Bone mineral density, kidney function, weight gain and insulin resistance in women who switch from TDF/FTC/NNRTI to ABC/3TC/DTG.

OBJECTIVES: Tenofovir disoproxil fumarate (TDF) is associated with reduced bone mineral density (BMD). We evaluated changes in BMD in women who switched from TDF, emtricitabine and a nonnucleoside reverse transcriptase inhibitor (TDF/FTC/NNRTI) to abacavir, lamivudine and dolutegravir (ABC/3TC/DTG). METHODS: We conducted a randomized controlled trial in which women aged ≥40 years were randomized 1:2 to continue TDF/FTC/NNRTI or switch to ABC/3TC/DTG. The primary endpoint was change in total hip BMD measured by dual-energy X-ray absorptiometry at week 48. Secondary endpoints were changes in BMD of the lumbar spine and femoral neck and markers of bone turnover and kidney function up to week 48. We conducted exploratory analyses of weight gain, insulin resistance and metabolic syndrome. Primary and secondary endpoints were analysed by linear regression, with multiple imputation for missing time points. RESULTS: In all, 91 women [mean age = 50.4 (standard deviation [SD] = 6.6) years, median CD4 cell count = 600 (interquartile range: 479-800) cells/µL] were randomized. Women who switched to ABC/3TC/DTG maintained viral suppression and experienced improvements in total hip BMD (mean adjusted difference = 1%, P = 0.027) and lumbar spine BMD (3%, P = 0.002), with no change in specific markers of bone turnover or renal tubular function. Although participants in the ABC/3TC/DTG arm gained more weight (1.8 kg, P = 0.046), the switch strategy was not associated with reduced insulin sensitivity or new-onset metabolic syndrome. CONCLUSIONS: Switching from TDF/FTC/NNRTI to ABC/3TC/DTG resulted in improved BMD. Although weight gain was common in women who switched from TDF/FTC/NNRTI to ABC/3TC/DTG, we did not detect adverse effects on glucose homeostasis. Larger studies need to confirm these findings.

Early safety of tenofovir alafenamide in patients with a history of tubulopathy on tenofovir disoproxil fumarate: a randomized controlled clinical trial.

OBJECTIVES: The aim of the study was to assess the effect of tenofovir alafenamide (TAF) on kidney and bone biomarkers in patients who developed proximal renal tubulopathy (PRT) while receiving tenofovir disoproxil fumarate (TDF). METHODS: Individuals with a history of TDF-associated PRT and currently suppressed HIV infection on a tenofovir-sparing regimen were randomized 1:1 to continue current antiretroviral therapy or initiate emtricitabine (F)/TAF with discontinuation of nucleoside reverse transcriptase inhibitors (NRTIs) as appropriate. Renal and bone biomarkers were analysed at baseline, week 4 and week 12. The primary outcome was the mean difference between study arms in urine retinol-binding protein:creatinine ratio (RBPCR) change from baseline to week 12. Data were analysed using linear regression, with robust standard errors (primary outcome), and repeated measures mixed effects models (secondary outcomes). The trial was registered under European Union Drug Regulating Authorities Clinical Trials Database 2016-003345-29. RESULTS: We randomized 31 individuals [mean age 52.4 (standard deviation 0.3) years; 97% male; 90% white); all completed the study. At 12 weeks, there was no difference in change in RBPCR (ß 19.6; 95% confidence interval -35.3, 74.5; P = 0.47), and no difference in change in estimated glomerular filtration rate (eGFR) (based on creatinine or cystatin C), albuminuria, proteinuria, renal phosphate or urea handling, (fasting) urine osmolality, parathyroid hormone and bone turnover markers in the control versus the F/TAF exposed groups. No cases of PRT were observed. CONCLUSIONS: In people with a history of proximal renal tubulopathy while on TDF, 12-week exposure to TAF did not adversely affect renal tubular function. These data support continued evaluation of the long-term safety of TAF in this group of patients.

Sleep changes during a spontaneous manic episode: PSG assessment in a clinical context.

Sleep plays a key role in the pathogenesis and clinical presentation of mood disorders. However, only a few studies have investigated sleep architecture during the manic episodes of Bipolar Disorder (BD) and changes in sleep parameters that follow clinical variations. Twenty-one patients (8 males, 13 females) affected by BD, manic phase, underwent polysomnographic recordings (PSG) at the beginning of the admission in our ward (T0) and after three weeks of hospital treatment (T1). All participants were clinically evaluated using Young Mania Rating Scale (YMRS), Pittsburgh Sleep Quality Index (PSQI) and Morningness-Eveningness Questionnaire (MEQ). During the admission, we observed an increase in both quantity (Total Sleep Time - TST) and quality (Sleep Efficiency - SE) of sleep. In addition, clinical improvement, evaluated with YMRS and PSQI scales, was accompanied by a significant increase in the percentage of REM sleep. According to our findings, the improvement of manic symptoms is accompanied by an increase in "REM pressure" (increase in REM% and REM density, reduction of REM latency). Overall, changes in sleep architecture appear to be markers sensitive to clinical variations during manic phases of Bipolar Disorder.

Influence of a functional polymorphism within the promoter of the serotonin transporter gene on the effects of total sleep deprivation in bipolar depression.

OBJECTIVE: A functional polymorphism in the transcriptional control region upstream of the coding sequence of the 5-hydroxytryptamine transporter (5-HTT) has been reported. This polymorphism has been shown to influence the antidepressant response to fluvoxamine and paroxetine. The authors tested the hypothesis that the allelic variation of the 5-HTT-linked polymorphic region (5-HTTLPR) could influence the response of depressed patients to total sleep deprivation. METHOD: Sixty-eight drug-free inpatients with bipolar depression underwent a night of total sleep deprivation. 5-HTTLPR was genotyped in these patients. Changes in perceived mood were rated on a visual analogue scale and analyzed by using repeated measures analysis of covariance. RESULTS: Patients who were homozygotic for the long variant of 5-HTTLPR showed a significantly better mood amelioration after total sleep deprivation than those who were heterozygotic and homozygotic for the short variant. CONCLUSIONS: The influence of 5-HTTLPR on response to total sleep deprivation is similar to its observed influence on response to serotonergic drug treatments. This finding supports the hypothesis of a major role for serotonin in the mechanism of action of total sleep deprivation in depression.

Sustained antidepressant effect of sleep deprivation combined with pindolol in bipolar depression. A placebo-controlled trial.

Total sleep deprivation (TSD) shows powerful but transient clinical effects in patients affected by bipolar depression. Pindolol blocks the serotonergic 5-HT1A autoreceptor, thus improving the antidepressant effect of selective serotonin reuptake inhibitors. We evaluated the interaction of TSD and pindolol in the treatment of acute episodes of bipolar depression. Forty bipolar depressed inpatients were randomized to receive pindolol 7.5 mg/day or placebo for nine days in combination with three consecutive TSD cycles. Pindolol significantly improved the antidepressant effect of TSD, and prevented the short-term relapse after treatment. The response rate (HDRS scores < 8) at the end of treatment was 15/20 for pindolol, and 3/20 for placebo. Coadministration of pindolol and TSD resulted in a complete response, which could be sustained for six months with lithium salts alone, in 65% of cases. This results suggest a major role for serotonergic transmission in the mechanism of action of TSD, and makes TSD treatment more effective in the treatment of bipolar depression.

Sleep phase advance and lithium to sustain the antidepressant effect of total sleep deprivation in bipolar depression: new findings supporting the internal coincidence model?

Recent European studies suggested that sleep phase advance (SPA) could sustain the effects of total sleep deprivation (TSD) both with or without a combined antidepressant drug treatment. Previous studies by our group showed that an ongoing lithium treatment could enhance and sustain the effect of repeated TSD. In the present study we studied the effect of a single TSD followed by 3 days SPA (beginning with sleep allowed from 17:00 until 24:00, with daily shiftbacks of 2 h) in consecutively admitted bipolar depressed inpatients who were taking a chronic lithium salts treatment (n=16) or who were devoid of psychotropic medications (n=14). Changes in mood during treatment were recorded with self administered visual analogue scales and with Hamilton rating scale for depression. Results showed that SPA could sustain the acute antidepressant effect of TSD, and that lithium enhanced the effect of the chronobiological treatment. According to the internal coincidence model, the better clinical effects observed in lithium-treated patients could be due to the phase delaying effect of lithium on biological rhythms, leading to a better synchronization of biological rhythms with the sleep-wake cycle.

35% CO2 challenge in panic and mood disorders.

20 patients with Panic Disorder (PD), 19 patients with Mood Disorder (MD) and 20 healthy controls inhaled one vital capacity of 35% CO2-65% O2 gas mixture and of compressed air in a double-blind, random, cross-over design. Only PD patients showed a strong reaction to 35% CO2 while MD patients and controls did not react significantly. These results support the specificity of the 35% CO2 challenge in PD patients and suggest that PD and MD are separate disorders.

Morning sunlight reduces length of hospitalization in bipolar depression.

BACKGROUND: Bright artificial light improves non-seasonal depression. Preliminary observations suggest that sunlight could share this effect. METHODS: Length of hospitalization was recorded for a sample of 415 unipolar and 187 bipolar depressed inpatients, assigned to rooms with eastern (E) or western (W) windows. RESULTS: Bipolar inpatients in E rooms (exposed to direct sunlight in the morning) had a mean 3.67-day shorter hospital stay than patients in W rooms. No effect was found in unipolar inpatients. CONCLUSIONS: Natural sunlight can be an underestimated and uncontrolled light therapy for bipolar depression. LIMITATIONS: This is a naturalistic retrospective observation, which needs to be confirmed by prospective studies.

Patterns of mood variation during antidepressant treatment.

Previous findings showed that, in a subgroup of patients administered heterogeneous antidepressant treatments, perceived mood levels during a major depressive episode fluctuate with day to day changes which follow cyclical patterns (termed "minicycles"). We investigated the predictability of infradian mood fluctuations during acute depressive episodes in patients standardly medicated with fluvoxamine. We applied time series analysis, by means of autocorrelation techniques, to time lagged serial recordings of perceived mood levels of 20 inpatients (13 Major Depression Recurrent, and 7 Bipolar Depressive Disorders). 5/20 patients exhibited predictable cyclical patterns in their perceived symptomathology, 8/20 exhibited an uneven, sawtooth pattern of progressive amelioration, and 7/20 showed an erratic pattern of unpredictable day-to-day variations. We confirmed the existence and the predictability of cyclical mood patterns in a subgroup of patients. The absence of a linear improvement in perceived mood did not worsen the final response to antidepressant therapy.

Infradian mood fluctuations during a Major Depressive episode.

We investigated the predictability of infradian mood fluctuations during acute depressive episodes in patients affected by mood disorders. Previous findings showed that in a subgroup of patients the depressive symptomathology fluctuates with day-to-day changes which follow cyclical patterns (termed "minicycles'). We applied time series analysis, by means of autocorrelation techniques, to time lagged serial recordings of perceived mood levels of 22 inpatients (13 Major Depressive Recurrent and 9 Bipolar Depressive Disorders). Five patients (22.7%) were shown to exhibit predictable cyclical patterns in their perceived symptomathology, ranging in length from 6 to 14 days. Our study confirms the existence and the predictability, in a subgroup of patients, of cyclical mood patterns. Preliminary evidence suggests that patients with minicycles receive more medication changes than patients without, and thus that cyclical mood fluctuations strongly interacts with both the clinical decision making process and the outcome of acute depressive episodes.

Response to clozapine in acute mania is more rapid than that of chlorpromazine.

The purpose of the present study was to compare the efficacy of clozapine with that of chlorpromazine in an open label manner (both given in association with lithium salts) in the treatment of acute mania. Thirty hospitalized manic patients were entered into the study. All patients met DSM-IV criteria for bipolar disorder, Manic Episode; 27 patients completed the study and three patients dropped for noncompliance. The duration of the study was 3 weeks. Patients were randomly assigned to two treatment groups; group 1 (n = 15) was treated with clozapine at a mean dose of 166 mg/day and group 2 (n = 12) was treated with chlorpromazine at a mean dose of 310 mg/day. Manic symptomatology was rated on Young Rating Scale for Mania (YRSM) each week; side effects were recorded on dosage records and treatment emergent symptoms; extrapyramidal acute side effects were rated on the Simpson-Angus Rating Scale performed at the beginning of the study and after 3 weeks of treatment. A two-way repeated measures analysis of variance on YRMS scores showed a significant time effect (p < 0.0001) and a significant time-group interaction (p < 0.0001). Post-hoc comparison between the two groups showed a significant difference after 2 weeks of treatment (p = 0.0001), with clozapine treated patients showing lower YRSM scores than chlorpromazine treated patients. YRSM scores at the end of the study were not significantly different. Patients treated with clozapine showed a more rapid trend toward amelioration. No clinically relevant side effect was observed during the study.

Sleep loss, a possible factor in augmenting manic episode.

Several reports suggest the role of sleep-wake rhythm in mood disorders. Sleep loss may be a possible trigger or augmenting factor in mania. In a group of 34 manic bipolar inpatients, we analyzed the correlation between night-time sleep duration and the intensity of manic symptomatology rated consecutively for 3 days with the Young Rating Scale for Mania and the Nurses' Observation Scale for Inpatient Evaluation (NOSIE). We found significant correlations between sleep duration and NOSIE cluster scores (cooperation and irritability).

Rate of switch from depression into mania after therapeutic sleep deprivation in bipolar depression.

Sleep deprivation is a potentially useful non-pharmacological treatment for depression. A relationship between sleep loss and the onset of mania has been reported, so it is possible that a switch from depression into mania after sleep deprivation might be expected in bipolar depressed patients who are treated with sleep deprivation. In a sample of 206 bipolar depressed treated with three cycles of sleep deprivation, alone or in combination with heterogeneous medications, we observed a 4.85% switch rate into mania and a 5.83% switch rate into hypomania. These percentages are comparable to those observed with antidepressant drug treatments.

Dopaminergic augmentation of sleep deprivation effects in bipolar depression.

Total sleep deprivation (TSD) has been used in association with lithium salts and with serotonergic and noradrenergic antidepressants, leading to sustained improvements in patients affected by major depression. Current theories on the neurobiological mechanism of action of TSD propose a major role for enhanced dopamine activity. To test the clinical relevance of dopaminergic enhancement in TSD, we treated a homogeneous sample of 28 bipolar depressed patients with three cycles of TSD combined with placebo or with the dopaminergic antidepressant amineptine. Changes in mood over time were rated with self-administered visual analogue scales and with the Montgomery-Asberg Depression Rating Scale. Patients showed improved mean daily-mood scores after TSD, an effect that was highest at the first cycle and decreased with treatment repetition. Amineptine enhanced the effects of TSD on perceived mood during the first two TSD cycles, but patients in the placebo and amineptine groups showed comparable results at the end of the treatment. Despite its theoretical importance, the clinical usefulness of combining TSD with a dopaminergic agent must be questioned.

Dopamine agonist amineptine prevents the antidepressant effect of sleep deprivation.

In a double-blind study, the effects of the interaction between the administration of amineptine versus placebo and repeated cycles of total sleep deprivation (TSD), which is thought to act through an enhancement in dopaminergic transmission, were analyzed. Twenty-two consecutively admitted patients with bipolar depression formed the study group. Repeated administrations of TSD significantly enhanced perceived mood levels in placebo-treated patients, while amineptine administration blocked the antidepressant action of TSD. Hypothesized changes in brain dopaminergic transmission attributable to amineptine pretreatment are discussed.

The unipolar-bipolar dichotomy and the response to sleep deprivation.

Fifty-one inpatients affected by a major depressive episode were divided into four groups according to mood disorder diagnosis and previous clinical history (bipolar disorder type I; bipolar disorder type II; major depressive disorder with at least three previous depressive episodes; and single depressive episode patients) and administered three consecutive total sleep deprivation (TSD) cycles. Mood changes were rated with a reduced version of the Hamilton Depression Rating Scale and with self-administered visual analogue scales. TSD caused better clinical effects in bipolar and single-episode patients; in particular, unipolar patients lacked effects in perceived mood after the first TSD and showed worse Hamilton ratings in respect to the other groups after the three TSD treatments. Discriminant function analysis could correctly classify 80% of bipolar patients, post hoc, based on TSD response. Further researches on the clinical efficacy of TSD must take into account the heterogeneity of depression and of its biological substrate.

Total sleep deprivation combined with lithium and light therapy in the treatment of bipolar depression: replication of main effects and interaction.

The clinical usefulness of total sleep deprivation (TSD) in the treatment of bipolar depression is hampered by a high-rate short-term relapse. Previous literature has suggested that both long-term lithium treatment and light therapy could successfully prevent relapse. We randomized 115 bipolar depressed inpatients to receive three cycles of TSD, alone or in combination with morning light exposure, given at an intensity of 150 or 2500 lux. Forty-nine patients were undergoing long-term treatment with lithium salts (at least 6 months), while 66 patients were taking no psychotropic medication. Mood was self-rated by the Visual Analogue Scale three times a day during treatment. The results showed that both light therapy and ongoing lithium treatment significantly enhanced the effects of TSD on the perceived mood, with no additional benefit when the two treatments were combined. Subjective sleepiness during TSD, as rated by the self-administered Stanford Sleepiness Scale, was significantly reduced by light exposure, and was correlated with the outcome. This study confirms the possibility of obtaining a sustained antidepressant response to TSD in bipolar patients.

Seasonal concordance of recurrence in mood disorder patients.

The aim of the present study is to evaluate the seasonal pattern of recurrences and the concordance among first episode (index episode) versus the subsequent recurrences in a sample of 210 patients affected by mood disorders, referred to the Mood Disorder Unit of San Raffaele Hospital. The most depressive recurrences are in spring for unipolar subjects and in fall for bipolars. Manic episodes are more frequent in summer. Patients presented a high concordance rate between the first and the second episode, female patients were more concordant than male subjects, and patients with low cycle of illness (one episode every six or more years) were the most concordant ones.

Sleep deprivation hastens the antidepressant action of fluoxetine.

Among ten bipolar depressed patients admitted to our psychiatric ward, five patients were treated with fluoxetine alone and five subjects were treated with fluoxetine in association with total sleep deprivation (TSD) in order to evaluate the effect of the interaction between the administration of the serotonergic antidepressant compound fluoxetine and repeated cycles of TSD. Patients treated with fluoxetine plus repeated TSD showed a faster amelioration of depressive symptomatology compared with the other group. We discuss our findings hypothesizing an enhancement in dopaminergic and possibly in serotonergic transmission due to repeated TSD adding to the increase in serotonergic transmission due to fluoxetine medication.

Ongoing lithium treatment prevents relapse after total sleep deprivation.

Forty bipolar depressed inpatients underwent three consecutive cycles of total sleep deprivation (TSD). At the beginning of the study, 20 patients were free of psychotropic drugs and 20 had been receiving lithium medication for at least 6 months. Mood was rated on the Hamilton Rating Scale for Depression before and after TSD; perceived mood changes during treatment were evaluated with self-administered visual analog scales. Patients undergoing long-term lithium treatment showed a significantly better response to TSD as rated on both scales: 13 of 20 patients (vs. 2 of 20 patients without lithium) showed a sustained response during a follow-up period of 3 months. This preliminary evidence of a positive interaction of TSD and long-term lithium treatment could be explained by a synergistic effect of both treatments on brain serotonergic function, possibly via a desensitization of 5-hydroxytryptamine-1A inhibitory autoreceptors.