Decreased retinal sensitivity in depressive disorder: a controlled study.

OBJECTIVE: To compare pupil responses in depressed patients with a seasonal pattern, depressed patients without a seasonal pattern and healthy controls as a function of daylight hours on the testing day. METHOD: Patients suffering from a major depressive episode were included in wintertime. The pupil light reflex was measured at inclusion and in the following summer using a binocular pupillometer. A protocol of low (1 lux) and high (400 lux) intensity red and blue lights was used to assess rod, cone and melanopsin-containing intrinsic photosensitive retinal ganglion cell input to the pupil reflex. RESULTS: The mean group pupil responses associated with a melanopsin-mediated sustained pupil response at 400 lux blue light were significantly reduced in the depressed subjects (N = 39) as compared to the healthy controls (N = 24) (P = 0.023). Across all groups, a reduction in number of daylight hours was significantly associated with a reduction in sustained pupil response (P = 0.007). All groups showed an equal effect of daylight hours on the melanopsin-mediated sustained pupil response. CONCLUSION: The melanopsin-mediated sustained pupil contraction to offset of high-intensity blue light is reduced in depressed patients. These results further emphasize the interaction of light exposure with depression.

Continuation of lithium after a diagnosis of chronic kidney disease.

OBJECTIVE: To investigate whether continued lithium or anticonvulsant treatment after a first diagnosis of chronic kidney disease (CKD) was associated with progression to irreversible end-stage kidney disease. METHODS: Nationwide cohort study including all individuals in Denmark in a period from 1995 to 2012 with a diagnosis of CKD and (i) a history of lithium treatment (N = 754, among whom 238 patients had a diagnosis of bipolar disorder) or (ii) a history of anticonvulsant treatment (N = 5.004, among whom 199 patients had a diagnosis of bipolar disorder). End-stage CKD was defined as chronic dialysis or renal transplantation. RESULTS: Continuing lithium (HR = 0.58 (95% CI: 0.37-0.90) and continuing anticonvulsants (HR = 0.53 (95% CI: 0.44-0.64) were associated with decreased rates of end-stage CKD. In the subcohorts of patients with a diagnosis of bipolar disorder, continuing lithium was associated with decreased end-stage CKD (HR = 0.40 (95% CI: 0.17-0.98), whereas continuing anticonvulsants was not (HR = 0.70 (95% CI: 0.21-2.37). There were no interactions of continuing lithium and anticonvulsants. CONCLUSION: After an initial diagnosis of CKD, patients who are selected by their physicians to continue lithium treatment may not necessarily have an increased risk of developing end-stage CKD. Shifting to an anticonvulsant per se may not be associated with an advantage; however, this requires further investigation.

Solar insolation in springtime influences age of onset of bipolar I disorder.

OBJECTIVE: To confirm prior findings that the larger the maximum monthly increase in solar insolation in springtime, the younger the age of onset of bipolar disorder. METHOD: Data were collected from 5536 patients at 50 sites in 32 countries on six continents. Onset occurred at 456 locations in 57 countries. Variables included solar insolation, birth-cohort, family history, polarity of first episode and country physician density. RESULTS: There was a significant, inverse association between the maximum monthly increase in solar insolation at the onset location, and the age of onset. This effect was reduced in those without a family history of mood disorders and with a first episode of mania rather than depression. The maximum monthly increase occurred in springtime. The youngest birth-cohort had the youngest age of onset. All prior relationships were confirmed using both the entire sample, and only the youngest birth-cohort (all estimated coefficients P < 0.001). CONCLUSION: A large increase in springtime solar insolation may impact the onset of bipolar disorder, especially with a family history of mood disorders. Recent societal changes that affect light exposure (LED lighting, mobile devices backlit with LEDs) may influence adaptability to a springtime circadian challenge.

Relapse Prevention in Major Depressive Disorder After Successful Acute Electroconvulsive Treatment: a 6-month Double-blind Comparison of Three Fixed Dosages of Escitalopram and a Fixed Dose of Nortriptyline - Lessons from a Failed Randomised Trial of the Danish University Antidepressant Group (DUAG-7).

INTRODUCTION: Electroconvulsive treatment (ECT) is an effective treatment for severe depression but carries a risk of relapse in the following months. METHODS: Major depressive disorder patients in a current episode attaining remission from ECT (17-item Hamilton Depression Rating Scale (HAM-D17) score≤9) received randomly escitalopram 10 mg, 20 mg, 30 mg or nortriptyline 100 mg as monotherapies and were followed for 6 months in a multicentre double-blind set-up. Primary endpoint was relapse (HAM-D17≥16). RESULTS: As inclusion rate was low the study was prematurely stopped with only 47 patients randomised (20% of the planned sample size). No statistically significant between-group differences could be detected. When all patients receiving escitalopram were compared with those receiving nortriptyline, a marginal superiority of nortriptyline was found (p=0.08). One third of patients relapsed during the study period, and one third completed. DISCUSSION: Due to small sample size, no valid efficacy inferences could be made. The outcome was poor, probably due to tapering off of non-study psychotropic drugs after randomisation; this has implications for future study designs. ClinicalTrials.gov Identifier: NCT00660062.

Prenatal antidepressant exposure and behavioral problems in early childhood--a cohort study.

OBJECTIVE: To estimate a potential association between in utero exposure to antidepressants and behavioral problems in childhood. METHOD: Information on exposures was obtained from the Danish National Birth Cohort. We studied the children of 127 mothers who had used antidepressants during pregnancy and compared these to 98 children of mothers with a prenatal depression with no use of antidepressants during pregnancy and 723 children of mothers with no prenatal depression and no use of antidepressant during pregnancy (unexposed). Behavioral problems were assessed at 4 or 5 years of age by the parent-reported Strengths and Difficulties Questionnaire (SDQ). RESULTS: Prenatal antidepressant exposure was not associated with abnormal SDQ scores compared with prenatal exposure to untreated prenatal depression or to no exposure. Untreated prenatal depression was associated with abnormal SDQ scores in the subscales of conduct [adjusted odds ratio (aOR) 2.3 (95% CI, 1.2-4.5)] and prosocial problems [aOR 3.0 (95% CI, 1.2-7.8)] compared with unexposed children. Total SDQ score was higher in children of mothers with untreated prenatal depression. These associations attenuated after adjusting for postnatal maternal psychiatric disease. CONCLUSION: Prenatal antidepressant exposure was not associated with behavioral or emotional problems in early childhood.

Lack of interaction between sertraline and lamotrigine in psychiatric patients: a retrospective study.

INTRODUCTION: This study evaluates the pharmacokinetic interaction between sertraline and lamotrigine in psychiatric patients. METHODS: We identifi ed patients with at least 1 measurement of trough lamotrigine plasma concentration (at steady-state) during lamotrigine therapy and compared dose and plasma concentrations between patients who received lamotrigine with sertraline and patients who received lamotrigine without sertraline. RESULTS: The dose corrected concentration of lamotrigine in patients receiving lamotrigine in combination with sertraline was 60.4 µmol/L × 1,000/mg/day (SD: 31.1) (N = 7) compared to 51.1 µmol/L × 1 000/mg/day (SD: 27.6) (N = 44) in patients using lamotrigine without sertraline (p = 0.42). DISCUSSION: The slightly slower metabolism of lamotrigine in patients receiving lamotrigine with sertraline compared with those receiving lamotrigine alone is not believed to be of clinical signifi cance. However, due to the limited power, we may have overlooked a diff erence that could be clinically relevant.

Risk factors of suicide in inpatients and recently discharged patients with affective disorders. A case-control study.

OBJECTIVE: Patients with affective disorders are at high risk of suicide, especially during inpatient treatment and during the first year after discharge. METHODS: A blinded case-control design was used. The study included a total national sample of patients with affective disorder admitted during the period from January 1, 1994 to December 31, 1995, who died because of suicide, either during admission or shortly after discharge. RESULTS: A history of suicide attempt was a significant risk factor (IRR 4.9; 95% CI 2.1-11.6). Loss of job during the year prior to the index admission was associated with an increase in suicide risk (IRR: 2.9; 95% CI 1.2-7.5). Clinical improvement during the index admission (IRR: 0.3; 95% CI 0.1-0.7), and treatment with antidepressant drugs at the censoring date (IRR: 0.3; 95% CI 0.1-0.7) were associated with a decrease in suicide risk. CONCLUSION: Improved treatment may be a key factor in suicide prevention in patients during, and shortly after hospitalisation with affective disorders. Also, there is a need to be especially aware of suicide risk in patients with little or no improvement at discharge.

Are antidepressants safe in the treatment of bipolar depression? A critical evaluation of their potential risk to induce switch into mania or cycle acceleration.

OBJECTIVE: To address whether switch of depression into hypomania or mania or cycle acceleration in patients with bipolar disorder is caused by antidepressants or whether this phenomenon is attributable to the natural history of bipolar disorder itself. METHOD: A critical review of the literature, pointing at sources of bias that have been previously overlooked. For examining the causation in question, the Bradford-Hill criteria were applied, i.e. specificity of the potential causative agent, strength of effect, consistency in findings, dose-response relation, temporal relation with exposure to agent preceding effect and biological plausibility. RESULTS: There is a scarcity of randomized studies addressing the question, and the available studies all suffer from various forms of bias. However, there is some evidence suggesting that antidepressants given in addition to a mood stabilizer are not associated with an increased rate of switch when compared with the rate associated with the mood stabilizer alone. CONCLUSION: When combined with a mood stabilizer, antidepressants given for acute bipolar depression seemingly do not induce a switch into hypomania or mania. Whether antidepressants may accelerate episode frequency and/or may cause other forms of destabilization in patients with bipolar disorder remain to be properly studied.

Modality shift effect in psychiatric disorders - a new look at an old paradigm.

BACKGROUND: There is a long tradition of reaction time studies in experimental psychopathology. Even though a diminishing interest in this paradigm has been seen over the last years, it is in line with more recent biological approaches to examine psychiatric disorders cross-diagnostically. METHODS: Patients (n=95) with a positive subtype of schizophrenia (n=22), a negative subtype of schizophrenia (n=18), a full major depressive episode (n=19), a full manic episode (n=16), or a mood disorder in remission (n=20) and subjects with no known psychiatric disorder (n=30), respectively, participated in a computer-based reaction time test consisting of four trials with 55 short visual and auditory stimuli presented in a random sequence. Each participant's median reaction time in milliseconds to light stimuli ipsimodal (light preceded by light) and cross-modal (light preceded by tone) and the difference between the two conditions (i.e. cross-modal retardation (CMR) to light) were recorded. Likewise, the median reaction time to tone stimuli ipsimodal and cross-modal and the difference between the two (CMR to tone) were recorded. RESULTS: Patient groups performed worse than the control group, with the exception of the group of patients with mood disorders in remission in both CMRs. When comparing patient groups, the schizophrenia negative subtype performed worse than the remission group in both CMRs. CONCLUSIONS: Our data support newer theories about underlying pathophysiological mechanisms and observable behavioural phenomena occurring across the different diagnostic categories, thereby supporting a dimensional approach in the diagnosis and clinical management.

Diagnostic conversion to bipolar disorder in unipolar depressed patients participating in trials on antidepressants.

OBJECTIVE: In unipolar depressed patients participating in trials on antidepressants, we investigated if illness characteristics at baseline could predict conversion to bipolar disorder. METHOD: A long-term register-based follow-up study of 290 unipolar depressed patients with a mean age of 50.8 years (SD=11.9) participating in three randomized trials on antidepressants conducted in the period 1985-1994. The independent effects of explanatory variables were examined by applying Cox regression analyses. RESULTS: The overall risk of conversion was 20.7%, with a mean follow-up time of 15.2 years per patient. The risk of conversion was associated with an increasing number of previous depressive episodes at baseline, [HR 1.18, 95% CI (1.10-1.26)]. No association with gender, age, age at first depressive episode, duration of baseline episode, subtype of depression or any of the investigated HAM-D subscales included was found. LIMITATIONS: The patients were followed-up through the Danish Psychiatric Central Research Register, which resulted in inherent limitations such as possible misclassification of outcome. CONCLUSION: In a sample of middle-aged hospitalized unipolar depressed patients participating in trials on antidepressants, the risk of conversion was associated with the number of previous depressive episodes. Therefore, this study emphasizes that unipolar depressed patients experiencing a relatively high number of recurrences should be followed more closely, or at least be informed about the possible increased risk of conversion.

Uptake of apoptotic leukocytes by synovial lining macrophages inhibits immune complex-mediated arthritis.

Previously we have shown that synovial lining macrophages (SLMs) determine the onset of experimental immune complex-mediated arthritis (ICA). During joint inflammation, many leukocytes undergo apoptosis, and removal of leukocytes by SLMs may regulate resolution of inflammation. In this study we investigated binding and uptake of apoptotic leukocytes by SLMs and its impact on the onset of murine experimental arthritis. We used an in vitro model to evaluate phagocytosis of apoptotic cells on chemotaxis. Phagocytosis of apoptotic thymocytes resulted in a significant decrease (58%) of chemotactic activity for polymorphonuclear neutrophils (PMNs). If apoptotic cells were injected directly into a normal murine knee joint, SLMs resulted in a prominent uptake of cells. After ICA induction, electron micrographs showed that apoptotic leukocytes were evidently present in SLMs on days 1 and 2. Injection of apoptotic leukocytes into the knee joint 1 h before induction of ICA significantly inhibited PMN infiltration into the knee joint at 24 h (61% decrease). This study indicates that uptake of apoptotic leukocytes by SLM reduces chemotactic activity and inhibits the onset of experimental arthritis. These findings indicate an important mechanism in the resolution of joint inflammation.

Effects on cognitive and clinical insight with the use of Guided Self-Determination in outpatients with schizophrenia: A randomized open trial.

Poor insight has a negative impact on the outcome in schizophrenia; consequently, poor insight is a logical target for treatment. However, neither medication nor psychosocial interventions have been demonstrated to improve poor insight. A method originally designed for diabetes patients to improve their illness management, Guided Self-Determination (GSD), has been adapted for use in patients with schizophrenia (GSD-SZ). The purpose of this study was to investigate the effect on insight of GSD-SZ as a supplement to treatment as usual (TAU) as compared to TAU alone in outpatients diagnosed with schizophrenia. The design was an open randomized trial. The primary hypothesis was cognitive insight would improve in those patients who received GSD-SZ+TAU as assessed by the BCIS. We additionally explored whether the intervention led to changes in clinical insight, self-perceived recovery, self-esteem, social functioning and symptom severity. Assessments were conducted at baseline, and at 3-, 6- and 12-month follow-up. Analysis was based on the principles of intention to treat and potential confounders were taken into account through applying a multivariate approach. A total of 101 participants were randomized to GSD-SZ+TAU (n=50) or to TAU alone (n=51). No statistically significant differences were found on the cognitive insight. However, at 12-month follow-up, clinical insight (measured by G12 from the Positive and Negative Syndrome Scale), symptom severity, and social functioning had statistically significantly improved in the intervention group as compared to the control group. "Improving insight in patients diagnosed with schizophrenia", NCT01282307, http://clinicaltrials.gov/.

The neuropsychological profile of early and continuously treated phenylketonuria: orienting, vigilance, and maintenance versus manipulation-functions of working memory.

In this paper, we review neuropsychological test results of early and continuously treated Phenylketonuria (PKU) patients. To increase insight into the neuropsychological profile of this population, we have attempted to place the results within an attentional network model [Images of the mind, 1994], which proposes interacting but dissociable attentional networks for orienting, vigilance, and executive control of attention. Executive control of attention is discussed against the background of the process-specific theory of working memory (WM) [Handbook of neuropsychology, 1994], which postulates a distinction between the 'maintenance'-function of WM and the 'manipulation and monitoring'-function. Neuropsychological results are presented for 67 early and continuously treated PKU patients and 73 controls aged 7-14 years. Four neuropsychological tasks were employed to measure orienting, mnemonic processing, interference suppression, and top-down control in visual search. No differences were found in orienting and the maintenance-function of WM. In addition to previously reported impairments in sustained attention/vigilance and inhibition of prepotent responding, PKU patients exhibited deficits when top-down control was required in a visual search task, but showed no impairment when interference suppression was required. It is discussed how the specific neuropsychological impairments in PKU may be a consequence of mid-dorsolateral prefrontal cortex (DLPFC) dysfunctioning due to deficiencies in catecholamine modulation.

The development of lateral event-related potentials (ERPs) related to word naming: a four year longitudinal study.

Event-related potentials (ERPs) were recorded from the left and right temporal and parietal sites during a word naming task. Subjects were a group of children that were followed over four consecutive years starting at Kindergarten. ERP waveforms contained a sequence of positive and negative components (N150, P240, N360, N530 and SW). All components, except N150, showed changes in amplitude as a function of age, whereas SW, N360 and N150 also changed in hemispheric distribution. In addition, a relationship was found between reading performance and ERP amplitudes over the right parietal hemisphere in young children, and over the left temporal hemisphere in older children. Proficient readers showed larger (more negative) parietal N530 amplitudes than less proficient readers, especially when stimuli were degraded words. The results are discussed in terms of age-related changes in right and left hemisphere functions involved in early and advanced stages of reading, that might possibly be related to visual word recognition.

Sustained attention and inhibition of cognitive interference in treated phenylketonuria: associations with concurrent and lifetime phenylalanine concentrations.

Fifty-seven 7-14-year-old early- and continuously treated phenylketonuria (PKU) patients and 65 matched controls performed a sustained attention task. PKU patients with plasma phenylalanine (phe) levels higher than 360 micromol/l at the time of testing exhibited, compared to controls, lower speed of information processing, a lower ability to inhibit task-induced cognitive interference, less consistent performance, and a stronger decrease of performance level over time. Patients with concurrent phe levels lower than 360 micromol/l did not differ from controls and were significantly better than patients with levels higher than 360 micromol/l. Strong relationships were found with task performance for phe levels during the pre-school years and between ages 5 and 7. These correlations were stronger than those between concurrent phe level and task performance. Significant multiple regression models were found with age accounting for the largest proportion of variance of tempo and tempo fluctuation, and lifetime phe levels (particularly phe level between ages 5 and 7) accounting for the largest proportion of variance of the relative number of inhibition errors and its increase over time. Phe level between ages 5 and 7 also contributed significantly to the variance of tempo and tempo fluctuation. Neuropsychological outcome was independent of IQ. The results indicate that strict dietary adherence during these periods is beneficial to attentional control later in life. We suggest that phe levels should be maintained under 360 micromol/l until approximately age 12, when development of attentional control approaches an adult level.