Therapeutic Effects In Depression Research Articles

Sex differences in residual somatic symptoms in patients with first-episode depression after acute-phase treatment

BackgroundResidual somatic symptoms (RSS) are common in depressed patients, predicting treatment effectiveness. However, sex differences in RSS have received little systematic study. This study was conducted to compare sex differences of RSS in patients with first-episode depression (FED).MethodsNine hundred eighty-two patients with FED were selected and treated for 8 to 12 weeks. We evaluated the subjects' socio-demographic characteristics and residual depressive symptoms. Using the Patient Health Questionnaire-15 (PHQ-15) scale to assess residual somatic symptoms, the Sheehan Disability Scale (SDS) for the assessment of patients' function, the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF) for quality of life.ResultsThe incidence of RSS with FED was 46.4%. For patients with residual symptoms, the age and age of onset in females were higher than males, but males had more years of education than females. The degree of "stomach pain" in females was more severe than in males, while "trouble sleeping" in males was more severe than that in females. Multiple regression analysis showed that the total Q-LES-Q-SF score was an independent influencing factor of RSS in both males and females, while the total SDS score only affected female RSS.ConclusionsThe prevalence of RSS in FED after acute-phase treatment is high. The symptom of "stomachache" is more pronounced in females, while "trouble sleeping" is more severe in males. Quality of life plays an essential role in RSS in both genders. Thus, sex needs to be considered when assessing the relationship between RSS and therapeutic effect in depression.

Treatment-Resistant Depression – What is the Effective Maintenance Treatment

IntroductionTreatment-resistant depression (TRD) presents a significant challenge in clinical practice. Besides antidepressant medications, neurostimulation methods (ECT, rTMS) and ketamine are viable treatment options.ObjectivesTo objectively evaluate the real effectiveness of treatments within interventional psychiatry in the maintenance treatment.MethodsThe extensive literature review of the efficacy of ECT, rTMS, and ketamine treatment in the maintenance treatment of TRD and the author’s clinical and research experience will be included in this presentation.ResultsNeurostimulation, particularly ECT and ketamine treatment are usually effective treatments for patients with TRD. However, both of these treatment modalities do not have sustained benefits and after discontinuing treatment the majority of patients relapse. Ketamine has rapid therapeutic effects in depression, but these effects are short-lived. Continuation treatment with ketamine in the form of intranasal ketamine is an option, but concerns over cognitive impairment, interstitial cystitis and significant addictive potential related to longer use of ketamine are significant limiting factors. rTMS is a first-line treatment option for patients with TRD according to the Canadian CANMAT guidelines. However, the majority of patients may relapse following the course of rTMS. The maintenance rTMS over an extended period of time is usually not feasible as it may significantly affect the waiting time for newly referred patients. Portable TMS machine for home use would be an alternative option for a limited number of patients.ConclusionsMaintenance treatment has been always a big clinical challenge in mood disorder psychiatry. Only well-established multimodal treatment is a realistic option for getting long-term benefits in treating patients with TRD.DisclosureNo significant relationships.

Hederagenin Protects PC12 Cells Against Corticosterone-Induced Injury by the Activation of the PI3K/AKT Pathway.

Depression is a prevalent psychiatric disorder and a leading cause of disability worldwide. Despite a variety of available treatments currently being used in the clinic, a substantial proportion of patients is unresponsive to these treatments, urging the development of more effective therapeutic approaches. Hederagenin (Hed), a triterpenoid saponin extracted from Fructus Akebiae, has several biological activities including anti-apoptosis, anti-hyperlipidemic and anti-inflammatory properties. Over the years, its potential therapeutic effect in depression has also been proposed, but the information is limited and the mechanisms underlying its antidepressant-like effects are unclear. The present study explored the neuroprotective effects and the potential molecular mechanisms of Hederagenin action in corticosterone (CORT)-injured PC12 cells. Obtained results show that Hederagenin protected PC12 cells against CORT-induced damage in a concentration dependent manner. In adittion, Hederagenin prevented the decline of mitochondrial membrane potential, reduced the production of intracellular reactive oxygen species (ROS) and decreased the apoptosis induced by CORT. The protective effect of Hederagenin was reversed by a specific phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002 and AKT (also known as protein kinase B) inhibitor MK2206, suggesting that the effect of Hederagenin is mediated by the PI3K/AKT pathway. In line with this, western blot analysis results showed that Hederagenin stimulated the phosphorylation of AKT and its downstream target Forkhead box class O 3a (FoxO3a) and Glycogen synthase kinase-3-beta (GSK3β) in a concentration dependent manner. Taken together, these results indicate that the neuroprotective effect of Hederagenin is likely to occur via stimulation of the PI3K/AKT pathway.

The Role of Inflammatory Proteins in Anti-Glucocorticoid Therapy for Treatment-Resistant Depression.

Background: Optimising treatments for patients with treatment-resistant depression (TRD) is key to reducing the burden of this severe illness. The anti-glucocorticoid medication metyrapone has mixed evidence supporting a role as a possible augmentation treatment in TRD. The degree of treatment resistance in depression has been associated prospectively and retrospectively with elevated inflammation, and inflammatory activity may influence responses to antidepressant treatments. Aims: To investigate whether levels of pro-inflammatory cytokines are associated with clinical outcomes to metyrapone or placebo. Methods: A double-blind RCT randomised patients with TRD to 3 weeks of placebo or metyrapone augmentation to ongoing serotonergic antidepressants. No benefit of metyrapone was reported in the primary analysis. The current study assessed levels of pro-inflammatory proteins interleukin-6 (IL-6), tumour necrosis factor (TNFα), c-reactive protein (CRP) and interleukin-10 (IL-10) before randomisation and after treatment as potential moderators and/or mediators of clinical outcomes. Results: The three pro-inflammatory proteins (but not IL-10) were elevated in this sample of patients with TRD compared to a non-affected control group. High pre-treatment IL-6 levels predicted a poorer response in the trial overall but did not moderate response to metyrapone versus placebo. Changes in IL-6 indirectly mediated depression outcome, with metyrapone increasing IL-6 levels and IL-6 increase associated with a poorer outcome on depression. Other inflammatory proteins did not mediate or moderate treatment outcomes. Interpretation: Metyrapone is hypothesised to have a therapeutic effect in depression on the basis of inhibiting the synthesis of cortisol. In this study, metyrapone did not reduce cortisol, possibly due to glucocorticoid system overcompensation). The mediation effect of IL-6 may support this and perhaps help to indicate why the treatment was not effective.

Phytotherapic use of the Crocus sativus L. (Saffron) and its potential applications: A brief overview.

Crocus sativus L. (Saffron) has long been known for multiple target therapeutic uses. The plant metabolism is well investigated and the main metabolites related to saffron organoleptic qualities are crocin, crocetin, picrocrocin, and safranal. Particularly, the most abundant of them, such as crocin and safranal, are investigated for their multiple biological activities and known as potential drugs. We aimed to review the constituent features of the plant, along with its potential therapeutic effects in depression, neurodegenerative diseases, diabetes mellitus, atherosclerosis, cancer, and sexual dysfunction. A systematic literature search was conducted in PubMed, Medline, Scopus, and EMBASE, with particular attention to preclinical and clinical studies. Although saffron and its components showed potential clinical applications, further investigations are necessary to confirm the effective use of "Red Gold" and its real applications in clinical practice.

Antidepressant-Like Effect of Low-Intensity Transcranial Ultrasound Stimulation.

Transcranial ultrasound stimulation (TUS) is a noninvasive neuromodulation technique with good spatial resolution and deep penetration. This study aims to investigate whether TUS has antidepressant-like effect to depressed rats. Rats were divided into five groups, including two groups (ST-Ctr and ST-Res) for evaluating the short-term impact of restraint stress and three groups (LT-Ctr-ShamTUS, LT-Res-ShamTUS and LT-Res-TUS) for studying the long-term effects of restraint and TUS stimulation. The TUS-treated rats were subjected to 15min TUS stimulation to the prelimbic cortex every day for 2 weeks after the restraint. Then, depressive symptoms related behavioral outcomes were estimated in ST-Ctr and ST-Res groups (1 week after restraint), as well as in the other three groups (3 weeks after restraint). The 48-h-restraint stress could lead to long lasting reduction of exploratory behavior (1 and 3 weeks after restraint) and protracted anhedonia (only observed 3 weeks after restraint). TUS application successfully reversed the core depressive phenotype, anhedonia, indicated by significantly higher sucrose preference index in LT-Res-TUS group [Formula: see text] than LT-Res-ShamTUS group [Formula: see text]. Furthermore, the brain derived neurotrophic factor expression in left hippocampus was significantly promoted in LT-Res-TUS group [Formula: see text] compared to LT-Res-ShamTUS group [Formula: see text]. In addition, the histologic results of hematoxylin and eosin staining showed no TUS-induced brain tissue injury. These results demonstrated that low intensity TUS had antidepressant-like effect. TUS has been speculated to have therapeutic effect in depression. This study provide evidence for the antidepressant-like effects of TUS in rats for the first time.

The role of magnetic resonance imaging in predicting the efficacy of depression

Depression is a common mental disorder with high incidence rate and low remission rate.The prediction of therapeutic effect in depression is limited to clinical features and neuroimaging.Reviewed the results of magnetic resonance imaging for predicting the treatment response in depression and explored the objective image markers for predicting the therapeutic effect in depression. It showed that the studies mainly focused on emotion regulation neural circuitry and few on reward neural circuitry.Prefrontal cortex, cingulate cortex, amygdala and hippocampus play important roles on predicting therapeutic effect. The study of magnetic resonance imaging for predicting therapeutic effect in depression is a feasible research field.More researches of finding the role of reward neural circuits in predicting the effect of antidepressants are needed. The brain structure and function of the neural circuits involved in depression and predicting the effect of anti-depression need to be studied by multimodal MRI method. Key words: Depression; Magnetic resonance imaging; Efficacy; Prediction

Potential antidepressant-like properties of the TC G-1008, a GPR39 (zinc receptor) agonist

Some forms of depression appear to be more related to the glutamatergic system. G-coupled protein receptor 39 (GPR39) is the metabotropic zinc receptor, which may be involved in the pathophysiology of depression and in the antidepressant response. Its deficiency abolishes the antidepressant response, which means that GPR39 is required to obtain a therapeutic effect in depression. This raises the possibility that agonists of the zinc receptor may have a role in antidepressant treatment. To explore this possibility we investigated animal behaviour in the forced swim test, the tail suspension test (to assess antidepressant-like properties), the light/dark test and the elevated plus maze test (to assess anxiolytic-like properties), following acute administration of a GPR39 agonist (TC G-1008). We found an antidepressant response (as measured by the forced swim test but not by the tail suspension test) in mice following the GPR39 agonist treatment. Additionally, we observed the opposite results in the light/dark box (decreased overall distance; increased time spent in the lit compartment; decreased time spent in the dark compartment; increased freezing time) and elevated plus maze (no significant changes), which may be a consequence of the sedative effect of TC G-1008. We also found hippocampal GPR39 and brain-derived neurotrophic factor (BDNF) up-regulation following administration of the GPR39 agonist, which may be undiscovered so far as a possible novel agent in the treatment of mood disorders.

Antidepressant-like effect of the hydroethanolic leaf extract of Alchornea cordifolia (Schumach. & Thonn.) Mull. Arg. (Euphorbiaceae) in mice: Involvement of monoaminergic system

Ethnopharmacological relevanceThe leaf of Alchornea cordifolia (Euphorbiaceae) is used in traditional African medicine in the treatment of various neurological and psychiatric disorders including depression. Previous studies have shown its potent antidepressant-like effect in the forced swimming test (FST). Hence, this study sought to investigate the involvement of monoaminergic systems in the antidepressant-like effect elicited by hydroethanolic leaf extract of Alchornea cordifolia (HeAC) in the FST. Materials and methodsHeAC (25–400mg/kg, p.o.) was administered 1h before the FST. To investigate the contribution of monoaminergic systems to antidepressant-like effect, receptors antagonists were injected 15min before oral administration of HeAC (200mg/kg) to mice and 1h thereafter, subjected to FST. ResultsHeAC (200 and 400mg/kg, p.o.) produced dose dependent and significant (P<0.001) antidepressant-like effect, in the FST, without accompanying changes in spontaneous locomotor activities in the open-field test. The anti-immobility effect of HeAC (200mg/kg) in the FST was prevented by pretreatment of mice with SCH 23390 (0.05mg/kg, s.c., a dopamine D1 receptor antagonist), sulpiride (50mg/kg, i.p., a dopamine D2 receptor antagonist), prazosin (1mg/kg, i.p., an α1-adrenoceptor antagonist), yohimbine (1mg/kg, i.p., an α2-adrenoceptor antagonist), and GR 127993 (5-HT1B receptor antagonist). Similarly, 3 days intraperitoneal injection of p-chlorophenylalanine (pCPA, 150mg/kg, i.p., an inhibitor of serotonin synthesis) prevented the antidepressant-like effect elicited by HeAC. The combination of subeffective doses of imipramine (5mg/kg, p.o.) or fluoxetine (5mg/kg, p.o.), with HeAC (25mg/kg, p.o., subeffective dose) produced a synergistic antidepressant-like effect in the FST. ConclusionThe hydroethanolic extract of Alchornea cordifolia possesses antidepressant-like effect mediated through interaction with dopamine (D1 and D2), noradrenergic (α1 and α2 adrenoceptors), and serotonergic (5HT1B receptors) systems. Also, the potentiation of the anti-immobility effect of conventional antidepressants (fluoxetine and imipramine) by Alchornea cordifolia suggest potential therapeutic effect in depression.

Positive antidepressant effects of generic yoga in depressive out-patients: A comparative study

Context:Therapeutic effects in depression of yoga adopted from different schools have been demonstrated. The efficacy of a generic module of yoga on depressed patients has not yet been tested in the literature.Aims:The study was aimed to compare the therapeutic effect of a generic yoga module with antidepressant drugs in non-suicidal out-patients of major depression attending a psychiatric hospital.Settings and Design:The study was outpatient-based using an open-labeled design.Materials and Methods:A total of 137 out-patients of depressive disorders received one of the three treatments as they chose – yoga-only, drugs-only or both. The yoga was taught by a trained yoga physician for over a month in spaced sessions totaling at least 12. Patients were assessed before treatment, after 1 and 3 months on depression and Clinical Global Impression Scales. Out of 137, 58 patients completed the study period with all assessments.Results:Patients in the three arms of treatment were comparable on demographic and clinical variables. Patients in all three arms of treatment obtained a reduction in depression scores as well as clinical severity. However, both yoga groups (with or without drugs) were significantly better than the drugs-only group. Higher proportion of patients remitted in the yoga groups compared with the drugs-only group. No untoward events were spontaneously reported in the yoga-treated patients.Conclusion:Within the limitations of this study, it can be concluded that the findings support a case for prescribing yoga as taught in the study in depressive non-suicidal out-patients.

Application of Electroconvulsive Therapy in Treatment of Retinitis Pigmentosa Comorbid With Major Depressive Disorder and Panic Disorder

A substantial proportion of retinitis pigmentosa (RP) patients have depression/anxiety and a phobic pathology that may be related to changes in melatonin secretion. We discuss electroconvulsive therapy (ECT) in a patient with RP comorbid with depression and panic disorder. A 51-year-old man was admitted because of major depression, panic disorder, and RP. Ultrabrief pulse (0.3 millisecond) right unilateral ECT was performed 9 times in total. The symptoms relieved, and patient tolerated the treatments well. Electroconvulsive therapy increases serum melatonin, providing therapeutic effects in depression. The application of ECT in this population therefore appears to be an alternative treatment.

Effects of eicosapentaenoic acid and fluoxetine on plasma cortisol, serum interleukin-1beta and interleukin-6 concentrations in patients with major depressive disorder

Treatment studies have suggested that omega-3 fatty acids (ω-3 FAs) as monotherapy or adjunctive treatment have therapeutic effects in depression. The authors recently reported a study in which fluoxetine and eicosapentaenoic acid (EPA), which is an omega-3 fatty acid, appeared to be equally effective in controlling depressive symptoms and their combination was superior to either of them alone. Regulation of hypothalamus–pituitary–adrenal (HPA) axis activity and reduction of inflammatory cytokines are among several biological mechanisms which potentially explain the impact of ω-3 FAs on depression. In the present study, plasma cortisol and serum interleukin-1beta (IL-1 β) and interleukin-6 (Il-6) were measured in patients with a diagnosis of major depressive disorder (MDD) participating in aforementioned trial to determine the effects of 8 weeks of treatment of depression with 1000 mg EPA alone or in combination with 20 mg fluoxetine on HPA axis activity and inflammatory cytokine production and compare the changes in these variables with those of treating with 20 mg fluoxetine alone. Forty-two patients were included in analysis. Two-way repeated measures analysis of variance (ANOVA) showed that plasma cortisol decreased significantly after 8 weeks of intervention without significant difference among the groups. There was no interaction between group and response to treatment over time in the cortisol response based on three-way ANOVA. Serum concentrations of IL-1β and IL-6 did not change significantly after intervention. In conclusion, EPA alone or in combination with fluoxetine, as well as fluoxetine alone decreased serum cortisol after 8 weeks of treatment in patients with major depression disorder (MDD) without any significant effect of response to treatment. Serum IL-1β and IL-6 did not change significantly after intervention. These findings suggest that EPA may exert its therapeutic effects through reduction of cortisol.

Prescribing of tricyclic antidepressant drugs in a South African primary care patient population

Abstract Objective The primary aim of the study was to determine the prescribing patterns of tricyclic anti-depressants (TCAs) in two private primary care patient populations in South Africa, with specific emphasis on the dosages in which TCAs were prescribed. Setting Patients who are members of a private medical aid scheme in South Africa. Method A retrospective drug utilisation study was conducted. TCA prescription data for 1996 (1982 patients) and 2002/2003 (2345 patients) were analysed. Key findings The average ages of the two patient populations were 52.99 (standard deviation (SD) = 16.02) years (1996 group) and 42.66 (SD =16.48) years (2002/2003 group). In 1996, 67.41% of patients were female, and 57.53% in 2002/2003. A total number of 11 074 prescriptions (1996) and 9888 prescriptions (2002/2003) for TCAs were prescribed. Amitriptyline, dothiepin and imipramine together accounted for 69.57% of all TCA prescriptions during 1996, while they accounted for 91.64% of TCA prescriptions during 2002/2003. Average prescribed daily doses (PDDs) were calculated, and were in all cases (except for lofepramine in 1996) considerably lower than their respective defined daily doses (DDDs). The average PDD for amitriptyline was 46.59 mg (1996) and 37.51 mg (2002/2003) (DDD =75 mg), for dothiepin 70.77 mg (1996) and 56.99 mg (2002/2003) (DDD = 100 mg) and for imipramine 50.85 mg (1996) and 48.02 mg (2002/2003) (DDD =100 mg). It is possible that TCAs may be prescribed in doses that are too low for optimal therapeutic effect in depression. In this study, 78.79% (1996) and 85.92% (2002/2003) of all TCA prescriptions were prescribed at doses lower than their respective DDDs. Conclusion The findings are in agreement with findings of at least two other studies that have been conducted in different South African patient settings. TCAs remain an important therapeutic class, and more studies linking dosages to age groups and specific diagnoses are recommended.

Mass spectrometric quantification of MIF-1 in mouse brain by multiple reaction monitoring

MIF-1 (Pro-Leu-Gly-NH 2) has potent therapeutic effects in depression and Parkinson's disease, but its CNS sites of production are not yet clear. In this study, the concentration of MIF-1 in different brain regions was measured by the multiple reaction monitoring technique on a 4000 QTRAP mass spectrometer. The limit of quantification was 300 fg of MIF-1, and limit of detection was 60 fg. The low molecular weight fractions of tissue homogenates from different regions of mouse brain were analyzed. The concentration of MIF-1 ranged from 22 ± 3 fg/μg protein in cerebral cortex to 930 ± 60 fg/μg protein in the hypothalamus. Moderate concentrations were also detected in all other regions tested, including the striatum, thalamus, and hippocampus. By incubation of stable isotope-labeled oxytocin with tissue preparations, it was also confirmed that oxytocin at least partially contributed to the production of MIF-1 in the hypothalamus by action of peptidases. Regional differences were also found. The results are the first to show the ultrasensitive quantification of MIF-1 in different brain regions, and support the neuromodulatory actions of MIF-1 in the striatum.

Sigma-1 receptor ligands: potential in the treatment of neuropsychiatric disorders.

The sigma receptor was originally proposed to be a subtype of the opioid receptor. However, it is now clear that sigma receptors are unique non-opioid, non-phencyclidine brain proteins. Two types of sigma receptor exist, the sigma-1 receptor and the sigma-2 receptor. sigma-1 receptors have been cloned and their distribution, physiological functions and roles in signal transduction were recently characterised. Certain sex hormones in the brain (neurosteroids) are known to interact with sigma-1 receptors. sigma-1 receptors regulate glutamate NMDA receptor function and the release of neurotransmitters such as dopamine. They are thus proposed to be involved in learning and memory as well as in certain neuropsychiatric disorders. Selective sigma-1 receptor ligands have been suggested to represent a new class of therapeutic agents for neuropsychiatric disorders, although none have yet been introduced into therapeutic use. Early studies showed that psychotomimetic benzomorphans, as well as several antipsychotics, can bind to sigma-1 receptors. As a result of these findings, sigma-1 receptor ligands have been proposed as being of potential use in the treatment of schizophrenia. Nevertheless, the relationship of sigma-1 receptors to the underlying pathogenesis of schizophrenia is still unclear. sigma-1 receptor ligands have failed to improve acute psychotic symptoms of schizophrenia in clinical trials, but, interestingly, a few studies have shown an improvement in negative symptoms in schizophrenic patients. A number of preclinical studies have shown that selective agonists of sigma-1 receptors affect higher-ordered brain functions such as learning and memory, cognition and mood. These studies indicate that sigma-1 receptor agonists may exert therapeutic effects in depression and senile dementia. Indeed, the sigma-1 receptor agonist igmesine, has been shown to improve depression in a clinical trial. The most distinctive feature of the action of sigma-1 receptor ligands is their "modulatory" role. In behavioural studies of depression and memory, they exert beneficial effects only when brain functions are perturbed. Given the recently accumulated preclinical and clinical data, it is time to reconstruct the concept of sigma-1 receptors and the associated pathophysiological conditions that ligands of these receptors target. This would allow clinical trials to be performed more efficiently, and the results may confirm a long-speculated possibility that sigma-1 receptor ligands represent a new class of therapeutic agents for neuropsychiatric disorders.

Comprehensive survey of the relationship between serum concentration and therapeutic effect of amitriptyline in depression.

The relationship between serum concentration (C(s)) of amitriptyline and its therapeutic effect in depression has been investigated frequently over the last 3 decades; however, the results were controversial and no consensus was reached. Therefore, we have performed a comprehensive survey and meta-analysis of the subject. All relevant literature was included, and the design of studies on the serum concentration-therapeutic effect relationship (SCTER) of amitriptyline was evaluated. Pooled original data from SCTER studies with adequate design were analysed by various statistical methods: regression analysis of therapeutic effect and C(s); comparison of the mean therapeutic effect in various ranges of C(s); dichotomisation of outcome and analysis according to sensitivity of receiver operation curves; frequency of responders and nonresponders in ranges determined by points of sensitivity; analysis of the distribution of C(s) in responders and nonresponders; logistic regression of responders and nonresponders with C(s) and other independent variables; calculation of effect size (g) and mean effect size (g(m)). Forty-five SCTER studies of amitriptyline were identified, and 27 studies met the minimum criteria of adequate study design. Inadequate study design predicted the finding of no SCTER. Analysis of the pooled data from studies with adequate design confirmed a therapeutic window of the sum of C(s) of amitriptyline and its active metabolite nortriptyline of about 80 to 200 microg/L. A moderate and significant positive g(m) (0.538, 95% confidence interval 0.167 to 0.909) was calculated for treatment with C(s) within the therapeutic window in comparison with treatment with C(s) outside the therapeutic window (19 studies with adequate design and original data available, n = 583). In conclusion, the evidence for a biphasic SCTER of amitriptyline in depression is considerably improved, and the results may help to find a consensus in the future. However, the clinical benefit of therapeutic drug monitoring of amitriptyline can only be demonstrated in a controlled and randomised study. Furthermore, the results provide further evidence that antidepressants at optimum C(s) are superior to placebo in the treatment of depression.

The role of thyroid hormones in depression

During the last 30 years a huge number of scientific articles have appeared on the subject of relationships between psychiatric disease and thyroid hormones. These studies have demonstrated the presence of numerous changes in the hypothalamo–pituitary– thyroid (HPT) axis, mainly in patients with depression, but also in patients with other psychiatric diseases. Simultaneously, many studies have been published on the possible therapeutic effects in depression of the hormones involved in the HPT axis. Despite great efforts to standardize the classification of depression, this is still a less well-defined disease, possibly including several subtypes with different pathogenesis and biochemical abnormalities. Furthermore the classification has changed over time, making it difficult to interpret previously published data. The most accepted classifications are the DSM-IV and ICD-10. These cover a spectrum from minor depression (neurotic depression) through major depression to melancholic (endogenous and psychotic) depression. Furthermore major and melancholic depressions are divided into uniand bipolar depressions, the latter also demonstrating episodes of mania. Rapid cycling bipolar psychosis is a subgroup of the bipolar depression, demonstrating four or more episodes in any year of observation. The present review focuses on the concentrations of hormones of the HPT-axis seen in uniand bipolar depression, their relation to relapse after antidepressive treatment, and a survey of therapeutic trials with thyrotropin-releasing hormone (TRH), thyroid-stimulating hormone (TSH) and thyroid hormones, as well as the effect of the various drugs used in depression on the HPT-axis. The hypothesis is put forward that the changes seen in the HPT-axis during depression might be explained by cerebral serotonin deficiency, and that tri-iodothyronine (T3) treatment, to some degree, can revert this deficiency.