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Subanesthetic ketamine infusion therapy can produce fast-acting antidepressant effects in patients with major depression. How single and repeated ketamine treatment modulates the whole-brain functional connectome to affect clinical outcomes remains uncharacterized.
Data-driven whole brain functional connectivity (FC) analysis was used to identify the functional connections modified by ketamine treatment in patients with major depressive disorder (MDD). MDD patients (N = 61, mean age = 38, 19 women) completed baseline resting-state (RS) functional magnetic resonance imaging and depression symptom scales. Of these patients, n = 48 and n = 51, completed the same assessments 24 h after receiving one and four 0.5 mg/kg intravenous ketamine infusions. Healthy controls (HC) (n = 40, 24 women) completed baseline assessments with no intervention. Analysis of RS FC addressed effects of diagnosis, time, and remitter status.
Significant differences (p < 0.05, corrected) in RS FC were observed between HC and MDD at baseline in the somatomotor network and between association and default mode networks. These disruptions in FC in MDD patients trended toward control patterns with ketamine treatment. Furthermore, following serial ketamine infusions, significant decreases in FC were observed between the cerebellum and salience network (SN) (p < 0.05, corrected). Patient remitters showed increased FC between the cerebellum and the striatum prior to treatment that decreased following treatment, whereas non-remitters showed the opposite pattern.
Results support that ketamine treatment leads to neurofunctional plasticity between distinct neural networks that are shown as disrupted in MDD patients. Cortico-striatal-cerebellar loops that encompass the SN could be a potential biomarker for ketamine treatment.
Multivariable risk algorithms (MVRP) predicting the personal risk of depression will form an important component of personalized preventive interventions. However, it is unknown whether providing personalized depression risk will lead to unintended psychological harms. The objectives of this study were to evaluate the impact of providing personalized depression risk on non-specific psychological distress and functional impairment over 12 months.
A mixed-methods randomized controlled trial was conducted in 358 males and 354 females who were at high risk of having a major depressive episode according to sex-specific MVRPs, and who were randomly recruited across Canada. Participants were assessed at baseline, 6 and 12 months.
Over 93% of participants were interested in knowing their depression risk. The intervention group had a greater reduction in K10 score over 12 months than the control group; complete-case analysis found a significant between-group difference in mean K10 change score (d = 1.17, 95% CI 0.12–2.23) at 12 months. Participants in the intervention group also reported significantly less functional impairment in the domains of home and work/school activities, than did those in the control group. A majority of the qualitative interviewees commented that personalized depression risk information does not have a negative impact on physical and mental health.
This study found no evidence that providing personalized depression risk information will lead to worsening psychological distress, functional impairment, and absenteeism. Provision of personalized depression risk information may have positive impacts on non-specific psychological distress and functioning.
It is unclear whether olfactory deficits improve after remission in depressed patients. Therefore, we aimed to assess in drug-free patients the olfactory performance of patients with major depressive episodes (MDE) and its change after antidepressant treatment.
In the DEP-ARREST-CLIN study, 69 drug-free patients with a current MDE in the context of major depressive disorder (MDD) were assessed for their olfactory performances and depression severity, before and after 1 (M1) and 3 (M3) months of venlafaxine antidepressant treatment. They were compared to 32 age- and sex-matched healthy controls (HCs). Olfaction was assessed with a psychophysical test, the Sniffin’ Sticks test (Threshold: T score; Discrimination: D score; Identification: I score; total score: T + D + I = TDI score) and Pleasantness (pleasantness score: p score; neutral score: N score; unpleasantness score: U score).
As compared to HCs, depressed patients had lower TDI olfactory scores [mean (s.d.) 30.0(4.5) v. 33.3(4.2), p < 0.001], T scores [5.6(2.6) v. 7.4(2.6), p < 0.01], p scores [7.5(3.0) v. 9.8(2.8), p < 0.001)] and higher N scores [3.5(2.6) v. 2.1(1.8), p < 0.01]. T, p and N scores at baseline were independent from depression and anhedonia severity. After venlafaxine treatment, significant increases of T scores [M1: 7.0(2.6) and M3: 6.8(3.1), p < 0.01] and p scores [M1: 8.1(3.0) and M3: 8.4(3.3), p < 0.05] were evidenced, in remitters only (T: p < 0.01; P: p < 0.01). Olfaction improvement was mediated by depression improvement.
The olfactory signature of MDE is restored after venlafaxine treatment. This olfaction improvement is mediated by depression improvement.
Little is known about the post-acute effects of repetitive transcranial magnetic stimulation (rTMS) in patients with major depression. The present study focused on the 6-month follow-up of a sample of patients with major depression, after the completion of an acute 4 weeks rTMS trial, with the aim of evaluating response (in terms of sustained and late response) and relapse rates.
Following the completion of an acute trial of rTMS (T0-T4), 31 drug-resistant depressed patients (bipolar or unipolar) entered a naturalistic follow-up period of 6 months, with three timepoints (T5, T6, and T7) during which they were assessed with the Hamilton Depression Rating Scale and the Young Mania Rating Scale.
Results showed that in the 6 months following an acute transcranial magnetic stimulation (TMS) trial, a higher rate of late responders was observed among previously acute TMS nonresponders (63.64%, 7 out of 11) compared to the rate of relapse among those who had acutely responded to TMS (10%, 2 out of 20). In addition, an overall high rate of maintained response (90%) was observed.
Present findings seem to support the possibility of obtaining a clinical response also after the end of an acute TMS trial in patients with major depression. The concomitant low rate of relapse observed at the end of follow-up along with a high rate of maintained response provides further support to the post-acute efficacy of TMS. Nonetheless, further controlled studies, with larger samples and longer follow-up observation, are needed to confirm the reported results.
Major depression (MD) is often characterised as a categorical disorder; however, observational studies comparing sub-threshold and clinical depression suggest MD is continuous. Many of these studies do not explore the full continuum and are yet to consider genetics as a risk factor. This study sought to understand if polygenic risk for MD could provide insight into the continuous nature of depression.
Factor analysis on symptom-level data from the UK Biobank (N = 148 957) was used to derive continuous depression phenotypes which were tested for association with polygenic risk scores (PRS) for a categorical definition of MD (N = 119 692).
Confirmatory factor analysis showed a five-factor hierarchical model, incorporating 15 of the original 18 items taken from the PHQ-9, GAD-7 and subjective well-being questionnaires, produced good fit to the observed covariance matrix (CFI = 0.992, TLI = 0.99, RMSEA = 0.038, SRMR = 0.031). MD PRS associated with each factor score (standardised β range: 0.057–0.064) and the association remained when the sample was stratified into case- and control-only subsets. The case-only subset had an increased association compared to controls for all factors, shown via a significant interaction between lifetime MD diagnosis and MD PRS (p value range: 2.23 × 10−3–3.94 × 10−7).
An association between MD PRS and a continuous phenotype of depressive symptoms in case- and control-only subsets provides support against a purely categorical phenotype; indicating further insights into MD can be obtained when this within-group variation is considered. The stronger association within cases suggests this variation may be of particular importance.
Network analysis (NA) conceptualizes psychiatric disorders as complex dynamic systems of mutually interacting symptoms. Major depressive disorder (MDD) is a heterogeneous clinical condition, and very few studies to date have assessed putative changes in its psychopathological network structure in response to antidepressant (AD) treatment.
In this randomized trial with adult depressed outpatients (n = 151), we estimated Gaussian graphical models among nine core MDD symptom-domains before and after 8 weeks of treatment with either escitalopram or desvenlafaxine. Networks were examined with the measures of cross-sectional and longitudinal structure and connectivity, centrality and predictability as well as stability and accuracy.
At baseline, the most connected MDD symptom-domains were fatigue–cognitive disturbance, whereas at week 8 they were depressed mood–suicidality. Overall, the most central MDD symptom-domains at baseline and week 8 were, respectively, fatigue and depressed mood; in contrast, the most peripheral symptom-domain across both timepoints was appetite/weight disturbance. Furthermore, the psychopathological network at week 8 was significantly more interconnected than at baseline, and they were also structurally dissimilar.
Our findings highlight the utility of focusing on the dynamic interaction between depressive symptoms to better understand how the treatment with ADs unfolds over time. In addition, depressed mood, fatigue, and cognitive/psychomotor disturbance seem to be central MDD symptoms that may be viable targets for novel, focused therapeutic interventions.
Alterations in a number of neurobiological systems have been associated with suicidal behavior including the serotonergic and noradrenergic systems and the hypothalamic-pituitary-adrenal axis. Altered functioning of these systems may stem from both genetic and developmental causes. Adversity in early-life has developmental consequences on these systems that persist into adulthood. Genetic differences may also contribute to alterations in functioning of neurobiological systems. Moreover, the interaction of early-life experiences of adversity and genetic vulnerability is increasingly thought to play a role, including via epigenetic mechanisms.
An increased incidence of adverse cardiovascular events has been reported in psychiatric patients, but the exact mechanisms underlying this association are still uncertain. Elevated plasma level of lipoprotein(a) [Lp(a)] is an independent risk factor for atherothrombotic disease in the general population. To study the implications of Lp(a) in psychiatric patients, we measured the plasma levels of Lp(a) in 74 patients with psychiatric disorders (39 schizophrenia, 10 major depression, 13 bipolar disorder and 12 personality disorder) and 74 healthy controls. The Lp(a) levels of the patient groups with schizophrenia, major depression and bipolar disorder were significantly higher than that of the control group. The median Lp(a) value of these diagnostic groups was comparable with those reported in patients with prior atherothrombotic events. On the other hand, no differences were found among personality disorder and controls. Our findings suggest that the elevation of plasma Lp(a) may contribute to increased cardiovascular risk in several patients with psychiatric disorders.
The study focuses on the point prevalence of major depressive episode in the Estonian population in 2006 and assesses the relationship of sociodemographic factors, health status indicators, alcohol use, and previous depressive episodes to major depression.
The present major depressive episode was assessed within the nationally representative, cross-sectional 2006 Estonian Health Survey (EHIS 2006), in which non-institutionalized individuals aged 18–84 years (n = 6105) were interviewed using the Mini-International Neuropsychiatric Interview (MINI).
The point prevalence of major depressive episode in the Estonian population was 5.6%. Depression was higher among females, in the non-Estonian ethnic group, among people older than 40 years, and in the lower-income group.
The point prevalence of major depressive episodes was comparable with the results of other population surveys, being a little higher than the average. Age, income, ethnicity, health status, self-rated health, and previous depressive episode were independent associates of depression.
Antidepressant drugs affect monoamines and neuropeptides in human cerebrospinal fluid (CSF) and in rodent brain. The purpose of this study was to investigate if also electroconvulsive therapy (ECT) affects these compounds in a similar manner in the CSF of depressed patients. Homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and corticotropin-releasing hormone (CRH)-like immunoreactivity (-LI) and neuropeptide Y (NPY)-LI were determined in CSF in six drug resistant patients with major depression. Lumbar puncture was performed at baseline and after completion of eight ECTs. ECT was associated with an increase in NPY-LI (p = 0.009) and a decrease in CRH-LI (p ≤ 0.001). HVA (p = 0.003) and 5-HIAA (p = 0.002) were significantly increased after the ECT. Findings of NPY increase and CRH decrease were similar to those following chronic treatment with citalopram, indicating that these changes might constitute one of the common underpinnings of antidepressant treatment modalities.
Several risk factors of depression have been identified in retrospective as well as some prospective studies in the elderly. Confirmation in independent samples is needed. The present follow-up study prospectively investigated risk factors of depression in an elderly German sample.
One thousand four hundred and thirty-one subjects from a family study were re-investigated after 4.7 ± 2.5 years. Bivariate and multivariate forward logistic regression analyses were used to identify risk factors of the development of new depression in the elderly.
Risk factors of a new depressive episode in 1408 elderly without current depression were age, female gender, a previous depression, subjective memory impairment, previous anxiety and somatoform disorders. The presence of dementia or mild cognitive impairment were significant risk factors in bivariate, but not multivariate analysis controlling for possible confounding. Risk factors of a first geriatric depressive episode were age, gender and subjective memory impairment; age remained the only significant risk factor in multivariate analysis.
This investigation confirms previous studies from other countries concerning the relevance of risk factors for depression in the elderly. The knowledge of risk factors might help identify subjects at increased risk of depression for early intervention approaches. Elderly with a history of previous depression carry the highest risk.
GADIS aims at determining the prevalence of generalized anxiety disorder (GAD) and major depression (MD) in primary care and their impact on the patient’s functioning in Belgium and Luxemburg.
A large scale screening program was conducted at the consultation of general practitioners to detect patients with GAD and MD according to DSM-IV criteria. We collected additional data regarding the use of hypnotic, tranquilizer, antidepressant and analgesic medications. Impact on the patient was assessed with the Sheehan disability scale.
Three hundred GP’s in Belgium and Luxemburg were asked to screen 50 consecutive patients. Of the 13,677 analyzed patients, 8.3% were diagnosed to have GAD and 6.3% MD. Comorbidity was observed in 4.2% of patients. The prevalence was much higher in the French-speaking part of Belgium. GAD and MD were associated with impairment in social, familial and professional functioning. Only a minority of patients with GAD and/or MD was treated with an antidepressant and almost half of subjects with GAD and/or MD were treated with a tranquilizer.
Prevalence rates of GAD and MD in primary care in Belgium are comparable to other countries. GAD and MD are disabling conditions. Antidepressants are still used only in a minority of subjects with GAD and/or MD in primary care in Belgium and Luxemburg. The prevalence of GAD and MD appears to be much higher in French-speaking parts of Belgium.
Anxiety and depression are often interlinked as demonstrated by clinical, epidemiological, psychopharmacological and even genetic studies. However, robust biochemical and electrophysiological evidence for linkage or separation of mood and anxiety disorders is scarce. Brain stem auditory evoked potentials (BASEP) can easily and non-invasivly be measured in psychiatric patients and reflect neurophysiological processes in the brain stem. The aim of the present study was to evaluate BASEP in drug-free patients suffering from panic disorder or major depression and to compare these to healthy controls. Patients (n = 26; panic = 16, depression = 10) were diagnosed according to Diagnostic and Statistical Manual (DSM)-III-R criteria assessed by the Hamilton Anxiety and Hamilton Depression Scales, and all underwent 3 weeks of medications washout. All subjects (n = 36) completed the study. N3 latency was decreased in the patient group (P < 0.05), N3-5 interval was lengthened (P < 0.05), the N3 latency correlated with anxiety scores and depression scores correlated with the N3 and N5 latency periods. In conclusion, our small sample demonstrated shared electrophysiological variables in panic disorder and depression, further supporting the concept of spectrum disorder.
Venlafaxine is a selective serotonin norepinephrine reuptake inhibitor with no activity at muscarinic, histaminergic or adrenergic receptors. The antidepressant activity of venlafaxine has been demonstrated in placebo-controlled and active comparator-controlled clinical trials. Venlafaxine was effective in outpatients and hospitalized patients with major depression and in those with melancholia, agitated or retarded symptoms, and refractory or treatment-resistant depression. Venlafaxine was at least as effective as comparative antidepressants and was more effective than fluoxetine or imipramine in some trials. A positive dose-response relationship has been shown with venlafaxine. When doses of venlafaxine are titrated rapidly upward, an onset of antidepressant action has been detected within one week in some studies. Venlafaxine is well tolerated during short- and long-term treatment. The most common adverse effects are nausea, somnolence and dry mouth. The overall tolerability of venlafaxine appears to exceed that of tricyclic antidepressants and compares favorably with that of selective serotonin reuptake inhibitors. Venlafaxine is a novel antidepressant that is appropriate for first-line therapy in patients with major depression.
Clinical assessments of sleep and subjective state upon waking were performed in normal controls and patients with generalised anxiety disorder, panic disorder, obsessive-compulsive disorder, primary dysthymia and major depression. Subjects were selected according to DSM-III-R criteria. As compared to normal controls, patients with generalised anxiety, dysthymia and major depression exhibit pervasive and intense complaints of insomnia, and no clear distinctions can be drawn among these groups. Patients with panic disorder do not differ from normal controls, whereas obsessive compulsive patients present limited sleep symptoms. These findings suggest that subjective sleep variables are relevant for the diagnostic discrimination of panic and obsessive-compulsive disorders.
To examine the prevalence of obsessive-compulsive symptoms, we evaluated 69 outpatients with panic disorder. We found a 30% prevalence of obsessive-compulsive symptoms. The patients with obsessive-compulsive symptoms had an earlier onset of illness and were more likely to have current and past major depression than the other ones.
Anhedonia may be considered as a transnosological feature of depression and schizophrenia. The aim of the present study was to assess hedonic responses to sucrose solutions and sweet taste perception threshold in patients with major depression and in schizophrenic patients in comparison with healthy subjects (matched for age and gender with depressive patients), and to compare these responses to evaluations by the Physical and Social Anhedonia scale of Chapman and the Pleasure Scale of Fawcett, generally used to quantify anhedonia. Hedonic responses to sucrose solutions were similar in patients with major depression (n = 20), schizophrenia (n = 20), and healthy controls (n = 20). Sweet taste perception threshold was significantly higher in depressive patients than in controls. Hedonic response to sucrose was inversely correlated with physical Anhedonia Scores and sweet taste perception threshold with Pleasure Scale scores. Measures of hedonia/anhedonia were not related with the intensity of depression or anxiety as measured by the Montgomery-Asberg Depression Rating Scale (MADRS) and Hamilton Anxiety Scale, respectively. In 11 depressed patients hospitalised for 17 to 33 days, neither hedonic ratings to sucrose solutions, sweet taste perception threshold, Physical, Social Anhedonia scores nor Pleasure Scale scores were modified in spite of substantial decrease in MADRS or Hamilton Anxiety scores. Hedonic responses to sucrose solutions and sweet taste perception threshold may be used as complementary evaluation to quantify anhedonia.
In a double-blind study carried out on elderly patients (older than 65 years) the efficacy and tolerability of the new antidepressant moclobemide was compared. Moclobemide belongs to a new class of substances called RIMA (Reversible inhibitor of the monoamine oxidase type A). Fluvoxamine, a selective reuptake-inhibitor of 5-HT, belongs to a class of antidepressants known for their better tolerability compared to tricyclic especially with elderly patients. Forty elderly patients (mean age 75 years) with major depression (according to DSM III) were randomized to receive either moclobemide (300 mg) or fluvoxamine (100 mg) twice daily. Dosages were increased when necessary on day 8, to a maximum of 450 mg moclobemide or 200 mg fluvoxamine and in most cases were maintained at these levels for the remainder of the study period (four weeks). Moclobemide was more effective than fluvoxamine showing a marked antidepressant effect and an earlier effect on psychomotor retardation. The two drugs were well tolerated showing a low incidence of side effects.
The interest in social adjustment of psychiatric patients has increased since potent therapeutic strategies have become available, allowing patient treatment within their natural social habitat. DSM III has formally recognized the need to evaluate social variables for each patient, introducing Axis V into its multiaxial system. This is of particular relevance for personality disorders where the main pathology is manifested within the social context. In this study, 94 patients with a DSM III-R diagnosis of Panic Disorder, Major Depression, and Generalized Anxiety Disorder have been evaluated with PDE (Personality Disorders Examination) to detect the presence of DSM III personality disorders, and with SAS (Social Adjustment Scale) to assess social adjustment. Results have shown that both Axis I and Axis II diagnoses affect social adjustment, though in a slightly different manner.