Hypothalamic-pituitary-adrenal axis hyperactivity is normalized after successful intermittent theta-burst stimulation in resistant depressed patients.

The present pilot study assessed the effects of multi-session intermittent theta-burst stimulation (iTBS) applied to the left dorsolateral prefrontal cortex in 17 treatment resistant depressed inpatients (TRDs) showing cortisol non-suppression to the overnight dexamethasone suppression test (DST) at baseline (i.e., maximum post-DST cortisol [CORmax] level > 130 nmol/L). After 20 iTBS sessions, the DST was repeated in all TRDs. At baseline, post-DST CORmax levels were higher in TRDs compared to healthy control subjects (HCs; n = 17) (p < 0.0001). After 20 iTBS sessions, post-DST CORmax levels decreased from baseline (p < 0.03) and were comparable to HCs. Decreases in post-DST CORmax levels were related to decreases in 17-item Hamilton Depression Rating Scale (HAMD-17) scores (ρ = 0.53; p < 0.03). At endpoint, 10 TRDs showed DST normalization (among them 7 were responders [i.e., HAMD-17 total score > 50% decrease from baseline]), and 7 did not normalize their DST (among them 6 were non-responders) (p < 0.05). Our results suggest that successful iTBS treatment may restore normal glucocorticoid receptor feedback inhibition at the pituitary level.

Potential efficacy of dopaminergic antidepressants in treatment resistant anergic-anhedonic depression results of the chronic anergic-anhedonic depression open trial - CADOT.

Introduction: Among treatment-resistant depression (TRD), we identified anergic-anhedonic clinical presentations (TRAD) as putatively responsive to pro-dopaminergic strategies. Based on the literature, non-selective monoamine oxidase inhibitors (MAOI) and dopamine D2 receptor agonists (D2RAG) were sequentially introduced, frequently under the coverage of a mood stabilizer. This two-step therapeutic strategy will be referred to as the Dopaminergic Antidepressant Therapy Algorithm (DATA). We describe the short and long-term outcomes of TRAD managed according to DATA guidelines. Method: Out of 52 outpatients with TRAD treated with DATA in a single expert center, 48 were included in the analysis [severity - QIDS (Quick Inventory of Depressive Symptomatology) = 16 ± 3; episode duration = 4.1 ± 2.7 years; Thase and Rush resistance stage = 2.9 ± 0.6; functioning - GAF (Global Assessment of Functioning) = 41 ± 8]. These were followed-up for a median (1st - 3rd quartile) of 4 (1-9) months before being prescribed the first dopaminergic treatment and remitters were followed up 21 (11-33) months after remission. Results: At the end of DATA step 1, 25 patients were in remission (QIDS <6; 52% [38-66%]). After DATA step 2, 37 patients were in remission (77% [65-89%]) to whom 5 patients with a QIDS score = 6 could be added (88% [78-97%]). Many of these patients felt subjectively remitted (GAF = 74 ± 10). There was a significant benefit to combining MAOI with D2RAG which was maintained for at least 18 months in 30 patients (79% [62-95%]). Conclusion: These results support TRAD sensitivity to pro-dopaminergic interventions. However, some clinical heterogeneities remain in our sample and suggest some improvement in the description of dopamine-sensitive form(s).

Hypothalamic-prolactin axis regulation in major depressed patients with suicidal behavior.

BACKGROUND: So far, little is known about the control of hypothalamic-prolactin axis activity by dopamine (DA) and thyrotropin-releasing hormone (TRH) in depressed patients with suicidal behavior disorder (SBD). METHODS: We evaluated prolactin (PRL) responses to apomorphine (APO; a DA direct receptor agonist) and 0800 h and 2300 h protirelin (TRH) tests in 50 medication-free euthyroid DSM-5 major depressed inpatients with SBD (either current [n = 22], or in early remission [n = 28]); and 18 healthy hospitalized controls (HCs). RESULTS: Baseline (BL) PRL levels were comparable across the three diagnostic groups. SBDs in early remission did not differ from HCs regarding PRL suppression to APO (PRLs), PRL stimulation to 0800 h and 2300 h TRH tests (∆PRL), and ∆∆PRL values (difference between 2300 h-∆PRL and 0800 h-∆PRL values). Current SBDs showed lower PRLs and ∆∆PRL values than HCs and SBDs in early remission. Further analyses revealed that current SBDs with a history of violent and high-lethality suicide attempts were more likely to exhibit co-occurrence of low ∆∆PRL and PRLS values. CONCLUSIONS: Our results suggest that regulation of the hypothalamic-PRL axis is impaired in some depressed patients with current SBD, particularly those who have made serious suicide attempts. Considering the limitations of our study, our findings support the hypothesis that decreased pituitary D2 receptor functionality (possibly adaptive to increased tuberoinfundibular DAergic neuronal activity) together with decreased hypothalamic TRH drive might be a biosignature for high-lethality violent suicide attempts.

Dopamine Function and Hypothalamic-Pituitary-Thyroid Axis Activity in Major Depressed Patients with Suicidal Behavior.

Involvement of the dopaminergic (DA) and hypothalamic-pituitary-thyroid (HPT) systems in suicidal behavior is still poorly understood. We assessed multihormonal responses to apomorphine (APO; a short acting DA receptor agonist) and 8 AM and 11 PM protirelin (TRH) tests in 30 medication-free DSM-5 euthyroid major depressed inpatients with suicidal behavior disorder (SBD) (current, n = 14; in early remission, n = 16) and 18 healthy hospitalized control subjects (HCs). Compared to HCs, responses to APO and TRH tests were unaltered in SBDs in early remission. However, current SBDs exhibited increased APO-induced growth hormone (GH) and adrenocorticotropin (ACTH) stimulation, and reduced 11 PM thyrotropin (TSH) and ∆∆TSH values (difference between 11 PM and 8 AM TRH-TSH responses). In current SBDs, the association between high APO-GH concentrations and low ∆∆TSH values was more common in recent suicide attempters than in past suicide attempters. These preliminary results suggest that co-occurring alterations in the DA and HPT systems (i.e., DA receptor hyperresponsiveness associated with decreased hypothalamic TRH drive) may contribute to the pathophysiology of suicidal behavior. Conversely, normalization of DA and TRH functions might reflect a process of recovery from suicidality. Thus, our findings suggest that drugs targeting the DAergic and TRH systems could be relevant in suicide prevention.

Neuroendocrine Assessment of Dopaminergic Function during Antidepressant Treatment in Major Depressed Patients.

The effects of antidepressants on dopamine (DA) receptor sensitivity in the mesolimbic-hypothalamic system have yielded contradictory results. The postsynaptic DA receptor function was evaluated by the cortisol response to apomorphine (APO; 0.75 mg SC) in 16 drug-free DSM-5 major depressed inpatients and 18 healthy hospitalized control (HC) subjects. Cortisol response to the dexamethasone suppression test (DST) was also measured. After two and four weeks of antidepressant treatment (ADT), the DST and APO test were repeated in all patients. Cortisol response to APO (∆COR) was not influenced by the hypothalamic-pituitary-adrenal (HPA) axis activity, as assessed by the DST. Pre-treatment ∆COR values did not differ significantly between patients and HCs. During ADT, ∆COR values were lower than in HCs at week 2 and 4. After four weeks of treatment, among the eight patients who had blunted ∆COR values, seven were subsequent remitters, while among the eight patients who had normal ∆COR values, seven were non-remitters. Considering the limitations of our study, the results suggest that following chronic ADT, the desensitization of postsynaptic DA receptors connected with the regulation of the HPA axis at the hypothalamic level is associated with clinical remission. These results could reflect increased DA levels in the mesolimbic pathway.