amphetamine-induced psychosis - a separate diagnostic entity or primary psychosis triggered in the vulnerable?

Use of amphetamine and methamphetamine is widespread in the general population and common among patients with psychiatric disorders. Amphetamines may induce symptoms of psychosis very similar to those of acute schizophrenia spectrum psychosis. This has been an argument for using amphetamine-induced psychosis as a model for primary psychotic disorders. To distinguish the two types of psychosis on the basis of acute symptoms is difficult. However, acute psychosis induced by amphetamines seems to have a faster recovery and appears to resolve more completely compared to schizophrenic psychosis. The increased vulnerability for acute amphetamine induced psychosis seen among those with schizophrenia, schizotypal personality and, to a certain degree other psychiatric disorders, is also shared by non-psychiatric individuals who previously have experienced amphetamine-induced psychosis. Schizophrenia spectrum disorder and amphetamine-induced psychosis are further linked together by the finding of several susceptibility genes common to both conditions. These genes probably lower the threshold for becoming psychotic and increase the risk for a poorer clinical course of the disease.The complex relationship between amphetamine use and psychosis has received much attention but is still not adequately explored. Our paper reviews the literature in this field and proposes a stress-vulnerability model for understanding the relationship between amphetamine use and psychosis.

Stereospecific determination of citalopram and desmethylcitalopram by capillary electrophoresis and liquid-phase microextraction.

A chiral capillary electrophoresis (CE) system allowing simultaneous enantiomer determination of citalopram (CIT) and its pharmacologically active metabolite desmethylcitalopram (DCIT) was developed. Excellent chiral separation was obtained using 1% sulfated-beta-cyclodextrin (S-beta-CD) as chiral selector in combination with 12% ACN in 25 mM phosphate pH 2.5. Samples were prepared by liquid-phase microextraction (LPME) based on a rodlike porous polypropylene hollow fibre. CIT and DCIT were extracted from 1 ml plasma made alkaline with NaOH, into dodecyl acetate impregnated in the pores of a hollow fibre, and into 20 mM phosphate pH 2.75, inside the hollow fibre. The acceptor solution was directly compatible with the CE system. Efficient sample clean-up was seen, and the recoveries were 46 and 29% for the enantiomers of CIT and DCIT, respectively, corresponding to 31 and 19 times enrichment. The limit of quantification (S/N=10) was <11.2 ng/ml, intra-day precision was <12.8% RSD, and inter-day precision was <14.5% RSD, for all enantiomers. The validated method was successfully applied to simultaneous determination of enantiomer concentrations of CIT and DCIT in plasma samples from nine patients treated with racemic citalopram. The results confirm LPME-CE as a suitable and promising tool for enantiomeric determination of chiral drugs and metabolites in biological matrices.

Personality and physical symptoms in nonpsychiatric patients with functional gastrointestinal disorder

OBJECTIVE We investigated the relationship between personality and reported pain and somatic distress in patients with functional gastrointestinal disorder (FGD) without psychopathology. METHODS Fifty-six patients and 55 controls completed Buss-Durkee Hostility Inventory (BDHI), NEO Personality Inventory (NEO-PI), Eysenck Personality Questionnaire (EPQ: N+L scales), and Giessener Physical Complaints Checklist (GBB). Patients also completed McGill Pain Questionnaire (MPQ) and Visual Analogue Scale (VAS) for abdominal pain and target symptom (abdominal distress). RESULTS Patients displayed significantly higher levels of neuroticism and covert aggression than controls. Number of words chosen (NWC) to describe pain and sensory pain index (MPQ), but not pain intensity on VAS, were predicted by indirect aggression -- and less so by neuroticism -- in females and covert aggression in males (stepwise regression model). Patients reported far more extraintestinal somatic complaints than controls. CONCLUSION Out of nine dimensions of hostility and five dimensions of personality, only neuroticism and concealed aggression are increased in FGD patients without psychiatric comorbidity compared with healthy controls. These personality traits influence pain reports and should be taken into account when evaluating and treating patients with FGD. Neuroticism and concealed aggression are most likely markers of vulnerability to FGD and not merely reflections of being chronic ill or explained by sample bias secondary to illness behavior.

Effectiveness of Injectable Extended-Release Naltrexone vs Daily Buprenorphine-Naloxone for Opioid Dependence: A Randomized Clinical Noninferiority Trial

Importance To date, extended-release naltrexone hydrochloride has not previously been compared directly with opioid medication treatment (OMT), currently the most commonly prescribed treatment for opioid dependence. Objective To determine whether treatment with extended-release naltrexone will be as effective as daily buprenorphine hydrochloride with naloxone hydrochloride in maintaining abstinence from heroin and other illicit substances in newly detoxified individuals. Design, Setting and Participants A 12-week, multicenter, outpatient, open-label randomized clinical trial was conducted at 5 urban addiction clinics in Norway between November 1, 2012, and December 23, 2015; the last follow-up was performed on October 23, 2015. A total of 232 adult opioid-dependent (per DSM-IV criteria) individuals were recruited from outpatient addiction clinics and detoxification units and assessed for eligibility. Intention-to-treat analyses of efficacy end points were performed with all randomized participants. Interventions Randomization to either daily oral flexible dose buprenorphine-naloxone, 4 to 24 mg/d, or extended-release naltrexone hydrochloride, 380 mg, administered intramuscularly every fourth week for 12 weeks. Main Outcomes and Measures Primary end points (protocol) were the randomized clinical trial completion rate, the proportion of opioid-negative urine drug tests, and number of days of use of heroin and other illicit opioids. Secondary end points included number of days of use of other illicit substances. Safety was assessed by adverse event reporting. Results Of 159 participants, mean (SD) age was 36 (8.6) years and 44 (27.7%) were women. Eighty individuals were randomized to extended-release naltrexone and 79 to buprenorphine-naloxone; 105 (66.0%) completed the trial. Retention in the extended-release naltrexone group was noninferior to the buprenorphine-naloxone group (difference, −0.1; with 95% CI, −0.2 to 0.1; P = .04), with mean (SD) time of 69.3 (25.9) and 63.7 (29.9) days, correspondingly (P = .33, log-rank test). Treatment with extended-release naltrexone showed noninferiority to buprenorphine-naloxone on group proportion of total number of opioid-negative urine drug tests (mean [SD], 0.9 [0.3] and 0.8 [0.4], respectively, difference, 0.1 with 95% CI, −0.04 to 0.2; P < .001) and use of heroin (mean difference, −3.2 with 95% CI, −4.9 to −1.5; P < .001) and other illicit opioids (mean difference, −2.7 with 95% CI, −4.6 to −0.9; P < .001). Superiority analysis showed significantly lower use of heroin and other illicit opioids in the extended-release naltrexone group. No significant differences were found between the treatment groups regarding most other illicit substance use. Conclusions and Relevance Extended-release naltrexone was as effective as buprenorphine-naloxone in maintaining short-term abstinence from heroin and other illicit substances and should be considered as a treatment option for opioid-dependent individuals. Trial Registration clinicaltrials.gov Identifier: NCT01717963

Neuropsychological functioning in late-life depression

Background: The literature describing neurocognitive function in patients with late-life depression (LLD) show inconsistent findings in regard to incidence and main deficits. Reduced information processing speed is in some studies found to explain deficits in higher order cognitive function, while other studies report specific deficits in memory and executive function. Our aim was to determine the characteristics of neuropsychological functioning in non-demented LLD patients. Methods: A comprehensive neuropsychological battery was administered to a group of hospitalized LLD patients and healthy control (HC) subjects. Thirty-nine patients without dementia, 60 years or older meeting DSM-IV criteria for current episode of major depression, and 18 non-depressed control subjects were included. The patient group was characterized by having a long lasting current depressive episode of late-onset depression and by being non-responders to treatment with antidepressants. Neurocognitive scores were calculated for the domains of information processing speed, verbal memory, visuospatial memory, executive function, and language. Number of impairments (performance below the 10th percentile of the control group per domain) for each participant was calculated. Results: Nearly half of the patients had a clinically significant cognitive impairment in at least one neurocognitive domain. Relative to HC subjects, LLD patients performed significantly poorer in the domains of information processing speed and executive function. Executive abilities were most frequently impaired in the patient group (39% of the patients). Even when controlling for differences in processing speed, patients showed more executive deficits than controls. Conclusions: Controlling for processing speed, patients still showed impaired executive function compared to HCs. Reduced executive function thus appears to be the core neurocognitive deficit in LLD. Executive function seems to be an umbrella concept for several connected but distinct cognitive functions. Further studies of neuropsychological functioning in LLD patients are needed to characterize more specific what kinds of executive impairments patients have. Additional studies of remitted LLD patients are needed to separate episode-related and persistent impairments.

Clinical efficacy of formula-based bifrontal versus right unilateral electroconvulsive therapy (ECT) in the treatment of major depression among elderly patients: A pragmatic, randomized, assessor-blinded, controlled trial

BACKGROUND No prior study has compared the efficacy of bifrontal (BF) vs right unilateral (RUL) electroconvulsive therapy (ECT) by including the subgroup that is most likely to receive it: only elderly patients with major depression (MD). METHODS This single-site, randomized, assessor-blinded, controlled trial was conducted from 2009 to 2013. Seventy-three elderly patients with MD, unipolar and bipolar, were treated with a course of formula-based BF ECT or RUL ECT. The 17-item Hamilton Rating Scale for Depression (HRSD17) was used to measure efficacy. Safety was assessed with the Mini Mental State Examination (MMSE). RESULTS Both electrode placements resulted in highly significant downward trends in symptom severity (all p<0.001), with a non-significant difference between methods (p=0.703). At the end of the ECT course, response rates for the BF and RUL group were 63.9% and 67.6%, respectively. Short-term remission, defined as an HRSD17 score≤7, was achieved in 14 (38.9%) patients in the BF group and 19 (51.4%) patients in the RUL group. Global cognitive function, as measured by the MMSE, did not deteriorate in the two treatment groups. LIMITATIONS The small number of subjects may have led to reduced power to detect real differences. The MMSE is not sufficient to ascertain the negative effect of ECT on cognition. CONCLUSIONS This study indicates that formula-based BF and RUL ECT are equally efficacious, and that remission rates of formula-based dosing are lower than those previously reported for titrated dosing, in a clinical sample of elderly patients with MD. TRIAL REGISTRATION ClinicalTrials.gov NCT01559324.

Evidence of both systemic inflammation and neuroinflammation in fibromyalgia patients, as assessed by a multiplex protein panel applied to the cerebrospinal fluid and to plasma

In addition to central hyperexcitability and impaired top–down modulation, chronic inflammation probably plays a role in the pathophysiology of fibromyalgia (FM). Indeed, on the basis of both animal experiments and human studies involving the analysis of cytokines and other inflammation-related proteins in different body fluids, neuroinflammatory mechanisms are considered to be central to the pathophysiology of many chronic pain conditions. However, concerning FM, previous human plasma/serum and/or cerebrospinal fluid (CSF) cytokine studies have looked only at a few predetermined cytokine candidates. Instead of analyzing only a few substances at a time, we used a new multiplex protein panel enabling simultaneous analysis of 92 inflammation-related proteins. Hence, we investigated the CSF and plasma inflammatory profiles of 40 FM patients compared with CSF from healthy controls (n=10) and plasma from blood donor controls (n=46). Using multivariate data analysis by projection, we found evidence of both neuroinflammation (as assessed in CSF) and chronic systemic inflammation (as assessed in plasma). Two groups of proteins (one for CSF and one for plasma) highly discriminating between patients and controls are presented. Notably, we found high levels of CSF chemokine CX3CL1 (also known as fractalkine). In addition, previous findings concerning IL-8 in FM were replicated, in both CSF and plasma. This is the first time that such an extensive inflammatory profile has been described for FM patients. Hence, FM seems to be characterized by objective biochemical alterations, and the lingering characterization of its mechanisms as essentially idiopathic or even psychogenic should be seen as definitively outdated.

Symptoms of depression and anxiety in functionally disabled rheumatic pain patients

The aim of the present work was to study correlations between self-assessment of symptoms of depression, anxiety, rheumatic pain and functional disability. One hundred patients admitted to a university rheumatology clinic were tested in a consecutive manner, applying the Hospital Anxiety and Depression Scale (HADS). In addition, the patients were asked to express a quantitative measure of their subjective pain and functional disability on visual analogue scales (VAS). Regression analysis (analysis of variance) showed significant correlation between rheumatic pain and depression (P=0.04), between rheumatic pain and anxiety (P=0.03) and between rheumatic pain and functional disability (P<0.000). Significant correlations were also seen between depressive symptoms and functional disability (P=0.01) and between anxiety and functional disability (P=0.002). The correlation between symptoms of anxiety and depression was at a P=0.000 level. Applying the experience from this study and introducing, as part of a clinical examination, a minimum of psychiatric investigation based on self-assessment of anxiety and depression will provide relevant and reliable information sufficient for following up with specific psychiatric investigations and therapy. This in turn will be positive for those of the rheumatic patients having a comorbid mental health problem.

Cognitive Side-effects of Electroconvulsive Therapy in Elderly Depressed Patients

Knowledge about cognitive side-effects induced by electroconvulsive therapy (ECT) in depressed elderly patients is sparse. In this study we investigated changes in the cognitive functioning of non-demented elderly depressed patients receiving ECT (n = 62) compared with healthy elderly people (n = 17). Neuropsychological tests were administered at the start of treatment and again within 1 week after treatment. We computed reliable change indices (RCIs) using simple regression methods. RCIs are statistical methods for analyzing change in individuals that have not yet been used in studies of the acute cognitive side-effects of ECT. At the group level, only letter fluency performance was found to be significantly reduced in the ECT group compared with the controls, whereas both groups demonstrated stable or improved performance on all other measures. At the individual level, however, 11% of patients showed retrograde amnesia for public facts post-ECT and 40% of the patients showed a significant decline in neuropsychological functioning. Decline on a measure of delayed verbal anterograde memory was most common. Our findings indicate that there are mild neurocognitive impairments in the acute phase for a substantial minority of elderly patients receiving ECT. Analysis of reliable change facilitated the illumination of cognitive side-effects in our sample.