P105 Healthy light exposure enhances SSRI efficacy in depression: case study

Introduction: Light is the strongest zeitgeber (time cue) for the human central circadian clock, and its effects on health may vary depending on the time of day by either strengthening or dampening circadian rhythms. However, the relations between various light exposures and human health remain largely unknown, partly due to the lack of available measurements. Hypothesis: We hypothesized that greater nighttime and evening light exposure would be associated with a higher mortality risk, while greater daytime light exposure would be associated with a lower mortality risk. Methods: This population-based prospective cohort study included 7,909 participants aged ≥20 years, with ≥4 days of data from wrist-worn accelerometers with light sensors measuring ambient light (lux) at 1 Hz from the U.S National Health and Nutrition Examination Survey 2011-2014. Mortality data through 2019 were obtained via linkage to the National Death Index. The average intensity of ambient light exposure during daytime (6:00 AM-7:59 PM), evening (8:00-11:59 PM), and nighttime (0:00-5:59 AM) were calculated. Cox models were used to estimate hazard ratios (HRs) for mortality. Results: During a median (IQR) follow-up of 6.8 (5.7-7.8) years, 803 deaths were documented, including 255 from cardiovascular disease and 192 from cancer. The multivariable-adjusted HRs (95% CIs) for all-cause mortality were 0.82 (0.66-1.03) for the second quartile of daytime light exposure, 0.83 (0.67-1.04) for the third quartile, and 0.67 (0.51-0. 89) for the highest quartile, compared to the lowest quartile ( P for trend <0.001). Conversely, there was no association between nighttime ( P for trend = 0.14; HR for the highest vs lowest quartile: 0.94 [0.75-1.19]) or evening light exposure ( P for trend = 0.46; HR for the highest vs lowest quartile: 0.85 [0.71-1.03]) and all-cause mortality risk. Similar inverse associations of daytime light exposure were observed for cardiovascular disease mortality ( P for trend = 0.04; HR for highest vs lowest quartile: 0.65 [0.36-1.20]) but not for cancer mortality ( P for trend = 0.27; HR for highest vs lowest quartile: 0.89 [0.54-1.48]). Conclusions: In this nationally representative sample of U.S. adults, greater objectively measured ambient light exposure during daytime was inversely associated with all-cause and cardiovascular disease mortality risk. These findings may have significant public health implications given the reduced exposure to daytime light in modern society.

Sertraline increases extracellular levels not only of serotonin, but also of dopamine in the nucleus accumbens and striatum of rats

Depression is characterized by a wide range of diverse symptoms, the severity of which can be quantified by various depression rating scales, such as the Montgomery Asberg Depression Rating Scale. Analyses of the individual items of this scale in patients treated with the selective serotonin reuptake inhibitors (SSRIs) have shown that not all items respond equally or with the same time of onset of improvement (Table 1).1,2 The items which respond less well or more slowly with SSRIs include lassitude, loss of energy, retardation of thoughts or actions, as well as concentration difficulties and loss of alertness. The loss of interest or pleasure that depressed patients experience (anhedonia) also responds poorly to SSRIs, and patients often complain of emotional indifference or blunting. Certain sleep difficulties are sometimes worsened by SSRIs. Appetite loss can be aggravated by certain SSRIs, an effect which can be made worse by nausea at the beginning of treatment. Table 1 Comparison of core symptoms of depression which respond less well or more slowly to SSRIs and depressive symptoms specifically related to a deficiency of noradrenergic neurotransmission Similarly, a cluster of common depressive symptoms of “decreased positive affect”, including loss of interest or pleasure, fatigue, loss of energy, and decreased motivation, which do not respond adequately to serotonergic antidepressants, have been identified. Antidepressants that enhance noradrenergic (and dopaminergic) activity appear to offer a therapeutic advantage over serotonergic antidepressants in the treatment of these symptoms.3 Based mainly on theoretical considerations, the symptoms of depression have been associated with deficiencies of one or more of the monoamine neurotransmitters.4 In this scheme, decreased concentration, retardation, loss of energy, lassitude, tiredness, and reduced self-care are associated with decreased noradrenergic activity (Table 1). Thus, clinical and theoretical considerations combine to define the noradrenergic symptom cluster, ie, decreased concentration, retardation, loss of energy, lassitude, tiredness, and reduced self-care. This supplement, which is based on a symposium held at the International Forum on Mood and Anxiety at Vienna in November 2010, discusses the noradrenergic symptom cluster, the importance of these symptoms in the burden of depression, their clinical and neuropharmacological nature, and how these symptoms can be improved by the serotonin and noradrenaline reuptake inhibitor (SNRI) antidepressant, milnacipran. In the first paper, Lepine presents recent epidemiological data on the prevalence of depression and the associated risk of mortality by suicide, as well as cardiovascular and other deaths. Studies of the familial and financial burden of depression show an increased risk of loss of productivity and absenteeism in depression, which frequently result in decreased income or unemployment. The importance of the burden of depression is underlined by the estimation of the World Health Organization that, by 2030, unipolar major depression will become the leading worldwide cause of disease burden. The second paper by Moret examines the importance of norepinephrine in the etiology of depression. Evidence for the involvement of norepinephrine including recent studies on neuronal pathways and symptoms, highlights the determinant role of norepinephrine in key symptoms, including executive functioning, which regulates cognition, motivation, and intellect, which are of fundamental importance in social relationships, that are impoverished in depression. In the third paper, Blier explains the reciprocal interactions between the serotonin system and norepinephrine and dopamine neurotransmission. Enhanced serotonin transmission, as during SSRI treatment, attenuates noradrenergic and dopaminergic activity. This can contribute to the residual symptoms of fatigue and lack of energy that are often reported by patients responding to SSRI. Milnacipran, by increasing norepinephrine (and dopamine), as well as serotonin neurotransmission is less likely to induce or aggravate such residual symptoms. Milnacipran’s potentiation of norepinephrine and serotonin (and indirectly dopamine) neurotransmission contributes to its antidepressant action, while its attenuation of phasic noradrenergic reactivity reduces the risk of anxiety. In the fourth and final paper, Kasper discusses the importance of social dysfunction in depressed patients which can lead to family disruption, social isolation, absenteeism, and potential unemployment. The symptoms of the noradrenergic symptom cluster are important factors in social dysfunction, and antidepressants with a strong noradrenergic component improve social functioning. Preliminary data suggest that milnacipran improves social functioning to a greater extent than SSRIs.

In the literature, disagreement exists on the impact of Axis II comorbidity on the treatment outcome of depression. The aim of the present study was to examine in a naturalistic treatment setting the 1-year outcome and treatment characteristics of depressed adolescent outpatients with and without comorbid Axis II disorders. The 151 participants were interviewed for Axis I and II diagnoses at baseline and follow-up. Those diagnosed with a personality disorder were significantly more impaired at follow-up than those without. The given treatment did not differ between the two groups in length, intensity, or hospitalization, but the group with Axis II comorbidity received more psychotropic medication. The treatment outcome of depression was poorer for the group with Axis II disorders compared to those without. In conclusion, a personality disorder diagnosis is a sign of more severe overall symptoms. Special attention should be paid to Axis II traits when planning and conducting the treatment of adolescent depression.

Although alcohol and/or substance use disorders have been significantly associated with depression, data on the treatment outcomes of depression in this patient population are still scarce, especially among the higher risk of resistance to treatment. This study examines the management outcomes of depression in patients with alcohol and substance dependence during the last decade by searching the medical literature. The literature was searched through Medline, PsycInfo, Embase, and Ovid database from 2010 to 2020. Searching terms included were a combination of ‘’treatment’’ AND ‘’Depression’’ AND ‘’alcohol’’ OR “substance abuse". A total of 617 articles were retrieved. After this, original articles investigating depression treatment outcomes in patients with alcohol or substance use disorders or both were selected. Following the exclusion of review studies and including only original research studies, 23 articles appeared. We selected eight articles as eligible, covering a total of 132,373 patients with depression and either alcohol dependence or substance use disorder. Anti-depressants (mainly selective serotonin reuptake inhibitors) combined with psychotherapy and alcohol or substance abuse treatment represent the best treatment modality for depression in this clinical setting. In conclusion, patients with alcohol or substance dependence usually suffer from treatment-resistant depression. However, the treatment of depressive symptoms would help in substance or alcohol abstinence and reduce recurrent substance abuse.

The mechanisms underlying age-related changes in the signal from the biological clock have yet to be determined. The authors sought to determine if the phase advance of circadian melatonin rhythm during the middle years of life is related to different patterns of habitual light exposure. Forty-one healthy subjects between the ages of 22 and 58 y were studied. Habitual light exposure was measured by a wrist monitor for 7 days. Participants underwent a 25-h constant routine. They provided saliva samples every 30 min, and melatonin concentration was determined by radioimmunoassay to assess salivary dim light melatonin onset (S-DLMO(1.3)). Aging was associated with earlier S-DLMO(1.3). Increasing age was not related to the time spent at different light intensities. However, it was associated with lower percentage of light exposure during the night (between 0200-0400, 0600-0700, and 2300-2400 h) and with higher percentage of light exposure in the morning (between 0800-1100 h). Earlier S-DLMO(1.3) was associated with lower percentage of light exposure early on in the night (between 2200-0000, 0000-0100, and 0200-0300 h) as well as in the afternoon (between 1500-1600 h) and with higher percentage of light exposure in the morning (between 0800-1100 h). When the effects of age were controlled, there was no significant relationship between S-DLMO(1.3) and percentages of light exposure. Yet increasing age was associated with earlier S-DLMO(1.3) regardless of light exposure patterns. Earlier habitual wake time explained the earlier light exposure patterns of older subjects. Both habitual wake time and age contributed to the prediction of S-DLMO(1.3). The results suggest a phase advance of circadian rhythms in the middle years of life. Whereas a clear change in habitual light exposure patterns was associated with aging and with shifts in S-DLMO(1.3), it did not explain entirely the age-related advance of melatonin circadian phase.

The treatment of unipolar major depression with antidepressant medication is well established on the basis of scores of randomized placebo-controlled trials involving thousands of patients. Tricyclic antidepressants (TCAs) were the first to be studied extensively; meta-analyses of placebo-controlled trials show them to be consistently and significantly more efficacious than a placebo. Because of a narrow safety margin and significant drug-induced adverse side effect problems, TCAs have now largely been replaced as the first-line treatment of depression by selective serotonin reuptake inhibitors (SSRIs)—fluoxetine, sertraline, paroxetine, citalopram, and escitalopram; serotonin norepinephrine reuptake inhibitors (SNRIs)—venlafaxine and duloxetine; as well as other compounds, including, for example, bupropion and mirtazapine. Each of these agents has been shown to be superior to a placebo and as effective as comparator TCAs or SSRIs in controlled trials. Clinical trials consistently show them to be better tolerated than TCAs, and they clearly have a wider margin of safety. However, there is a controversy concerning whether TCAs are more effective than SSRIs for the treatment of the most severely ill depressed patients. Monoamine oxidase inhibitors (MAOIs), while also more effective than placebo, have generally been reserved for treatment-refractory patients; however, a recently released transdermally delivered selegiline may be used in less refractory patients. It is now generally recognized that patients with recurrent major depression benefit from continued antidepressant treatment, and there is evidence that TCAs, SSRIs, SNRIs, and so forth are all effective for the long-term management of recurrent major depression. An important issue in evaluating the antidepressant literature is to distinguish between response rated as a reduction in the level of symptoms on a rating scale and response rated as true remission from illness.

Multi-Omic Sex-Specific Biology in MDD: eQTL Correlates of Depression and SSRI Treatment Outcomes

IntroductionLight has powerful effects on mood, sleep, and the circadian system. Humans evolved in an environment with a clear distinction between day and night, but our modern lighting environments have blurred this distinction. While the disruptive effects of night time light exposure are well described, the potential positive effects of daytime light exposure on these systems are less well studied.MethodParticipants were a subset of the UK Biobank cohort who were invited to complete a seven day wrist-worn actimetry and light sensor study (n = 8,372, 61% female, age range: 39–70). Hierarchical linear models assessed the association between average daytime light exposure and mood-, sleep- and circadian-related outcomes, adjusted for age, sex, and season of assessment.ResultsGreater daytime light exposure was associated with earlier chronotype (p < .001), greater ease of getting up in the morning (p < .001), lower odds of using antidepressant medication (p < .001), less frequent low-mood (p = .002), less frequent anhedonia (p < .001), greater happiness (p < .001), less frequent insomnia symptoms (p = .01) and less frequent tiredness (p < .001).ConclusionsIn the largest study to-date, we observe that greater daytime light predicts better outcomes across a range of mood-, sleep- and circadian-related measures. Our findings are consistent with the known effects of light on the circadian system, whereby greater daytime light enhances the strength of the rhythm allowing for greater distinction between sleep and wake states. These findings

Diagnostic Accuracy of the SLU AMSAD Scale for Depression in Older Adults Without Dementia

Higher intensity of psychotherapy might improve treatment outcome in depression, especially in those with comorbid personality disorder. To compare the effects of 25 individual sessions (weekly) of two forms of psychotherapy - short-term psychoanalytic supportive psychotherapy (SPSP) and schema therapy - with the same treatments given for 50 sessions (twice weekly) in people with depression and personality disorder. Trial registration: NTR5941. We conducted a pragmatic, double-randomised clinical trial and, over 37 months, recruited 246 adult out-patients with comorbid depression/dysthymia and personality disorder. A 2 × 2 factorial design randomised participants to 25 or 50 sessions of SPSP or schema therapy. The primary outcome was change in depression severity over 1 year on the Beck Depression Inventory II (BDI-II). Secondary outcomes were remission both of depression and personality disorder. Compared with 25 sessions, participants who received 50 sessions showed a significantly greater decrease in depressive symptoms over time (time × session dosage, P < 0.001), with a mean difference of 5.6 BDI points after 1 year (d = -0.53, 95% CI -0.18 to 0.882, P = 0.003). Remission from depression was also greater in the 50-session group (74% v. 58%, P = 0.025), as was remission of personality disorder (74% v. 56%, P = 0.010). Greater intensity of psychotherapy leads to better outcomes of both depression and personality status in people with comorbid depression and personality disorder.

Objective: Optimizing treatment selection may improve treatment outcomes in depression. A promising approach is the Personalized Advantage Index (PAI), which predicts the optimal treatment for a given individual. To determine the generalizability of the PAI, models needs to be externally validated, which has rarely been done. Method: PAI models were developed within each of two independent trials, with substantial between-study differences, that both compared CBT and IPT for depression (STEPd: n = 151 and FreqMech: n = 200). Subsequently, both PAI models were tested in the other dataset. Results: In the STEPd study, post-treatment depression was significantly different between individuals assigned to their PAI-indicated treatment versus those assigned to their non-indicated treatment (d = .57). In the FreqMech study, post-treatment depression was not significantly different between patients receiving their indicated treatment versus those receiving their non-indicated treatment (d = .20). Cross-trial predictions indicated that post-treatment depression was not significantly different between those receiving their indicated treatment and those receiving their non-indicated treatment (d = .16 and d = .27). Sensitivity analyses indicated that cross-trial prediction based on only overlapping variables didn’t improve the results. Conclusion: External validation of the PAI has modest results and emphasizes between-study differences and many other challenges.

Depression is the leading cause of global disability, and many patients fail to respond to standard treatments. Preliminary evidence suggests that adjunctive nutrition therapy may improve treatment outcomes in depression. We review the evidence for the efficacy and/or mechanisms of the following nutrients: vitamin D, vitamins B12 and B9, vitamin C, zinc, selenium, omega-3 fatty acid, N-acetylcysteine, and nicotinamide riboside. Preliminary evidence suggests that these nutrients may facilitate mood regulation by regulating neurotransmitters, engaging in reduction-oxidation, or by modulating neuronal structure. Although initial evidence is promising, large, placebo-controlled studies are needed to validate their efficacy. [ Psychiatr Ann. 2019;49(1):21–25.]

Efficacy of venlafaxine in major depression resistant to selective serotonin reuptake inhibitors

P01-38 - Efficacy of adjunctive aripiprazole in patients with major depressive disorder: pooled analysis of subgroup data from three clinical trials