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.

Clinical Pharmacy in Psychiatry: Towards Promoting Clinical Expertise in Psychopharmacology.

Although clinical pharmacy is a discipline that emerged in the 1960s, the question of precisely how pharmacists can play a role in therapeutic optimization remains unanswered. In the field of mental health, psychiatric pharmacists are increasingly involved in medication reconciliation and therapeutic patient education (or psychoeducation) to improve medication management and enhance medication adherence, respectively. However, psychiatric pharmacists must now assume a growing role in team-based models of care and engage in shared expertise in psychopharmacology in order to truly invest in therapeutic optimization of psychotropics. The increased skills in psychopharmacology and expertise in psychotherapeutic drug monitoring can contribute to future strengthening of the partnership between psychiatrists and psychiatric pharmacists. We propose a narrative review of the literature in order to show the relevance of a clinical pharmacist specializing in psychiatry. With this in mind, herein we will address: (i) briefly, the areas considered the basis of the deployment of clinical pharmacy in mental health, with medication reconciliation, therapeutic education of the patient, as well as the growing involvement of clinical pharmacists in the multidisciplinary reflection on pharmacotherapeutic decisions; (ii) in more depth, we present data concerning the use of therapeutic drug monitoring and shared expertise in psychopharmacology between psychiatric pharmacists and psychiatrists. These last two points are currently in full development in France through the deployment of Resource and Expertise Centers in PsychoPharmacology (CREPP in French).

Thyroid axis activity and dopamine function in depression.

BACKGROUND: Several lines of evidence suggest alterations in both hypothalamic-pituitary-thyroid (HPT) axis and dopamine (DA) function in depressed patients. However, the functional relationships between HPT and DA systems have not been well defined. METHODS: We examined thyrotropin (TSH) response to 0800 h and 2300 h protirelin (TRH) challenges, and adrenocorticotropic hormone (ACTH), cortisol and growth hormone (GH) responses to apomorphine (APO, a DA receptor agonist), in 58 drug-free DSM-IV major depressed inpatients without a suicidal behavior, and 22 healthy hospitalized controls. RESULTS: Compared with controls, patients showed 1) lower basal serum 2300 h-TSH, 2300 h-∆TSH, and ∆∆TSH (difference between 2300 h-∆TSH and 0800 h-∆TSH) levels, and 2) lower cortisol response to APO (∆COR). A negative relationship between ∆∆TSH values and hormonal responses to APO was observed in the depressed group, but not in the control group. When patients were classified on the basis of their ∆∆TSH status, patients with reduced ∆∆TSH values (< 2.5 mU/L) showed hormonal APO responses comparable to those of controls. Patients with normal ∆∆TSH values exhibited lower ∆ACTH, ∆COR, and ∆GH values than patients with reduced ∆∆TSH values and controls. CONCLUSION: Taken together, these results suggest that hypothalamic DA function is unaltered in depressed patients with HPT dysregulation (i.e., increased hypothalamic TRH drive leading to altered TRH receptor chronesthesy on pituitary thyrotrophs). Conversely, hypothalamic DA-receptor function is decreased in patients with normal HPT axis activity. These findings are discussed in the context of the role of TRH as a homeostatic neuromodulator in depression.

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.

First-Dose Methylphenidate-Induced Changes in the Anti-Saccade Task Performance and Outcome in Adults with Attention-Deficit/Hyperactivity Disorder.

Objective: We examined whether the anti-saccade task (AST) performance after the first methylphenidate (MPH) dose could be associated with subsequent clinical outcome in adults with attention-deficit/hyperactivity disorder (ADHD). Methods: Ninety-seven drug-naive DSM-5 ADHD adults participated in this study. The AST parameters were measured at baseline, after the first MPH-dose (10 mg orally), and 6 months after chronic MPH treatment. Results were compared with those of 50 healthy control (HC) subjects. Results: At baseline, ADHDs showed longer saccadic reaction times and more direction errors than HCs (both p < 0.00001). Acute and chronic MPH administration resulted in normalization of the AST performances. Multivariate regression analysis after adjusting for age, sex, weight, and severity of symptoms at baseline, revealed that a low percentage of direction errors after the first MPH-dose (i.e., ≤10%) could predict remission at month 6 (OR: 5.84; 95% CI: 2.00-17.11; p = 0.001). Conclusions: Our findings indicate that: (1) impairments of motor planning and response inhibition in adults with ADHD are improved with MPH, and (2) a low direction error percentage after the first MPH-dose may be an independent predictor of remission.ClinicalTrials.gov identifier: NCT03411434.

Dopaminergic, Noradrenergic, Adrenal, and Thyroid Abnormalities in Psychotic and Affective Disorders.

BACKGROUND: This study aimed to assess hypothalamic-pituitary dopaminergic (DA), noradrenergic (NA), thyroid (HPT), and adrenal (HPA) activity in schizophrenia, in schizoaffective disorder, and in bipolar disorder. METHOD: We investigated a combined approach of hormone responses to (1) apomorphine (APO), a short-acting DA receptor agonist which decreases prolactin secretion (PRL), and stimulates secretion of growth hormone (GH), adrenocorticotropin (ACTH), and cortisol; (2) clonidine (CLO), an alpha 2-adrenoceptor agonist which stimulates GH secretion; (3) 8 AM and 11 PM protirelin (TRH) which stimulates thyrotropin (TSH) secretion; and (4) dexamethasone which suppresses cortisol secretion, in 13 hospitalized healthy male controls and 39 untreated male inpatients: 13 with DSM-IV paranoid schizophrenia, 13 with DSM-IV schizoaffective disorder (bipolar subtype, depressed at the time of the study), and 13 with DSM-IV bipolar disorder (depressed). RESULTS: Compared to controls, paranoid schizophrenic patients showed (1) lower APO-induced ACTH and cortisol stimulation, and (2) higher post-dexamethasone cortisol values. Compared to controls, schizoaffective and bipolar patients showed (1) lower ΔΔTSH values (i.e., difference between 11 PM and 8 AM TRH-TSH responses), (2) lower APO-induced PRL suppression, (3) lower CLO-induced GH stimulation, and (4) higher post-dexamethasone cortisol values. CONCLUSIONS: Although results must be interpreted with caution because of the small sample, this preliminary study suggests that depressed bipolar and schizoaffective patients share common biological dysregulations, distinct from that of paranoid schizophrenic patients. From a pathophysiological viewpoint, paranoid schizophrenic patients can be characterized by hyposensitivity of the hypothalamic DA receptors (possibly resulting from an increase in presynaptic DA release) associated with increased HPA axis activity, while depressed bipolar and schizoaffective patients can be characterized by hyposensitivity of the pituitary TRH and DA-D2 receptors (possibly linked to the activation of the hypothalamic TRH and tuberoinfundibular DA neurons, respectively), together with subsensitive postsynaptic α2-adrenoreceptors at the hypothalamic level (possibly secondary to an erratic release of NA) and increased HPA axis activity.

Are the thyroid and adrenal system alterations linked in depression?

BACKGROUND: Disturbances in the hypothalamic-pituitary-thyroid (HPT) and hypothalamic-pituitary-adrenal (HPA) axes have been frequently found in major depression. Given that glucocorticoids may inhibit thyrotropin (TSH) and thyrotropin-releasing hormone (TRH) secretion, it has been hypothesized that hypercortisolemia could lead to HPT axis abnormalities. So far, data on interactions between the HPA and HPT axes in depression remain inconclusive. METHODS: In order to investigate this issue, we examined circadian rhythms of serum TSH and cortisol (sampled at 4 -hly intervals throughout a 24 -h span), TSH responses to 0800 h and 2300 h protirelin (TRH) tests and cortisol response to dexamethasone suppression test (DST) in 145 unmedicated inpatients meeting DSM-IV criteria for major depressive disorder (MDDs) and 25 healthy hospitalized control subjects (HCs). RESULTS: The secretion of TSH and cortisol exhibited a significant circadian rhythm both in HCs and MDDs. However, compared to HCs, MDDs showed: 1) reduced TSH mesor and amplitude values; 2) blunted 2300 h-ΔTSH and ΔΔTSH values (i.e. differences between 2300 h and 0800 h TRH-TSH responses); and 3) increased cortisol mesor and post-DST cortisol values. DST nonsuppresssors (n = 40, 27 %) showed higher cortisol mesor than DST suppressors (n = 105, 73 %). There was no difference between DST suppressors and nonsuppressors in their TSH circadian parameters and TRH-TSH responses. In addition, cortisol values (circadian and post-DST) were not related to TRH test responses. CONCLUSION: Our results do not confirm a key role for hypercortisolemia in the HPT axis dysregulation in depression.

Relationship between chronobiological thyrotropin and prolactin responses to protirelin (TRH) and suicidal behavior in depressed patients.

BACKGROUND: So far, investigations of the relationships between suicidality and the activity of the thyrotropic and lactotropic axes are scarce and have yielded conflicting results. METHODS: We studied the thyrotropin (TSH) and prolactin (PRL) responses to 0800h and 2300h protirelin (TRH) stimulation tests, carried out on the same day, in 122 euthyroid DSM-5 major depressed inpatients with suicidal behavior disorder (SBD) (either current [n=71], or in early remission [n=51]); and 50 healthy hospitalized controls. RESULTS: Baseline TSH and PRL measurements did not differ across the 3 groups. In SBDs in early remission, the TSH and PRL responses to TRH tests (expressed as the maximum increment above baseline value after TRH [Δ]) were indistinguishable from controls. Current SBDs showed (1) lower 2300h-ΔTSH and lower ΔΔTSH values (differences between 2300h-ΔTSH and 0800h-ΔTSH) than controls and SBDs in early remission; and (2) lower baseline free thyroxine (FT4B) levels than controls. In the current SBD group, ΔΔPRL values (differences between 2300h-ΔPRL and 0800h-ΔPRL) were correlated negatively with lethality. Moreover, in current SBDs (1) violent suicide attempters (n=15) showed lower FT4B levels, lower TSH-TRH responses (both at 0800h and 2300h), and lower ΔΔTSH and ΔΔPRL values than controls, while (2) non-violent suicide attempters (n=56) showed lower ΔΔTSH values than controls and higher TSH-TRH responses (both at 0800h and 2300h) than violent suicide attempters. CONCLUSIONS: Our results suggest that central TRH secretion is not altered in depressed patients with SBD in early remission. The findings that current SBDs exhibit both decreased FT4B levels and decreased evening TSH responses (and consequently, decreased ΔΔTSH values) support the hypothesis that hypothalamic TRH drive is reduced-leading to an impaired TSH resynthesis in the pituitary during the day after the morning TRH challenge. In violent suicide attempters, the marked abnormalities of TRH test responses might indicate a greatest reduction in hypothalamic TRH drive. These results further strengthen the possibility that a deficit in central TRH function may play a key role in the pathogenesis of suicidal behavior.

Chronobiological hypothalamic-pituitary-thyroid axis status and antidepressant outcome in major depression.

BACKGROUND: We previously demonstrated that the difference between 2300h and 0800h TSH response to protirelin (TRH) tests on the same day (ΔΔTSH test) is an improved measure in detecting hypothalamic-pituitary-thyroid (HPT) axis dysregulation in depression. This chronobiological index (1) is reduced in about three quarters of major depressed inpatients, and (2) is normalized after successful antidepressant treatment. In the present study, we examined whether early changes in HPT axis activity during the first 2 weeks of antidepressant treatment could be associated with subsequent outcome. METHODS: The ΔΔTSH test was performed in 50 drug-free DSM-IV euthyroid major depressed inpatients and 50 hospitalized controls. After 2 weeks of antidepressant treatment the ΔΔTSH test was repeated in all inpatients. Antidepressant response was evaluated after 6 weeks of treatment. RESULTS: At baseline, ΔΔTSH values were significantly lower in patients compared to controls and 38 patients (76%) showed reduced ΔΔTSH values (i.e., <2.5mU/L). After 2 weeks of antidepressant treatment, 20 patients showed ΔΔTSH normalization (among them 18 were subsequent remitters), while 18 patients did not normalize their ΔΔTSH (among them 15 were non-remitters) (p<0.00001). Among the 12 patients who had normal ΔΔTSH values at baseline, 8 out 9 who had still normal values after 2 weeks of treatment were remitters, while the 3 with worsening HPT axis function (i.e., reduced ΔΔTSH value after 2 weeks of treatment) were non-remitters (p<0.02). A logistic regression analysis revealed that ΔΔTSH levels after 2 weeks of treatment could predict the probability of remission (odds ratio [OR]=2.11, 95% confidence interval [CI]=1.31-3.41). CONCLUSIONS: Our results suggest that after 2 weeks of antidepressant treatment: (1) chronobiological restoration of the HPT axis activity precedes clinical remission, and (2) alteration of the HPT axis is associated with treatment resistance.