Differential effectiveness between Ketamine and Esketamine: the predictive role of dissociative features. A treatment-resistant depression case.

More than 10 years ago, the discovery of the antidepressant effects of Ketamine opened the opportunity to develop a novel class of antidepressants. Ketamine induces dissociative symptoms as a major side effect. This rapid-acting antidepressant is available as an endovenous racemic compound and as an intranasal S-enantiomer: Esketamine; which is four-fold more potent for the NMDA receptor. Here we present the critical case of a patient who took both molecules experiencing remission just with endovenous Ketamine, whose impact in terms of dissociative symptoms was greater. In this short report, we discuss the differences between the two drugs and the possibility of dissociative features to predict their efficacy.

Sleep architecture modifications after double chronotherapy: A case series of bipolar depressed inpatients.

The aim of this study is to objectively evaluate sleep architecture changes of depressed bipolar subjects treated with chronoterapeutics. Eleven depressed bipolar inpatients received 3 cycles of Total Sleep Deprivation, followed by daily light therapy sessions for one week. Polysomnography was performed before and after the treatment. Depressive symptoms significantly reduced, and sleep architecture changed with significant differences in N2% and N3% and REM density. Change in N3% was also positively correlated to depressive symptoms reduction. Although, previous studies reported sleep architecture changes after chronoterapeutics in unipolar depression, this is the first study to demonstrate changes also in bipolar depressed subjects.

Antidepressant chronotherapeutics normalizes prefrontal 1H-MRS glutamate in bipolar depression.

BACKGROUND: Dysfunctional glutamatergic neurotransmission has been proposed both, as a biological underpinning of mood disorder and as a target for rapid-acting antidepressant treatments. Total sleep deprivation and light therapy (TSD + LT) can prompt antidepressant response in drug-resistant bipolar depression. Here we explored the effects of TSD + LT on dorsolateral prefrontal cortex (DLPFC) glutamate and/or glutamine+glutamate (Glx) levels. METHODS: We studied single voxel 1H-MRS measures of DLPFC Glu and Glx levels of 48 healthy participants and 55 inpatients with a major depressive episode in course of Bipolar Disorder, a subset of which (N = 23) underwent three cycles of repeated TSD + LT and were evaluated before and after treatment. Treatment effects of mood and on Glu and Glx concentrations were analyzed in the context of the Generalized Linear Model (GLM), correcting for age, sex and ongoing lithium treatment. RESULTS: Higher concentration of Glu (adjusted Z = -2189, p = 0,0285) and Glx (adjusted Z = -3,13, p = 0,0017) were observed in BD patients compared to HC. Treatment caused a significant rapid reduction of depressive symptom severity over time (F = 63.98, p < 0.01). Change in depression levels after TSD + LT treatment was significantly influenced by delta change in Glu levels (LR χ2 = 4.619, p = 0.0316) and in Glx levels (LR χ2 = 4.486, p = 0.0341). CONCLUSION: A reduction in Glu and Glx levels associated with depression could contribute to the mechanism of action of TSD + LT, directly acting on glutamatergic neurons, or to the interaction between the glutamatergic system and dopamine (DA) and serotonin (5-HT) levels, known to be targeted by TSD. This is in line with several studies showing a glutamatergic modulation effects of antidepressants and mood stabilizing agents. This finding deepens our understanding of antidepressant effect of chronoterapeutics.

Effective Antidepressant Chronotherapeutics (Sleep Deprivation and Light Therapy) Normalize the IL-1ß:IL-1ra Ratio in Bipolar Depression.

BACKGROUND: Mood disorders associate with peripheral markers of low-grade inflammation, among which circulating levels of interleukin-1ß (IL-1ß) consistently predict diagnosis and poor outcomes. Antidepressant chronotherapeutics (total sleep deprivation and light therapy, TSD+LT) prompts response in drug-resistant bipolar depression, but its effect on peripheral inflammation were never assessed. Here we explored the effects of TSD+LT on IL-1ß signaling. METHODS: We studied the ratio between IL-1ß and its receptor antagonist (IL-1ß:IL1ra) in 33 healthy participants, and in 26 inpatients with a major depressive episode in course of Bipolar Disorder, before and after treatment with three cycles of repeated TSD+LT, interspersed with sleep recovery nights, administered during 1 week. Treatment effects of mood and on IL-1ß:IL1ra were analyzed in the context of the Generalized Linear Model (GLM). RESULTS: At baseline, patients had higher IL-1ß, IL1ra, and IL-1ß:IL1ra than controls. Treatment significantly decreased IL-1ß:IL1ra, by decreasing IL-1ß and increasing IL1ra, the effect being proportional to baseline levels and normalizing values. Patients with higher baseline levels showed the highest decrease in IL-1ß:IL-1ra, which associated with the immediate antidepressant response at the first cycle; while patients with lower baseline values showed negligible changes in the IL-1ß:IL-1ra, unrelated to treatment response. CONCLUSION: We observed a parallel change of inflammatory biomarkers and severity of depression after chronotherapeutics, suggesting that a reduction in inflammation associated with depression could contribute to the mechanism of action of TSD+LT, and warranting interest for controlled studies addressing the role of inflammation in the recovery from bipolar depression.

Bright light therapy accelerates the antidepressant effect of repetitive transcranial magnetic stimulation in treatment resistant depression: a pilot study.

Objectives: We performed a randomized single-blinded study to assess the superiority of the combination strategy of repetitive Transcranial Magnetic Stimulation (rTMS) and Bright Light Therapy (BLT) over rTMS treatment alone in reducing depressive symptoms in treatment-resistant depression (TRD).Methods: We enrolled 80 inpatients with a diagnosis of TRD. All patients were randomly assigned into two groups: group A was treated with rTMS, compared to group B treated with a combination of rTMS and BLT. Depressive symptoms were weekly assessed (T0, T1, T2, T3) through the 17-item Hamilton depression rating scale (HDRS-17).Results: rANOVA (F=2.766, p=0.043) and post-hoc in HDRS-17 showed significant better scores in favour of group B every week (p<0.025, T1: 22.075 vs 17.200; T2: 16.100 vs 12.775; T3: 12.225 vs 8.900).Conclusions: The antidepressant effect of rTMS was enhanced and accelerated by its combination with BLT in treating resistant depression.KEYPOINTSAlmost one third of depressed patients does not respond to antidepressants; emerging neuromodulation and chronobiological techniques are effective antidepressant augmentation treatments.The aim of this study was to assess the superiority of the combination strategy of Light Therapy and TMS over TMS treatment alone in a group of treatment resistant depressed patients.The implication of this study in clinical practice is that a safe, low risk and cost-effective treatment, as Light Therapy, improves and accelerates the antidepressant effect of TMS.

Transcranial direct current stimulation: A novel approach in the treatment of vascular depression.

BACKGROUND: Despite the impact of depression in terms of personal suffering and socioeconomic burden, most currently available treatment options are often ineffective. A particularly difficult-to-treat depressive disorder characteristic of the elderly is vascular depression, a late-life depressive syndrome related to a variety of potential vascular mechanisms. Transcranial Direct Current Stimulation (tDCS), a non-invasive and effective somatic approach to depression, also showed positive effects on cognitive deficits. AIM: We performed a double-blind randomized study to investigate the efficacy of tDCS as augmentation strategy to sertraline in the treatment of vascular depression, hypothesizing a positive effect in both depressive symptoms and cognitive functions. METHODS: We enrolled 93 inpatients over 60 years of age with a diagnosis of vascular depression. Depressive symptoms were weekly assessed (T0, T1, T2) with the 21-items Hamilton depression rating scale (HDRS). Cognitive functioning was evaluated with the Milan Overall Dementia Assessment (MODA) at baseline and after the treatment protocol. All patients were randomly assigned into three groups, Group I: one tDCS stimulation per day, Group II: two tDCS stimulations per day, Sham group: one sham tDCS stimulation per day. Stimulation was performed for 10 consecutive working days. RESULTS: A significant interaction time∗treatment was observed on HDRS scores (F = 14, p < 0.001). All groups improved at T1 but whereas Group II significantly differed from the Sham group (p < 0.001) we observed no difference between Sham and Group I. At T2 all groups improved but Group II showed the greater improvement (vs. Sham p < 0.001; vs. Group I p < 0.001) and the Sham group the smallest (vs. Group I p = 0.005). A significant interaction time∗treatment was also observed on MODA scores (F = 3.31, p = 0.04). Only subjects treated with tDCS improved at T2 (Group I: p < 0.001; Group II: p = 0.007). However, no difference between Group I and II was shown. CONCLUSION: tDCS as augmentation treatment of an adequate pharmacotherapy is a potential strategy in the management of vascular depression, a disease known to be often unresponsive to antidepressants only. Non-invasiveness, the absence of severe side effects and the possibility of administering it to outpatients at an affordable price make tDCS an important tool in clinical practice.

Mental health services for mood disorder outpatients in Milan during COVID-19 outbreak: The experience of the health care providers at San Raffaele hospital.

The spread of COVID-19 throughout Italy, particularly Lombardy, led to adopt quarantine measures, known to exacerbate pre-existing psychiatric conditions. We described a telephone-based surveillance on 101 euthymic Mood Disorder outpatients in Milan by a non-standardized survey to evaluate reactions to lockdown measures and the presence of quarantine stressors. Frustration was the most represented quarantine stressor. Being jobless was significantly related to the presence of frustration, somatization, increased alertness, psychic anxiety and low mood; younger age to the presence of psychic anxiety, alertness and financial concerns. No recurrences were observed at the time of writing.

Changes of white matter microstructure after successful treatment of bipolar depression.

BACKGROUND: Diffusion tensor imaging (DTI) measures suggest a widespread alteration of white matter (WM) microstructure in patients with bipolar disorder (BD). The chronotherapeutic combination of repeated total sleep deprivation and morning light therapy (TSD+LT) can acutely reverse depressive symptoms in approximately 60% of patients, and it has been confirmed as a model antidepressant treatment to investigate the neurobiological correlates of rapid antidepressant response. METHODS: We tested if changes in DTI measures of WM microstructure could parallel antidepressant response in a sample of 44 patients with a major depressive episode in course of BD, treated with chronoterapeutics for one week. We used both a tract-wise and a voxel-wise approach for the whole-brain extraction of DTI measures of WM microstructure: axial (AD), radial (RD), and mean diffusivity (MD), and fractional anisotropy (FA). RESULTS: Compared to baseline level, at one-week follow up we observed a significant increase in average FA measures paralleled by a significant decrease in MD measures of several WM tracts including cingulum, corpus callosum, corona radiata, cortico-spinal tract, internal capsule, fornix and uncinate fasciculus. The degree of change was associated to clinical response. CONCLUSIONS: This is the first study to show changes of individual DTI measures of WM microstructure in response to antidepressant treatment in BD. Our results add new evidence to warrant a role for chronotherapeutics as a first-line treatment for bipolar depression and contribute identifying generalizable neuroimaging-based biomarkers of antidepressant response.

Thiopental is better than propofol for electroconvulsive therapy.

BACKGROUND AND AIM OF THE WORK: electroconvulsive therapy is a psychiatric procedure requiring general anesthesia. The choice of the hypnotic agent is important because the success of the intervention is associated to the occurrence and duration of motor convulsion. However, all available anesthetic agents have anti-convulsant activity. We compared the effect of thiopental and propofol on seizures. METHODS: We designed a retrospective study at Mood Disorders Unit of a teaching Hospital. Fifty-six consecutive patients undergoing electroconvulsive therapy were enrolled. Patients received fentanyl followed by either thiopental or propofol. We evaluated the incidence and the duration of seizure after electric stimulus at the first session of electroconvulsive therapy for each patient. Adverse perioperative effects were recorded. RESULTS: Patients were 60±12.1 years old and 64% was female. There was a statistically significant higher number of patients who had motor convulsion activity in the thiopental group when compared to the propofol group (25 vs 13, p=0.023). Seizure duration was statistically significant longer in the thiopental group than in the propofol group (35 sec vs 11 sec, p=0.046). No hemodynamic instability, oxygen desaturation episodes, prolonged recovery time from anesthesia and adverse effects related to anesthesia were recorded. CONCLUSIONS: Thiopental induction has a favourable effect on seizure when compared to propofol in patients undergoing electroconvulsive therapy.

Optimized light therapy for non-seasonal major depressive disorder: effects of timing and season.

BACKGROUND: Light Therapy (LT) when combined with standard antidepressant treatment for unipolar depression hastens recovery. We studied the influence of LT timing on the antidepressant efficacy of LT and the influence of the season of treatment and recurrence on the response to treatment. METHODS: We studied 70 inpatients affected by Unipolar Depression, treated for three weeks with combined LT and venlafaxine. Two-third of the patients received LT following a predictive algorithm based on MEQ scores; the others received LT at 11:00 a.m. Severity of depression was rated on the Hamilton Depression Rating Scale (HDRS). A subgroup of patients wore activity monitors. RESULTS: HDRS scores significantly decreased during treatment (Friedman's ANOVA: χ2=186.82, p<0.00001). LT administered in the early morning showed a better relative efficacy than late morning (F=4.576; p=0.012) with the clinical improvement correlating with an advance in rest-activity rhythm acrophase (r=-0.336; p=0.017). Season of hospitalization interacted with LT timing and time in influencing response to treatment (F=3.101; p=0.049) and season of episode recurrence significantly interacted with LT timing, season of hospitalization and time (F=5.925; p=0.0035). LIMITATIONS: The major limitation of the study is the small sample size when considering simultaneously LT schedules, season of treatment and recurrence. Moreover, even if none of the patients fulfilled DSM-IV criteria for seasonal pattern of recurrence, they were not administered any questionnaire about seasonality. CONCLUSIONS: We confirmed the usefulness of LT as a non-pharmacological antidepressant therapy for non-seasonal depression. Season and timing of administration and timing of the rest-activity cycle affected response to treatment.

Seasonality and sleep: a clinical study on euthymic mood disorder patients.

Background. Research on mood disorders has progressively focused on the study of seasons and on the mood in association with them during depressive or manic episodes yet few studies have focused on the seasonal fluctuation that characterizes the patient's clinical course both during an illness episode and during euthymic periods. Methods. 113 euthymic outpatients 46 affected by major recurrent depression and 67 affected by bipolar disorder were recruited. We evaluated the impact of clinical "rhythmical" factors: seasonality, sleep disturbance, and chronotype. Patients completed the SPAQ+ questionnaire, the MEQ questionnaire, and the medical outcomes study (MOS) sleep scale. We used t-test analyses to compare differences of clinical "rhythmical" and sociodemographic variables and of differences in the assessment scales among the diagnostic groups. Results. Patients reporting a family history for mood disorders have higher fluctuations throughout seasons. Sleep disturbance is more problematic in unipolars when compared to bipolars. Conclusions. Sleep, light, and seasonality seem to be three interconnected features that lie at the basis of chronobiology that, when altered, have an important effect both on the psychopathology and on the treatment of mood disorders.

Acute antidepressant response to sleep deprivation combined with light therapy is influenced by the catechol-O-methyltransferase Val(108/158)Met polymorphism.

Catechol-O-methyltransferase (COMT) inactivates norepinephrine and dopamine via methyl conjugation, and a G-A transition in the COMT gene (rs4680) influences the enzyme activity. It is a current area of debate whether rs4680 can influence antidepressant response in major depressive disorder, and whether this influence extends to bipolar depression. Chronotherapeutic interventions, such as sleep deprivation and light therapy, are multi-target in nature and are effective in bipolar depression. Here we studied the effect of rs4680 on response to sleep deprivation combined with light therapy (36 h awake followed by a night of undisturbed sleep, with 10,000 lx light administered for 30 min during the night awake and upon awakening) in 87 bipolar depressed inpatients. Patients who were homozygotic for the Val/Val variant showed a significantly less efficient antidepressant effect after the night awake than those who were heterozygotic and homozygotic for the Met variant. This effect of rs4680 is similar to its observed influence on response to serotonergic and noradrenergic drug treatments in major depressive disorder. This is the first study reporting an influence of rs4680 on antidepressant response in bipolar depression. This finding supports the hypothesis of a major role for catecholamines in the mechanism of action of chronotherapeutics, and for rs4680 in modulating this effect.

New perspectives on techniques for the clinical psychiatrist: Brain stimulation, chronobiology and psychiatric brain imaging.

This review summarizes a scientific dialogue between representatives in non-pharmacological treatment options of affective disorders. Among the recently introduced somatic treatments for depression those with most evidenced efficacy will be discussed. The first part of this article presents current opinions about the clinical applications of transcranial magnetic stimulation in the treatment of depression. The second part explains the most relevant uses of chronobiology in mood disorders, while the last part deals with the main perspectives on brain imaging techniques in psychiatry. The aim was to bridge gaps between the research evidence and clinical decisions, and reach an agreement on several key points of chronobiological and brain stimulation techniques, as well as on relevant objectives for future research.

Serotonin 5-HT2A receptor gene variants influence antidepressant response to repeated total sleep deprivation in bipolar depression.

5-HT2A receptor density in prefrontal cortex was associated with depression and suicide. 5-HT2A receptor gene polymorphism rs6313 was associated with 5-HT2A receptor binding potential, with the ability of individuals to use environmental support in order to prevent depression, and with sleep improvement after antidepressant treatment with mirtazapine. Studies on response to antidepressant drugs gave inconsistent results. Here we studied the effect of rs6313 on response to repeated total sleep deprivation (TSD) in 80 bipolar depressed inpatients treated with three consecutive TSD cycles (each one made of 36 h awake followed by a night of undisturbed sleep). All genotype groups showed comparable acute effects of the first TSD, but patients homozygotes for the T variant had better perceived and observed benefits from treatment than carriers of the C allele. These effects became significant after the first recovery night and during the following days, leading to a 36% higher final response rate (Hamilton depression rating<8). The higher density of postsynaptic excitatory 5-HT2A receptors in T/T homozygotes could have led to higher behavioural effects of increased 5-HT neurotransmission due to repeated TSD. Other possible mechanisms involve allostatic/homeostatic adaptation to sleep loss, and a different effect of the allele variants on epigenetic influences. Results confirm the interest for individual gene variants of the serotonin pathway in shaping clinical characteristics of depression and antidepressant response.

Phase advance is an actimetric correlate of antidepressant response to sleep deprivation and light therapy in bipolar depression.

The combination of total sleep deprivation (TSD) and light therapy (LT) in bipolar depression causes rapid antidepressant effects, and its mechanism of action has been hypothesized to involve the enhancement of all of the monoaminergic systems targeted by antidepressant drugs (serotonin, dopamine, norepinephrine). It is still unknown if the clinical effects are paralleled by changes in biological rhythms. In a before/after design of a study of biological correlates of response, 39 inpatients affected by Type I Bipolar Disorder whose current depressive episode was without psychotic features were treated for one week with repeated TSD combined with morning LT. Wrist actigraphy was recorded throughout the study. Two-thirds of the patients responded to treatment (50% reduction in Hamilton Depression score). Responders showed an increase in daytime activity, phase-advance of the activity-rest rhythm of 57 min compared to the pre-treatment baseline, and reduced nighttime sleep. Non-responders did not show significant changes in the parameters of their activity-rest rhythm. Phase advance of the activity-rest rhythm is an actimetric correlate of the antidepressant response to TSD and LT in bipolar depression. Results are consistent with the known effects of sleep-wake manipulations and neurotransmitter function on the suprachiasmatic nucleus.

Chronotherapeutics in a psychiatric ward.

Psychiatric chronotherapeutics is the controlled exposure to environmental stimuli that act on biological rhythms in order to achieve therapeutic effects in the treatment of psychiatric conditions. In recent years some techniques (mainly light therapy and sleep deprivation) have passed the experimental developmental phase and reached the status of powerful and affordable clinical interventions for everyday clinical treatment of depressed patients. These techniques target the same brain neurotransmitter systems and the same brain areas as do antidepressant drugs, and should be administered under careful medical supervision. Their effects are rapid and transient, but can be stabilised by combining techniques among themselves or together with common drug treatments. Antidepressant chronotherapeutics target the broadly defined depressive syndrome, with response and relapse rates similar to those obtained with antidepressant drugs, and good results are obtained even in difficult-to-treat conditions such as bipolar depression. Chronotherapeutics offer a benign alternative to more radical treatments of depression for the treatment of severe depression in psychiatric wards, but with the advantage of rapidity of onset.

Actimetric evidence that CLOCK 3111 T/C SNP influences sleep and activity patterns in patients affected by bipolar depression.

Depressive insomnia and diurnal fluctuations of mood and activity are core clinical features of mood disorders. Here we studied the effect of CLOCK 3111 T/C SNP (rs1801260) on the actimetric recorded diurnal activity and nocturnal sleep of 39 bipolar depressed inpatients. Compared to T/T homozygotes, carriers of the C allele had a similar degree of severity of depression, but showed higher activity levels in the evening, a delayed sleep onset (mean 79 min later), and a reduced amount of sleep during the night (mean 75 min less). Ongoing lithium treatment significantly interacted with rs1801260 by enhancing activity levels in the evening and reducing the differences among genotype groups. Individual characteristics of the molecular clock can influence sleep symptoms in mood disorders.