Psychotropic drugs and the risk of fall injuries, hospitalisations and mortality among older adults.

OBJECTIVE: To investigate whether psychotropics are associated with an increased risk of fall injuries, hospitalizations, and mortality in a large general population of older adults. METHODS: We performed a nationwide matched (age, sex, and case event day) case-control study between 1 January and 31 December 2011 based on several Swedish registers (n = 1,288,875 persons aged ≥65 years). We used multivariate conditional logistic regression adjusted for education, number of inpatient days, Charlson co-morbidity index, dementia and number of other drugs. RESULTS: Antidepressants were the psychotropic most strongly related to fall injuries (ORadjusted : 1.42; 95% CI: 1.38-1.45) and antipsychotics to hospitalizations (ORadjusted : 1.22; 95% CI: 1.19-1.24) and death (ORadjusted : 2.10; 95% CI: 2.02-2.17). Number of psychotropics was associated with increased the risk of fall injuries, (4 psychotropics vs 0: ORadjusted : 1.53; 95% CI: 1.39-1.68), hospitalization (4 psychotropics vs 0: ORadjusted : 1.27; 95% CI: 1.22-1.33) and death (4 psychotropics vs 0: ORadjusted : 2.50; 95% CI: 2.33-2.69) in a dose-response manner. Among persons with dementia (n = 58,984), a dose-response relationship was found between number of psychotropics and mortality risk (4 psychotropics vs 0: ORadjusted : 1.99; 95% CI: 1.76-2.25). CONCLUSIONS: Our findings support a cautious prescribing of multiple psychotropic drugs to older patients. © 2016 The Authors. International Journal of Geriatric Psychiatry Published by John Wiley & Sons, Ltd.

Antidepressants and antipsychotics classified with torsades de pointes arrhythmia risk and mortality in older adults - a Swedish nationwide study.

AIM: The aim of the study was to examine mortality risk associated with use of antidepressants and antipsychotics classified with torsades de pointes (TdP) risk in elderly. METHODS: A matched case-control register study was conducted in people 65 years and older dying outside hospital from 2008-2013 (n = 286,092) and matched controls (n = 1,430,460). The association between prescription of antidepressants and antipsychotics with various TdP risk according to CredibleMeds (www.crediblemeds.org) and all-cause mortality was studied by multivariate conditional logistic regression adjusted for comorbidity and several other confounders. RESULTS: Use of antidepressants classified with known or possible TdP risk, was associated with higher adjusted risk for mortality (OR 1.53, 95% CI 1.51, 1.56 and OR 1.63, 95% CI 1.61, 1.67, respectively) compared with antidepressants classified with conditional TdP risk (OR 1.25, 95% CI 1.22, 1.28) or without TdP classification (OR 0.99, 95% CI 0.94, 1.05). Antipsychotics classified with known TdP risk were associated with higher risk (OR 4.57, 95% CI 4.37, 4.78) than antipsychotics with possible risk (OR 2.58, 95% CI 2.52, 2.64) or without TdP classification (OR 2.14, 95% CI 2.03, 2.65). The following risk ranking was observed for commonly used antidepressants: mirtazapine > citalopram > sertraline > amitriptyline and for antipsychotics: haloperidol > risperidone >olanzapine > quetiapine. CONCLUSION: The CredibleMeds system predicted drug-associated risk for mortality in the elderly at the risk class level. Among antipsychotics, haloperidol, and among antidepressants, mirtazapine and citalopram, were associated with the highest risks. The results suggest that the TdP risk with antidepressants and antipsychotics should be taken into consideration when prescribing to the elderly.

Mortality, attempted suicide, re-hospitalisation and prescription refill for clozapine and other antipsychotics in Sweden-a register-based study.

PURPOSE: The aim of this study was to analyse prescription refill, re-hospitalisation, total mortality, mortality because of suicide and attempted suicide among patients who were taking various types of antipsychotics. METHODS: A population-based cohort study analysed all patients (n=26046) in Sweden who had been treated for schizophrenia from 2006 to 2009 with regard to re-hospitalisation and prescription refill for various types of antipsychotic treatment. A case-control study nested within the cohort analysed all-cause mortality, mortality because of suicide and attempted suicide in relation to antipsychotic use. The study adjusted for history of hospitalisation for psychiatric and medical care, attempted suicide and use of antidepressants. RESULTS: Aripiprazole users were the only ones who showed significantly lower all-cause risks of death, but so few events occurred among users of this relatively new drug that the results should be interpreted with caution. Clozapine users showed lower odds of death by suicide (odds ratio [OR]=0.45 [95%CI 0.20-0.98]) and of attempted suicide (OR=0.44 [0.28-0.70]) than haloperidol users after adjustment for age, sex and year of discharge. Olanzapine users showed approximately the same favourable pattern. Patients who used clozapine were most likely to refill prescriptions and had lower rates of re-hospitalisation. Only one death and 23 cases of agranulocytosis were reported compared with 223 suicides and 831 suicide attempts. An etiologic fraction calculation suggests that the use of clozapine rather than traditional drugs could have prevented 95 suicide attempts during the period. CONCLUSION: Clozapine and olanzapine reduce the risk of suicide, attempted suicide and re-hospitalisation.

Does multidisciplinary assessment of long-term sickness absentees result in modification of sick-listing diagnoses?

AIMS: The aim was to study whether sick-leave diagnoses of long-term sickness absentees were modified after a multidisciplinary assessment and if modifications differed with type of medical specialty of the latest physician to sick-list the patient. METHODS: A sample of 635 long-term sickness absentees referred to a multidisciplinary assessment by Social Insurance Offices was included. Data were obtained through sickness certificates and medical records. Patients were examined by board-certified specialists in psychiatry, orthopaedic surgery, and rehabilitation medicine. Descriptive statistics were used. RESULTS: The multidisciplinary assessment resulted in an increase from 1-2 to 2-3 diagnoses for most patients. Forty-five per cent of the male and 47% of the female patients had only somatic diagnoses at referral. After the multidisciplinary assessment these percentages were 20% and 29%, respectively. The rate of women and men given both psychiatric and somatic diagnoses increased from 30% at referral to about 55%. The shift from either only psychiatric or only somatic diagnoses to having these diagnoses in combination was associated with type of specialty of the physician who had sick-listed the patient. CONCLUSIONS: The study indicates that many patients on long-term sick-leave with unclear diagnoses may suffer from unrecognized, and therefore probably untreated, medical disorders and co-morbidity.

Outcome of multidisciplinary investigations of long-term sickness absentees.

OBJECTIVE: The aim was to investigate the results of multidisciplinary investigations of long-term sickness absentees regarding diagnoses, degree and prognoses of work incapacity, and need of rehabilitation measures and whether this was associated with socio-demographic factors. METHOD: A cross-sectional study of 545 long-term (>1 year) sickness absentees referred to multidisciplinary investigations by the Social Insurance Office. Data was obtained from questionnaires and medical records. The patients were examined by specialists in psychiatry, orthopaedic surgery, and rehabilitation medicine who afterwards agreed on diagnoses, work incapacity, time to return to work (RTW), and rehabilitation measures. Descriptive statistics and logistic regression were used for description and analyses of data. Data on age, country of birth, education, employment and marital status were included. RESULTS: The prevalence of psychiatric diagnoses was 72%, and 58% of the patients had that in combination with somatic diagnoses. Most patients were assessed to be capable of RTW within 6 - 24 months after further rehabilitation measures. Higher age was associated with a negative prognosis of RTW and those patients were less often recommended additional rehabilitation. CONCLUSION: Despite long-term sickness absence and high rates of psychiatric and somatic diagnoses in combination, RTW was considered possible for most patients after further rehabilitation measures.

The effects of methylmercury on motor activity are sex- and age-dependent, and modulated by genetic deletion of adenosine receptors and caffeine administration.

Adenosine and its receptors are, as part of the brain stress response, potential targets for neuroprotective drugs. We have investigated if the adenosine receptor system affects the developmental neurotoxicity caused by the fish pollutant methylmercury (MeHg). Behavioral outcomes of low dose perinatal MeHg exposure were studied in mice where the A(1) and A(2A) adenosine receptors were either partially blocked by caffeine treatment or eliminated by genetic modification (A(1)R and A(2A)R knock-out mice). From gestational day 7 to day 7 of lactation dams were administered doses that mimic human intake via normal diet, i.e. 1microM MeHg and/or 0.3g/l caffeine in the drinking water. This exposure to MeHg resulted in a doubling of brain Hg levels in wild type females and males at postnatal day 21 (PND21). Open field analysis was performed at PND21 and 2 months of age. MeHg caused time-dependent behavioral alterations preferentially in male mice. A decreased response to amphetamine in 2-month-old males pointed to disturbances in dopaminergic functions. Maternal caffeine intake induced long-lasting changes in the offspring evidenced by an increased motor activity and a modified response to psychostimulants in adult age, irrespectively of sex. Similar alterations were observed in A(1)R knock-out mice, suggesting that adenosine A(1) receptors are involved in the alterations triggered by caffeine exposure during development. Perinatal caffeine treatment and, to some extent, genetic elimination of adenosine A(1) receptors, attenuated the behavioral consequences of MeHg in males. Importantly, also deletion of the A(2A) adenosine receptor reduced the vulnerability to MeHg, consistent with the neuroprotective effects of adenosine A(2A) receptor inactivation observed in hypoxia and Parkinson's disease. Thus, the consequences of MeHg toxicity during gestation and lactation can be reduced by adenosine A(1) and A(2A) receptor inactivation, either via their genetic deletion or by treatment with their antagonist caffeine.

Adenosine-dopamine interactions revealed in knockout mice.

Neurochemical and pharmacological evidence obtained over the past 30 yr has indicated that adenosine and dopamine interact functionally in the basal ganglia and that such interactions have pathophysiological and therapeutic implications. The receptors implicated are adenosine A1 and A2A, and dopamine D1 and D2. There is evidence that dopamine D2 receptor activation in vivo antagonizes tonic activation of adenosine A2A receptors. Thus, acute blockade of dopamine D2 receptors, or disruption of dopamine transmission, unmasks strong adenosine A2A activation. Effects of dopamine D2 blockade are different after adenosine A2A blockade or in A2A knockout mice. Possibly as an adaptation to this increase in adenosine A2A signaling, there is a decreased coupling of A2A receptors to biological effects in dopamine D2 knockout mice. Compared to wild-type mice, adenosine A2A knockout mice show decreased neurodegeneration after treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and show improved motor performance in models of Parkinson's disease Adenosine A1 receptors are not specifically located with any dopamine receptor, as is the A2A receptor with D2 receptors. Many A1 receptors are located presynaptically, where they regulate transmitter release. In A1 knockout mice, glutamatergic and dopaminergic transmission is therefore modified.

Behavioural analysis of melanin-concentrating hormone in rats: evidence for orexigenic and anxiolytic properties.

Melanin-concentrating hormone (MCH) is a cyclic neuropeptide, predominantly expressed in hypothalamus, and recognized as a key regulator in feeding behaviour and energy balance. In this study, we examined the behavioural effects of intracerebroventricularly administered MCH on food intake, anxiety, exploratory behaviour and body core temperature in rats. MCH (0.15-10.0 microg, i.c.v.) acutely increased food intake in a dose-dependent manner. In addition, MCH (0.6-10.0 microg, i.c.v.) produced effects similar to anxiolytics in an animal model of anxiety, Vogel's punished drinking test. Thus, punished drinking episodes were significantly increased. We found no effects of MCH (5.0-20.0 microg, i.c.v.) on locomotor activity either in habituated or non-habituated animals. Furthermore, MCH did not produce any changes in body core temperature. Together, these observations further support a role for MCH as an orexigenic neuropeptide and also suggest anti-anxiety properties for MCH.

Functional interactions between delta- and mu-opioid receptors in rat thermoregulation.

The selective delta-opioid receptor agonist deltorphin II (25.0-100.0 microg, i.c.v.) produced biphasic effects on core temperature in rats, in which hypothermia was followed by hyperthermia. Pretreatment with the selective delta-opioid receptor antagonist, naltrindole (25.0 microg, i.c.v.), blocked hypothermia produced by deltorphin II and had a tendency to potentiate the hyperthermic effect of deltorphin II. The non-selective opioid receptor antagonist naloxone (1.5 mg kg(-1), s.c.) potentiated hypothermia, and blocked hyperthermia, produced by deltorphin II (100.0 microg). Also, naloxone potentiated hypothermia produced by a lower dose of deltorphin II (25.0 microg), which did not produce hyperthermia. A similar pattern was found for the selective mu-opioid receptor antagonist, beta-funaltrexamine (5.0 microg, i.c.v.), which potentiated and blocked deltorphin II-induced hypo- and hyperthermia, respectively. The selective kappa-opioid receptor antagonist nor-binaltorphimine (20.0 microg, i.c.v.) had no effects on deltorphin II-induced temperature changes. The present results suggest that deltorphin II produces hypothermia through activation of delta-opioid receptors, whereas the hyperthermic effect of deltorphin II involves activation of mu-opioid receptors. This mu-opioid receptor stimulatory effect of deltorphin II is furthermore more pronounced than was anticipated based on the reported in vitro properties of this compound. The biphasic effect of deltorphin II implies a negative interaction between delta- and mu-opioid receptors in thermoregulation in rats.

Anti-cataleptic effects of clozapine, but not olanzapine and quetiapine, on SCH 23390- or raclopride-induced catalepsy in rats.

The present study investigated potential anti-cataleptic properties of the prototype atypical antipsychotic clozapine and two newly developed atypical antipsychotics, olanzapine and quetiapine, which are structurally related and display similar pharmacological profiles to clozapine. Clozapine (2.5 mg kg(-1), s.c.), but not olanzapine (2.0 mg kg(-1), s.c.) and quetiapine (20.0 mg kg(-1), s.c.), blocked catalepsy induced either by the dopamine D(1/5) receptor antagonist SCH 23390 (50.0 microg kg(-1), s.c) or the selective dopamine D(2/3) receptor antagonist raclopride (4.0 mg kg(-1), s.c.). Such findings are consistent with the beneficial effects of clozapine in the management of drug-induced psychosis in parkinsonian patients, and suggest that neither olanzapine nor quetiapine may be a safe alternative to clozapine in this field. Furthermore, the results indicate that clozapine has a unique pharmacological profile that distinguishes it from olanzapine and quetiapine. The mechanisms underlying anti-cataleptic or anti-parkinsonian properties of clozapine are unclear but may be related to dopamine D(1) receptor agonism of clozapine.

An association between initiation of selective serotonin reuptake inhibitors and suicide - a nationwide register-based case-crossover study.

BACKGROUND: Treatment with selective serotonin reuptake inhibitors (SSRI) is one of the most common treatments for depression. It is however not clear whether or not there is an increased short-term suicide risk during initiation with SSRI. METHODS: A register-based nationwide case-crossover study including 5,866 suicides, 1,698 women and 4,168 men, from the Death Register 2007-2010 in Sweden. SSRI initiation was defined as a dispensed prescription of SSRI within 28 days prior to the date of suicide with no previous dispensed prescription of SSRI within 4 months prior that prescription. The control period took place one year earlier. Odds ratio (OR) was estimated using conditional logistic regression. RESULT: During the 28 day period prior to suicide 48 women and 138 men were exposed to SSRI initiation (while not being exposed in the control period) and 22 women and 43 men were exposed in the control period (while not being exposed in the case period). The OR for suicide after initiation with SSRI was 2.7 (95% CI: 1.6-44) for women, and 4.3 (95% CI: 3.0-6.1) for men. The highest OR was found 8-11 days after initiation with SSRI 9.7 (95% CI: 3.0-31.7) for women and men combined. CONCLUSION: The main limitation in this study is confounding by indication, but the descriptive question is however not confounded by indication. Together with plausible biological mechanisms and previous clinical and epidemiological observations our findings, linking initiation of SSRI to increased short-term suicide risk, deserve further attention specifically in the clinical setting.

Multidisciplinary investigations recognize high prevalence of co-morbidity of psychiatric and somatic diagnoses in long-term sickness absentees.

AIMS: In Sweden, the Social Insurance Offices each year refer long-term sickness absentees to comprehensive investigations to clarify medical conditions. However, there is a lack of scientific knowledge about these patients and their morbidity. The aim was to characterize a population of these sickness absentees regarding prevalence of somatic and psychiatric diagnoses and possible associations with sociodemographic, lifestyle, and health characteristics. METHODS: A cross-sectional study was made up of 635 sickness absentees below the age of 64, who the local Social Insurance Offices in Stockholm County, Sweden, referred to a special unit for multidisciplinary investigation. Data was obtained from questionnaires and medical records. The patients were examined by board certified specialists in psychiatry, orthopaedic surgery, and rehabilitation medicine. Relative risks were estimated by use of modified Poisson regression to assess the associations between characteristics and diagnose outcomes. RESULTS: About 80% of the patients had more than one diagnosis. The vast majority had a psychiatric diagnosis, and approximately 55% had that in combination with at least one somatic diagnosis. An increased risk for being given a psychiatric diagnosis was found for men and unemployed people. In addition, lack of social life and friends and self-reported mental health problems were associated with psychiatric diagnoses but also among those who were given somatic diagnoses in combination with psychiatric diagnoses. Increased risks for somatic diagnoses were found for women and for patients with a higher education. CONCLUSIONS: Long-term sickness absentees referred to multidisciplinary investigations display high co-morbidity of psychiatric and somatic diagnoses and are a heterogeneous group with diverse sociodemographic and medical characteristics.

Perinatal caffeine, acting on maternal adenosine A(1) receptors, causes long-lasting behavioral changes in mouse offspring.

BACKGROUND: There are lingering concerns about caffeine consumption during pregnancy or the early postnatal period, partly because there may be long-lasting behavioral changes after caffeine exposure early in life. METHODOLOGY/PRINCIPAL FINDINGS: We show that pregnant wild type (WT) mice given modest doses of caffeine (0.3 g/l in drinking water) gave birth to offspring that as adults exhibited increased locomotor activity in an open field. The offspring also responded to cocaine challenge with greater locomotor activity than mice not perinatally exposed to caffeine. We performed the same behavioral experiments on mice heterozygous for adenosine A(1) receptor gene (A(1)RHz). In these mice signaling via adenosine A(1) receptors is reduced to about the same degree as after modest consumption of caffeine. A(1)RHz mice had a behavioral profile similar to WT mice perinatally exposed to caffeine. Furthermore, it appeared that the mother's genotype, not offspring's, was critical for behavioral changes in adult offspring. Thus, if the mother partially lacked A(1) receptors the offspring displayed more hyperactivity and responded more strongly to cocaine stimulation as adults than did mice of a WT mother, regardless of their genotype. This indicates that long-term behavioral alterations in the offspring result from the maternal effect of caffeine, and not a direct effect on fetus. WT offspring from WT mother but having a A(1)R Hz grandmother preserved higher locomotor response to cocaine. CONCLUSIONS/SIGNIFICANCE: We suggest that perinatal caffeine, by acting on adenosine A(1) receptors in the mother, causes long-lasting behavioral changes in the offspring that even manifest themselves in the second generation.

Dihydrexidine--the first full dopamine D1 receptor agonist.

The functional role of dopamine D(1) receptors is still controversial. One reason for this controversy is that for a long time the only available agonists for in vivo characterization of dopamine D(1) receptors were benzazepines. Among them was the prototype dopamine D(1) receptor partial agonist, SKF 38393. The lack of a selective and fully efficacious dopamine D(1) receptor agonist hampered basic research on dopamine D(1) receptors and left the potential clinical utility of dopamine D(1) receptor agonists elusive. The research situation improved when the first potent full dopamine D(1) receptor agonist dihydrexidine, a phenanthridine, was introduced in the late 1980s. In contrast to SKF 38393, dihydrexidine was shown to stimulate cyclic AMP synthesis just as well or better than dopamine, and potently displaced [(3)H]SCH 23390 from rat and monkey striatal membranes. Also, dihydrexidine was the first dopamine D(1) receptor agonist that had potent antiparkinsonian activity in a primate model of Parkinson's disease. This finding suggested clinical utility for dopamine D(1) receptor agonists in Parkinson's disease and that this utility might be critically dependent on the intrinsic efficacy of the drug. Clinical utility for dopamine D(1) receptor agonists in other central nervous disorders might also be dependent on the intrinsic efficacy of the drug. However, even though studies with dihydrexidine as a pharmacological tool have pointed to the clinical use for dopamine D(1) receptor agonists, dihydrexidine's unfavorable pharmacokinetic profile and various adverse effects are likely to restrict or even preclude its use in humans. This review article provides an updated overview of the pharmacology of dihydrexidine and discusses possible clinical utility of dopamine D(1) receptor agonists in various central nervous system disorders.