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Advances in psychopharmacology have been significantly slower to evolve than in other disciplines of medicine and therefore investigation into novel therapeutic approaches is required. Additionally, concurrent metabolic conditions are prevalent among people with mental disorders. Metformin is a widely used hypoglycaemic agent that is now being studied for use beyond diabetes management. Evidence is emerging that metformin has multiple effects on diverse neurobiological pathways and consequently may be repurposed for treating mental illness. Metformin may have beneficial neuroimmunological, neuroplastic, neuro-oxidative and neuro-nitrosative effects across a range of psychiatric and neurodegenerative illnesses. Mechanisms include glucose lowering effects and effects on AMP-activated protein kinase (AMPK) signalling, however the best evidence for clinical benefit is through the glucose lowering effects, with other mechanisms less supported by the current evidence base. This narrative review aims to draw together the existing evidence for use of metformin as a psychopharmaceutical and present the role of metformin in the context of physical and psychiatric ill health, including metabolic, endocrinological and cancer domains. It not only has therapeutic potential in medical comorbidity but may have potential in core illness domains.

Background Major depressive disorder (MDD) is a common and highly heterogeneous psychiatric disorder but little is known about the genetic characterisation of this heterogeneity. Understanding the genetic etiology of MDD can be challenging as large sample sizes are needed for gene discovery – often achieved with a trade-off in the depth phenotyping. Methods The Australian Genetics of Depression Study is the largest stand-alone depression cohort with both genetic data and in-depth phenotyping and comprises a total of 15,792 participants of European ancestry, 92% of whom, met diagnostic criteria for MDD. We leveraged the unique nature of this cohort to conduct a meta-analysis with the largest depression GWAS to date and subsequently used polygenic scores (PGS) to investigate genetic heterogeneity across various clinical subtypes of MDD. Results We increased the number of known genome-wide significant variants associated with depression from 103 to 126 and found evidence of association of novel genes implicated in neuronal development. We show that a PGS for depression explains 5.7% of variance in MDD liability in our sample. Lastly, we find strong support for genetic heterogeneity in depression with differential associations of multiple psychiatric and comorbid traits with age of onset, longitudinal course and various subtypes of MDD. Conclusions Until now, this degree of detailed phenotyping in such a large sample of MDD cases has not been possible. Along with discovery of novel loci, we provide support for differential pathways to illness models that recognize both the overlap with other common psychiatric disorders, as well as pathophysiological differences.

The specific phenotype of depression in recent-onset schizophrenia spectrum disorders (SSD) and its relation to non-psychotic depression is unknown. Symptom profile and network analysis are complementary statistical techniques that may provide important insights into the presentation and relative importance of individual symptoms that give rise to depression. The aim of the current study was to characterise the profile and network of depressive symptoms in SSD and compare it to individuals with major depressive disorder (MDD) without psychotic features. This study involved analysis of baseline data pertaining to 109 individuals with comorbid SSD and depression and 283 with MDD without psychotic features. Study cohorts were the Psychosis Recent Onset GRoningen Survey (PROGR-S) and Youth Depression Alleviation (YoDA) trials, respectively. Profile and network analyses revealed that SSD and MDD differed in the profile and relative importance of individual depressive symptoms. While reported sadness was the primary hallmark of depression in both SSD and MDD, individuals with depression in SSD were more likely to sleep more, and have lower lassitude and pessimism. While sadness had great importance in MDD and SSD, in SSD but not MDD lassitude, sleep, appetite, concentration difficulties, and inability to feel were important in the network of depressive symptoms. The specific phenotype of depression might be different in SSD compared to MDD. Symptom inequivalence or underlying functional mechanisms in SSD might result in depression in SSD that is similar to MDD with atypical features.

Metabolic syndrome (MetS) and its component factors, obesity, hypertension, dyslipidaemia and insulin resistance, have shown a bidirectional relationship with the prevalence and severity of bipolar disorder (BD). A systematic search of electronic databases (Pubmed, PsycINFO, clinicaltrials.gov) was conducted to explore and integrate current evidence about the role of MetS and its component factors with clinical outcomes of BD. Thirty-four articles met the inclusion criteria. Studies were grouped by the metabolic factors assessed, which included MetS, obesity and body mass index (BMI), dyslipidaemia, impaired glucose metabolism (IGM), diabetes mellitus and hypertension. They were then classified according to outcomes such as course of episodes, rapid cycling, suicidal behavior, treatment response, and global and cognitive functioning. Although current evidence remains controversial in most aspects of clinical outcomes, metabolic risk factors could alter the course of BD, with worse global functioning, poorer treatment response and a chronic course of illness, as well as enhancing rapid cycling. Further research is needed to elucidate the role of each risk factor in the mentioned outcomes.

The prevalence, correlates, and management of tobacco use disorder (TUD) or nicotine dependence (ND) among people with severe mental illness (SMI), namely schizophrenia, bipolar disorder (BD), and major depressive disorder (MDD), remain unclear. Therefore, a systematic review and meta-analysis was conducted. Electronic databases were systematically searched from inception to July 12, 2020, for observational studies documenting the prevalence, odds, and correlates of TUD/ND among people with SMI; randomized controlled trials (RCTs) informing the management of TUD/ND in people with SMI were also included. Random-effects meta-analyses were conducted. Sources of heterogeneity were explored. Nineteen observational studies, including 7527 participants with SMI met inclusion criteria. TUD/ND co-occurred in 33.4-65% of people with SMI. Rates were higher among males. While bupropion and varenicline represent promising treatment opportunities for schizophrenia with TUD/ND, non-pharmacological interventions require further research, mainly for people with primary mood disorders. TUD/ND represent prevalent co-occurring conditions among people with SMI. Further well-designed RCTs are warranted to inform their management.

Smoking represents a significant health threat to the population, however there remains a core group of consistent smokers that are largely unable to break the addiction. Novel therapies are required to assist this group with cessation. N-acetylcysteine (NAC) is a nutraceutical supplement that has shown efficacy compared to placebo in previous pilot studies for assisting smokers to quit or reduce their consumption of cigarettes. A double-blind, randomised trial with a treatment period of 16 weeks and a final follow-up at 42 weeks was conducted comparing 1.8g of effervescent NAC per day (n=47) with placebo (n=47) as an aide to smoking cessation. Both study arms received adjunctive online support through the QuitCoach program. Participants reported smoking at each timepoint (baseline and weeks 8, 16 & 42), which was confirmed through salivary cotinine and exhaled carbon monoxide testing. Primary and secondary analyses were undertaken using a modified intent-to-treat basis, including all participants with at least one valid post baseline outcome, regardless of treatment received or their withdrawal from the study. There was no significant difference in smoking outcomes between intervention groups among the 24 participants that competed follow-up. There were no significant differences in age, gender, or body mass index (BMI) between the groups lost to follow-up or recorded at follow-up. This study found no evidence to support NAC as a therapy for smoking cessation. The negative outcome could be the result of lack of treatment efficacy, or alternatively, small sample size, participant retention difficulties, dose, or duration of follow-up. Trial Registration: Australian New Zealand Clinical Trials registry (ANZCTR), ACTRN12617001478303. Registered on 19 October 2017.

INTRODUCTION: The COVID-19 (coronavirus disease 2019)-related pandemic represents a global source of societal and health burden. Yet, the impact of the pandemic on people with severe mental illness, including bipolar disorder (BD), remains unclear, warranting scoping review on the matter. METHODS: The MEDLINE and EMBASE databases were systematically searched from inception up to April 24, 2021, adopting broad inclusion criteria to assess a variety of clinical and public health themes related to people with a primary diagnosis of BD during the COVID-19 pandemics. The present work complying with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews (PRISMA-ScR) registered in the Open Science Framework (OSF) repository (https://osf.io/7evpx/). RESULTS: Fourteen papers informed the present scoping review. Four major themes were identified: (i) impact of COVID-19-related stressors on BD; (ii) impact of COVID-19 on mental health service utilization among people with BD; (iii) impact of BD on the risk of acquiring SARS-CoV-2 infection; (iv) engagement in preventative behaviors among people with BD. Additional themes warranting further research were nonetheless detected. LIMITATIONS: Further original studies are needed. CONCLUSION: The present study confirmed the high-vulnerability hypothesis concerning people with BD versus the general population, reinforcing the need for further research related to the COVID-19 pandemic. Additional information is warranted to compare the impact of the pandemic period among BD people against pre-pandemic records, the general population, and other severe mental illnesses, namely people with schizophrenia or major depressive disorder, to inform the public health and the delivery of patient-tailored interventions.

Infection, particularly prenatal infection leads to an enhanced risk of schizophrenia in the offspring. Interestingly, few data exist on the pathway(s) such as TLR and inflammasome, primarily involved in sensing the microorganisms and inducing downstream inflammatory responses, apoptosis and neuroprogressive changes in the prenatal infection-induced risk of schizophrenia. Herein, we aimed to discern whether prenatal infection-induced maternal immune activation (MIA) causes schizophrenia-like behaviors through activation of TLR and inflammasome pathways in the brain of offspring. Sprague Dawley rats (n=15/group) were injected either with poly (I:C) or LPS or saline at gestational day (GD)-12. Significantly elevated plasma levels of IL-1β, IL-6, TNF-α and IL-17A assessed after 24 hours were observed in poly (I:C) and LPS-treated rats, indicating MIA. The offspring rats of poly (I:C)-and LPS-treated dams displayed increased anxiety-like behaviors, deficits in social behaviors and prepulse inhibition. The hippocampus of offspring rats showed increased expression of TLR3, TLR4, NLRP3, IL-1β, and IL-18 of poly (I:C) and TLR3, TLR4, NLRP3, Cas1, IL-1β, and IL-18 of LPS-treated dams. Notably, the expression of these genes showed a positive correlation with apoptotic and a negative correlation with neuroprotective genes. Furthermore, TLR and inflammasome genes had significant impact on social deficits and impaired prepulse inhibition in offspring rats. The results suggest MIA due to prenatal infection perhaps trigger TLR, inflammasome and apoptotic pathways leading to the induction of schizophrenia-like behaviors in the later stages of life. Prenatal infections seem to drive neuroprogression and subsequently schizophrenia-like symptoms through a common central pathway involving TLR, inflammasome and apoptosis.

N-acetylcysteine (NAC) acts on glutamatergic and redox systems, two systems implicated in the pathophysiology of bipolar disorder (BD). This has led to the investigation of NAC as a potential candidate for the treatment of BD. The aim of this study was to investigate metabolomic markers to identify predictors of NAC response in a cohort of BD participants. This study is a secondary analysis of a 16-week, multi-site, randomized, double-blinded, parallel-group, placebo-controlled trial in BD participants with a current acute depressive episode. This study included trial participants who received either NAC 2000 mg/day, or placebo. Participants (NAC: n = 31, placebo: n = 29) were assessed at baseline and week 16 using the Montgomery Asberg Depression Rating Scale (MADRS) and were dichotomised into “responders” (MADRS at week 16 50% at baseline). Untargeted gas chromatography–mass spectrometry analysis was performed to analyse baseline levels of 68 serum metabolites. Of the nine metabolites that differentiated placebo and NAC groups, five were amino acids with lower levels in the NAC responder group compared with the NAC non-responders. Further analysis generated a predictive model of MADRS improvement including glycine, norleucine, threonine, proline, phenylalanine, tyrosine, glutamic acid, lysine and leucine (R2 = 0.853; adjusted R2 = 0.733). This prediction model predicted 85% of the variance in MADRS outcome after adjunctive treatment with NAC. BD participants with lower serum levels of free amino acids at baseline may be more likely to respond to adjunctive treatment with NAC.

Statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) treat dyslipidaemia and cardiovascular disease by inhibiting cholesterol biosynthesis. They also have immunomodulatory and anti-inflammatory properties. Beyond cardiovascular disease, cholesterol and inflammation appear to be components of the pathogenesis and pathophysiology of neuropsychiatric disorders. Statins may therefore afford some therapeutic benefit in mood disorders. In this paper, we review the pathophysiology of mood disorders with a focus on pharmacologically relevant pathways, using major depressive disorder and bipolar disorder as exemplars. Statins are discussed in the context of these disorders, with particular focus on the putative mechanisms involved in their anti-inflammatory and immunomodulatory effects. Recent clinical data suggest that statins may have antidepressant properties, however given their interactions with many known biological pathways, it has not been fully elucidated which of these are the major determinants of clinical outcomes in mood disorders. Moreover, it remains unclear what the appropriate dose, or appropriate patient phenotype for adjunctive treatment may be. High quality randomised control trials in concert with complementary biological investigations are needed if the potential clinical effects of statins on mood disorders, as well as their biological correlates, are to be better understood.

The pathophysiology of psychiatric and neurodegenerative disorders is complex and multifactorial. Polyphenols possess a range of potentially beneficial mechanisms of action that relate to the implicated pathways in psychiatric and neurodegenerative disorders. The aim of this review is to highlight the emerging clinical trial and preclinical efficacy data regarding the role of polyphenols in mental and brain health, elucidate novel mechanisms of action including the gut microbiome and gene expression, and discuss the factors that may be responsible for the mixed clinical results; namely, the role of interindividual differences in treatment response and the potentially pro-oxidant effects of some polyphenols. Further clarification as part of larger, well conducted randomized controlled trials that incorporate precision medicine methods are required to inform clinical efficacy and optimal dosing regimens.

We examined bipolar disorder (BD) as a risk factor for developing cancer and the role of lithium on cancer incidence. We conducted two systematic review and meta-analyses of population-based studies providing data on these associations. We screened articles indexed in MEDLINE, Scopus, Embase, and PsycINFO up to August 2020. The first random-effects meta-analysis, based on 4,910,661 individuals from nine studies estimated an increased risk of cancer of any kind [RR = 1.24 (1.05-1.46); p < 0.01], especially breast cancer [RR = 1.33 (1.15-1.55); p < 0.01] in BD. The second random-effects meta-analysis, based on 2,606,187 individuals from five studies did not show increased risk of cancer in people with BD using lithium, and even suggested a small protective effect both in overall [RR = 0.94 (0.72-1.22); p = 0.66] and urinary cancer [RR = 0.93 (0.75-1.14); p = 0.48] although these findings did not reach statistical significance. The current evidence highlights that cancer risk is increased in individuals with BD, particularly breast cancer in women. Lithium may have a potential protective effect on cancer, including urinary cancer. The role of lithium as a mainstay of treatment for BD is reinforced by this study.

We call on geriatric brain health care providers, executives and entrepreneurs to embrace our Brain Health Living Lab model-a user-centered, iterative ecosystem, integrating concurrent clinical care, research and innovation processes.

Fountoulakis K.N., Karakatsoulis G.N., Abraham S., Adorjan K., Ahmed H.U., Alarcón R.D., Arai K., Auwal S.S., Berk M., Bjedov S., Bobes J., Bobes-Bascaran T., Bourgin-Duchesnay J., Bredicean C.A., Bukelskis L., Burkadze A., Abud I.I.C., Castilla-Puentes R., Cetkovich M., Colon-Rivera H., Corral R., Cortez-Vergara C., Crepin P., De Berardis D., Delgado S.Z., De Lucena D., De Sousa A., Stefano R.D., Dodd S., Elek L.P., Elissa A., Erdelyi-Hamza B., Erzin G., Etchevers M.J., Falkai P., Farcas A., Fedotov I., Filatova V., Fountoulakis N.K., Frankova I., Franza F., Frias P., Galako T., Garay C.J., Garcia-Álvarez L., García-Portilla M.P., Gonda X., Gondek T.M., González D.M., Gould H., Grandinetti P., Grau A., Groudeva V., Hagin M., Harada T., Hasan T.M., Hashim N.A., Hilbig J., Hossain S., Iakimova R., Ibrahim M., Iftene F., Ignatenko Y., Irarrazaval M., Ismail Z., Ismayilova J., Jacobs A., Jakovljević M., Jakšić N., Javed A., Kafali H.Y., Karia S., Kazakova O., Khalifa D., Khaustova O., Koh S., Kopishinskaia S., Kosenko K., Koupidis S.A., Kovacs I., Kulig B., Lalljee A., Liewig J., Majid A., Malashonkova E., Malik K., Malik N.I., Mammadzada G., Mandalia B., Marazziti D., Marčinko D., Martinez S., Matiekus E., Mejia G., Memon R.S., Martínez X.E.M., Mickevičiūtė D., Milev R., Mohammed M., Molina-López A., Morozov P., Muhammad N.S., Mustač F., Naor M.S., Nassieb A., Navickas A., Okasha T., Pandova M., Panfil A.-L., Panteleeva L., Papava I., Patsali M.E., Pavlichenko A., Pejuskovic B., Da Costa M.P., Popkov M., Popovic D., Raduan N.J.N., Ramírez F.V., Rancans E., Razali S., Rebok F., Rewekant A., Flores E.N.R., Rivera-Encinas M.T., Saiz P., de Carmona M.S., Martínez D.S., Saw J.A., Saygili G., Schneidereit P., Shah B., Shirasaka T., Silagadze K., Sitanggang S., Skugarevsky O., Spikina A., Mahalingappa S.S., Stoyanova M., Szczegielniak A., Tamasan S.C., Tavormina G., Tavormina M.G.M., Theodorakis P.N., Tohen M., Tsapakis E.M., Tukhvatullina D., Ullah I., Vaidya R., Vega-Dienstmaier J.M., Vrublevska J., Vukovic O., Vysotska O., Widiasih N., Yashikhina A., Prezerakos P.E., Smirnova D.

Background: Network analysis provides opportunities to gain a greater understanding of the complex interplay of risk factors for depression and heterogeneous symptom presentations. This study used network analysis to discover risk factors associated with both depression severity and depression symptoms amongst Pacific adolescents in New Zealand.\ud \ud Methods: Mixed graphical models with regularization were fitted to data from a community sample of New Zealand born, Pacific adolescents, (n=561; 51% male; Mean age (SD) = 17 (0.35)) and associations between a wide range of potentially explanatory variables and depression severity and depression symptoms investigated. The associations identified were then tested for reliability, using resampling techniques and sensitivity analysis.\ud \ud Results: In the networks, the explanatory variables associated with both depression severity and depression symptoms were those related to quality of the relationships with mother or friends, school connectedness, and self-assessed weight, but the symptoms they were associated with varied substantially. In the depression severity networks, impulsivity appeared to be a bridging node connecting depression severity with delinquency and negative peer influence. \ud Limitations: The data were analysed cross-sectionally, so causal inferences about the directions of relationships could not be inferred and most of the data were self-reported.\ud \ud Conclusions: The results illustrate the varied way that adolescent depression can manifest itself in terms of symptoms and suggest specific items on the depression inventory that might be suitable targets for prevention strategies and interventions, based on the risk factor - depression symptom profiles of individuals or groups.

This systematic review aimed to synthesise the results from studies investigating the effects of prebiotics and probiotics on kynurenine pathway metabolism. Thirteen studies were identified for inclusion, comprising 12 probiotic and two prebiotic arms. Participants included healthy individuals and individuals with various clinical conditions. Twelve metabolites were examined across the studies, using a range of biological samples. Across all interventions, 11 reported an effect on ≤ metabolite. Although limited by clinical and methodological heterogeneity, pooled analysis (n = 253) found probiotics to significantly affect serum kynurenine (g = 0.315, CI = 0.070 to 0.560, p = 0.012, 4 studies, I2 = 0%) and the kynurenine:tryptophan ratio (g = 0.442, CI = 0.074 to 0.810, p = 0.018, 4 studies, I2 = 42 %). Risk of bias across the studies was generally low. The results provide preliminary evidence that probiotics can modulate kynurenine pathway metabolism, with less evidence available regarding prebiotics. Future studies which further consider methodological confounds and sample characteristics are required, to establish intervention efficacy. PROSPERO registration #CRD42019154677.

BACKGROUND: Suicidal ideation (SI) is a common feature of depression and is closely associated with suicidal behaviour. Social support is implicated as an important determinant of suicide, but it is unclear how different social support dimensions influence SI in young people with depression. This study examines relationships between social support dimensions and SI in young people with major depressive disorder (MDD). METHODS: 283 Australians aged 15-25, diagnosed with MDD, were recruited from two clinical trials conducted in youth-specific outpatient mental health services. The Multidimensional Scale of Perceived Social Support (MSPSS) was used to evaluate perceived support from Family, Friends, and a Significant Other. Suicidal ideation was assessed using the Suicidal Ideation Questionnaire (SIQ). Hierarchical regression was used to explore associations between social support and SI, controlling for demographics and depression severity. RESULTS: A hierarchical regression model predicted 9% of the variability in SI, with depression severity being the most significant predictor. Family Support was inversely related to SI and uniquely contributed 2% of the variance; β = -0.15 (95% CI -0.27 - -0.02) p < .05. Demographics and support from Friends or a Significant Other were not significantly associated with SI. LIMITATIONS: Findings are correlational; it cannot be determined that increasing family support would decrease SI severity. CONCLUSION: Perceived Family Support was negatively associated with SI in young people with MDD. This suggests that family members might play important roles in suicide prevention efforts. More work is needed exploring ways to empower families to develop adaptive family functioning and support.

Genetic susceptibility to methamphetamine use disorder is poorly understood. No twin or adequately powered genome-wide association studies (GWASs) have been conducted. However, there are a large number of hypothesis-driven candidate gene association studies, which were systematically reviewed herein. Seventy-six studies were identified, investigating markers of 75 different genes. Allele frequencies, odds ratios, 95 % confidence intervals and power were calculated. Risk of bias was also assessed as a quality measure. Meta-analyses were conducted for gene markers if three or more studies were available. Eleven markers from adequately powered studies were significantly associated with methamphetamine use disorder, with Fatty Acid Amide Hydrolase (FAAH) and Brain Derived Neurotrophic Factor (BDNF) representing promising targets. Limitations of these studies include unclear rationale for candidate gene selection, low power and high risk of bias. Future research should include replications to enable more meta-analyses, well-powered GWASs or whole exome or genome sequencing, as well as twin and family studies to further complement the findings of this review to uncover genetic contributions toward methamphetamine use disorder.

Background Personality disorder (PD) may affect the efficacy of pharmacological interventions for mood disorders, but the extent to which this occurs is uncertain. We aimed to examine the available published evidence concerning the role of PD in pharmacological treatment outcomes of randomised controlled trials (RCTs) for adults with mood disorders (i.e. depressive and bipolar spectrum disorders). Methods A systematic search of Cochrane Central Register of Controlled Clinical Trials, PubMed, EMBASE, PsycINFO, CINAHL Complete, and Google Scholar databases was undertaken to identify studies of interest. Data were independently extracted by two reviewers. The Cochrane Risk of Bias tool was used to assess methodological quality and risk of bias. A random effects model was utilised and statistical heterogeneity was assessed using the I2 statistic. This systematic review was registered with PROSPERO (CRD42018089279) and the protocol is published. Results The search yielded 11,640 studies. Subsequent to removing duplicates, 9657 studies were screened at title and abstract stage and 1456 were assessed at full-text stage. Eighteen studies met criteria for inclusion in this review. Meta-analysis did not reveal a significant difference between groups for treatment outcome (standardised mean difference 0.22 [-0.09, 0.54]; I2: 69%, p=0.17) and remission (risk ratio 0.84 [0.64, 1.11]; I2: 51%, p=0.22). Limitations This review was limited by lack of studies on bipolar disorder. Conclusion PD comorbidity does not appear to affect treatment efficacy of pharmacological interventions for adults with mood disorders.

Objectives Cardiovascular disease is disproportionally prevalent in bipolar disorder (BD) and has been linked to cognition in preliminary studies. Herein we evaluate the association between known risk factors for cardiovascular disease and executive function in BD patients compared to healthy controls. Methods In a sample of n=57 individuals (n=23 BD, n=34 controls) we assessed two subdomains of executive function; cognitive flexibility (using the Trail Making Test - Part B) and cognitive inhibition (using the Stroop Colour Word Interference Task). Cardiovascular risk was assessed by means of serum triglyceride levels, body mass index (BMI) and waist circumference, as well as dietary saturated fat intake and a sex-specific cumulative cardiovascular risk score calculated using the Framingham Heart Study method. Results Patients with BD had higher BMI and waist circumference, with more BD patients categorized as having central obesity than controls. In the BD group only, higher triglyceride levels were associated with worse cognitive flexibility, and elevated cumulative cardiovascular disease risk was associated with worse cognitive inhibition. No correlations between cardiovascular risk factors and executive function were evident in the control group. Limitations The study was limited by the small sample size and should be considered hypothesis-generating Conclusions The associations between triglyceride levels, cumulative cardiovascular disease risk and executive functioning evident in BD in this study preliminarily indicate the potential for mechanistic overlap of physical health and cognitive function in the disorder.

There are nine subfamilies of TAARs. They are predominantly intracellular, located in the central nervous system and peripherally. They have a role in homeostasis and rheostasis, and also in olfaction. They demonstrate significant cross-talk with the monoamine system and are involved in the regulation of cAMP signalling and K+ channels. There is evidence to suggest that TAAR1 may be a promising therapeutic target for the treatment of schizophrenia, psychosis in Parkinson's disease, substance use disorders, and the metabolic syndrome and obesity. TAAR1 expression may also be a prognostic biomarker for cancers. A number of TAAR modulators have been identified, including endogenous ligands and new chemical entities. Some of these agents have shown efficacy in animal models of addiction behaviours, depression and anxiety. Only one agent, SEP-363856, has progressed to randomised clinical trials in humans; however further, larger studies with SEP-363856 are required to clarify its suitability as a new treatment for schizophrenia spectrum disorders. SEP-363856 is an agonist of TAAR1 and 5HT1A and it is not clear to what extent its efficacy can be attributed to TAAR1 rather than to other drug targets. However, current research suggests that TAAR1 has an important role in human physiology and pathophysiology. TAAR1 modulators may become an important new drug class for the management of a wide array of mental disorders in the future.

Bipolar disorders are a complex group of severe and chronic disorders that includes bipolar I disorder, defined by the presence of a syndromal, manic episode, and bipolar II disorder, defined by the presence of a syndromal, hypomanic episode and a major depressive episode. Bipolar disorders substantially reduce psychosocial functioning and are associated with a loss of approximately 10-20 potential years of life. The mortality gap between populations with bipolar disorders and the general population is principally a result of excess deaths from cardiovascular disease and suicide. Bipolar disorder has a high heritability (approximately 70%). Bipolar disorders share genetic risk alleles with other mental and medical disorders. Bipolar I has a closer genetic association with schizophrenia relative to bipolar II, which has a closer genetic association with major depressive disorder. Although the pathogenesis of bipolar disorders is unknown, implicated processes include disturbances in neuronal-glial plasticity, monoaminergic signalling, inflammatory homoeostasis, cellular metabolic pathways, and mitochondrial function. The high prevalence of childhood maltreatment in people with bipolar disorders and the association between childhood maltreatment and a more complex presentation of bipolar disorder (eg, one including suicidality) highlight the role of adverse environmental exposures on the presentation of bipolar disorders. Although mania defines bipolar I disorder, depressive episodes and symptoms dominate the longitudinal course of, and disproportionately account for morbidity and mortality in, bipolar disorders. Lithium is the gold standard mood-stabilising agent for the treatment of people with bipolar disorders, and has antimanic, antidepressant, and anti-suicide effects. Although antipsychotics are effective in treating mania, few antipsychotics have proven to be effective in bipolar depression. Divalproex and carbamazepine are effective in the treatment of acute mania and lamotrigine is effective at treating and preventing bipolar depression. Antidepressants are widely prescribed for bipolar disorders despite a paucity of compelling evidence for their short-term or long-term efficacy. Moreover, antidepressant prescription in bipolar disorder is associated, in many cases, with mood destabilisation, especially during maintenance treatment. Unfortunately, effective pharmacological treatments for bipolar disorders are not universally available, particularly in low-income and middle-income countries. Targeting medical and psychiatric comorbidity, integrating adjunctive psychosocial treatments, and involving caregivers have been shown to improve health outcomes for people with bipolar disorders. The aim of this Seminar, which is intended mainly for primary care physicians, is to provide an overview of diagnostic, pathogenetic, and treatment considerations in bipolar disorders. Towards the foregoing aim, we review and synthesise evidence on the epidemiology, mechanisms, screening, and treatment of bipolar disorders.

Epidemiological evidence indicates the presence of dysregulated homeostatic biological pathways in depressed patients, such as increased inflammation and disrupted energy-regulating neuroendocrine signaling (e.g., leptin, insulin). Alterations in these biological pathways may explain the considerable comorbidity between depression and cardiometabolic conditions (e.g., obesity, metabolic syndrome, diabetes) and represent a promising target for intervention. This review describes how immunometabolic dysregulations vary as a function of depression heterogeneity by illustrating that such biological dysregulations map more consistently to atypical behavioral symptoms reflecting altered energy intake/expenditure balance (hyperphagia, weight gain, hypersomnia, fatigue, and leaden paralysis) and may moderate the antidepressant effects of standard or novel (e.g., anti-inflammatory) therapeutic approaches. These lines of evidence are integrated in a conceptual model of immunometabolic depression emerging from the clustering of immunometabolic biological dysregulations and specific behavioral symptoms. The review finally elicits questions to be answered by future research and describes how the immunometabolic depression dimension could be used to dissect the heterogeneity of depression and potentially to match subgroups of patients to specific treatments with higher likelihood of clinical success.

Background Major depressive disorder (MDD) and bipolar depression (BD) both share increased immune-inflammatory activation. However, there are unclear patterns of differences in peripheral immune profiles between them. Methods We examined such differences in 245 MDD and 59 BD patients, recruited in the same center, who were in an acute depressive episode of moderate severity. Hierarchical binary logistic regression analyses and generalized linear models were used to compare levels of plasma biomarkers between groups and to predict dichotomous classification. Results Interleukin (IL)-1β, tumor necrosis factor (TNF)-α, soluble TNF receptor (sTNFR)1, IL-12 and IL-10 were significantly higher in MDD than in BD, whereas IL-6, sTNFR2, IL-18, IL-33, ST2 (IL1R Like 1) and KLOTHO were significantly higher in BD than in MDD. Moreover, logistic regression analyses correctly classified BD and MDD patients with 98.1% accuracy, using a combination of IL-6, IL-8, ST2, sTNFR2 (directly associated with BD) and IL-12 and TNF-α (directly associated with MDD). Patients with MDD with melancholic features showed higher IL-1β levels than those without melancholia. The sTNFR1 / sTNFR2 ratio significantly predicted MDD and state and trait anxiety and negative affect. Results remained significant after covariate adjustment, including drug use. Limitations Cross-sectional study. Lack of control comparison group. Differences in exposure to medications among participants. Conclusions Differences in immune profiles between BD and MDD patients exist, especially for the compensatory immune-regulatory system (CIRS): increased IL-10 is the primary immune-regulatory mechanism in MDD, while increased sTNFR2 and KLOTHO are the primary regulatory mechanisms in BD.

Background Psychological distress is associated with risk markers for cardiovascular disease, including increased arterial stiffness and high blood pressure, but it's unclear when these first manifest. This study aims to investigate the effect of psychosocial stress and depression on arterial stiffness and blood pressure in a cohort study of Australian children followed through to adolescence. Method Depression and psychosocial stress in 520 young people (265 boys; M age = 11.6 y) were assessed via the Children's Depression Inventory and Children's Stress Questionnaire respectively. Carotid-femoral pulse wave velocity was assessed using applanation tonometry, with further assessments of supine brachial blood pressure and percent body fat (dual x-ray absorptiometry). All measures were repeated four years later at age 16-years. Results We found no cross-sectional or longitudinal evidence that children self-reporting higher levels of psychosocial stress or depressive symptoms had greater arterial stiffness. Children reporting an increase in depressive symptoms had an increase in diastolic blood pressure and mean arterial pressure over time. An effect was also evident for pulse pressure, where higher pulse pressure was found in children with lower psychosocial stress at baseline and in children self-reporting a decrease in stress between baseline and follow-up. Conclusions Findings from the current study contribute to the scant paediatric literature but only provide limited support for any influence of psychological factors on blood pressure. Depressive symptoms in apparently healthy adolescents may exert some influence on later risk for cardiovascular disease via increases in diastolic blood pressure and mean arterial pressure, but these effects were small.

The role that vitamin D plays in the cognitive and clinical characteristics of bipolar disorder (BD) is unclear. We examined differences in the levels and deficiency status of vitamin D in an Australian sample of BD patients compared to healthy controls; and determined the extent to which vitamin D is associated with clinical variables and cognitive function in the sample. 22 healthy controls and 55 stable outpatients with a diagnosis of BD and low-grade mood symptomatology provided a sample of blood and completed cognitive tests and clinical measures. Plasma concentrations of 25-hydroxyvitamin D (vitamin D) were assayed and used to segregate participants into subgroups with sufficient or deficient levels of vitamin D. Subgroups were then compared in terms of global cognition and a range of sociodemographic and clinical factors (number of past mood episodes, illness duration, seasonal mood pattern, mood symptom severity), while mean levels of vitamin D were compared between patients and controls. Although almost 27% of the current sample were vitamin D deficient, no significant differences in mean vitamin D levels or the prevalence of vitamin D deficiency were evident between BD patients and controls. Vitamin D was not associated with global cognition in either patients or controls, nor any of the clinical measures assessed in the study. In conclusion, we observed no difference in the vitamin D levels and deficiency status of an Australian sample of healthy individuals and BD patients with low grade mood symptomatology compared to controls. Clinical symptoms and global cognition also appear to be independent of vitamin D levels in BD.

Activated immune-inflammatory, oxidative and nitrosative stress (IO&NS) pathways and consequent mitochondrial aberrations are involved in the pathophysiology of psychiatric disorders including major depression, bipolar disorder and schizophrenia. They offer independent and shared contributions to pathways underpinning medical comorbidities including insulin resistance, metabolic syndrome, obesity and cardiovascular disease - herein conceptualized as somatoprogression. This narrative review of human studies aims to summarize relationships between IO&NS pathways, neuroprogression and somatoprogression. Activated IO&NS pathways, implicated in the neuroprogression of psychiatric disorders, affect the pathogenesis of comorbidities including insulin resistance, dyslipidaemia, obesity and hypertension, and by inference, metabolic syndrome. These conditions activate IO&NS pathways, exacerbating neuroprogression in psychiatric disorders. The processes whereby proinflammatory cytokines, nitrosative and endoplasmic reticulum stress, NADPH oxidase isoforms, PPARγ inactivation, SIRT1 deficiency and intracellular signalling pathways impact lipid metabolism and storage are considered. Through associations between body mass index, chronic neuroinflammation and FTO expression, activation of IO&NS pathways arising from somatoprogression may contribute to neuroprogression. Early evidence highlights the potential of adjuvants targeting IO&NS pathways for treating somatoprogression and neuroprogression.

An increase in the age of surgical patients as well as the volume of surgeries is associated with a rise in perioperative neurocognitive disorders. These disorders encompass acute delirium and longer-term cognitive dysfunctions. Brain derived neurotrophic factor (BDNF) is a neurotrophin that plays a dynamic role in a series of neurological functions including neuroplasticity, neurogenesis and synaptic regulation. Given the possible alterations to brain physiology in response to surgery, this review aims to explore the relationship between changes in central and peripheral BDNF concentrations and perioperative neurocognitive disorders. Higher levels of Brain tissue and blood BDNF have been associated with better cognitive function; however, the nature of the association between BDNF and delirium is uncertain. Preclinical models point to a significant depletion in BDNF expression and signalling within the brain post-operatively, while preliminary human studies demonstrate depletions in serum BDNF concentration after surgery. These findings suggest that the reduced BDNF concentrations may be associated with post-operative cognitive dysfunction. Thus, understanding the BDNF expression/signalling pathways may present a promising avenue for managing perioperative neurocognitive disorders symptoms. Nonetheless, given that results were primarily derived from preclinical models, it is critical for these findings to be validated in humans to confirm the relevance of this promising target.

The care of people with first-episode mania has been overlooked in comparison with the care of patients with other non-affective psychoses, despite evidence suggesting targeted treatments might be of benefit for this patient group. In this Personal View, we outline the general epidemiology of first-episode mania in the context of bipolar disorder, the natural history of mania (with an emphasis on its recurrent nature), current evidence for pharmacological, psychological, and service-level interventions, current guidelines for the treatment of first-episode mania, and provide a patient's point of view of the care pathway (appendix). We note the paucity of high-quality evidence for interventions in first-episode mania and the lack of agreement among treatment guidelines in relation to treatment, especially maintenance treatment. We suggest that, based on high morbidity and clinical need, research evidence to inform guideline development is necessary, and in the interim, clearer guidance on treatment and diagnosis should be given; specifically, we have suggested that patients should be cared for within a first-episode psychosis service, when such a service exists.

Background Interventions early in the course of bipolar disorder (BD) may have the potential to limit its functional and symptomatic impact. However, the implementation of specific early interventions for BD has been limited which may at least partly be due to the lack of guidelines focused on the early illness stages. We therefore aimed to review the current recommendations for early stage BD from clinical practice guidelines. Methods We searched PubMED and PsychINFO for clinical guidelines for BD published in the ten years prior to 1 November 2018. Recommendations from identified guidelines that addressed early stage BD or first episode mania were consolidated and compared. We also reviewed the guidelines relating to adolescents with BD to complement the guidelines related to those in the early illness course. Results We identified fourteen international and national guidelines on BD or affective psychoses. Most guidelines contained a separate section on adolescents, but only a few referred specifically to early stage BD. There were no consistent recommendations for early stage disorder, except with respect to the indications for maintenance medication treatments. For adolescents, there was a consistent recommendation for the use of second generation antipsychotics for treating acute mania. Limitation The main limitation is that the identified guidelines did not include primary data that clearly separated illness and developmental stages. Conclusions There is a lack of emphasis on early BD among widely-respected current clinical guidelines, likely reflecting the dearth of primary data. Future evidence or consensus-based recommendations could significantly inform clinical practice for this population.

Background : Data from the World Health Organization Study on global AGEing and adult health (SAGE) were used to estimate the prevalence of depression in older adults in six low- and middle-income countries (LMICs), namely China, Ghana, India, Mexico, the Russian Federation, and South Africa, and to examine the relationship between demographic and lifestyle characteristics and depression. Method : A total of 33,421 participants aged ≥ 50 years were included. A set of diagnostic questions from the World Mental Health Survey was used within SAGE to define depression. Results : The crude population prevalence of depression was 7.4% [95%CI: 6.5%–8.3%] ranging from 1.5% in China to 15.2% in India. It was higher in females 8.6% [7.6%–9.6%] compared to males 6.1% [5.0%–7.2%]. The age-standardized prevalence of depression was 7.8% [6.3%–9.6%] in pooled data, 8.9% [6.9%–11.1%] in females and 6.6% [4.6%–9.0%] in males. Greater fruit (0.89[0.84–0.93]) and vegetable intake (0.94 [0.89–1.00]) was associated with a lower prevalence of depression. Furthermore, those who were older, female, underweight, and with lower education and lower wealth, had higher prevalence of depression. Limitations : The cross-sectional design of this study precluded conclusions on causality. Conclusion : In nationally-representative samples of older adults in six LMICs, an average of one in every 13 participants suffered from depression. The prevalence of depression varied considerably between countries, sexes, and with wealth and educational disadvantage. Increased fruit and vegetable intake appeared to co-occur with significantly lower rates of depression, suggesting diet as a modifiable factor for addressing depression burden.

Background Bipolar disorder is a chronic, episodic mental illness, affecting around 2.4% of the population worldwide. Psychological and/or physiological comorbidities are a common consequence, and osteoporosis is one such possible comorbidity. Thus, this systematic review aimed to collate, evaluate, and discuss the literature examining the link between bipolar disorder and bone health. Methods We conducted an e-search of PubMed/OVID/MEDLINE, PsychINFO and CINAHL to identify studies that investigated associations between bipolar disorder and bone in adults aged ≥18. Two reviewers determined eligibility according to pre-determined criteria, and methodological quality was assessed using a previously published methodological scoring system. Due to heterogeneity, a best-evidence synthesis was performed. Results Our search yielded 1409 articles, of which three (all cohorts) met predetermined criteria. The studies from Taiwan and the United States of America analysed administrative data, albeit spanning different years, and comprised a total of 344,497 participants. No studies investigating bone quantity or quality were identified. Bipolar disorder was associated with an increased risk of fracture (range 20–80%); and fracture-free survival time for those with bipolar disorder decreased substantially with advancing age, and for women (10–30% shorter than men). Fracture incidence per 1000 person years (py) was 21.4 and 10.8 in those with and without bipolar disorder, respectively. Limitations Limited data and marked methodological heterogeneity prevented the pooling of these data for a numerical synthesis. Conclusions Increased fracture risk was observed in individuals with bipolar disorder, independent of older age, sex, comorbidities and medication use. The operative mechanisms, risk and treatment factors warrant further enquiry.

The re-emergence (i.e. ‘breakthrough’) of depressive symptoms despite maintenance treatment of depression with antidepressant drugs is a complex clinical phenomenon referred to as tolerance. Herein we critically appraise evidence from both pre-clinical and clinical studies, focusing on putative mechanisms as well as clinical correlates and implications of the emergence tolerance during antidepressant treatment for major depressive disorder (MDD). It is firstly unclear to what extent this phenotype reflects a pharmacological effect of an antidepressant, is driven by non-adherence, is a marker of latent bipolarity or another comorbidity, a marker of neuroprogression of the underlying disorder or the intrusion of the impact of psychosocial variables into the clinical course. The operational definitions of tolerance and its related phenomena have also been largely inconsistent. Several protective clinical indicators have been proposed, including a rapid-cycling course and comorbid chronic anxiety, whilst poor treatment adherence, proneness to emotional blunting and sub-threshold bipolarity have been identified as possible correlates of tolerance to antidepressant treatment in MDD. Putative neurobiological underpinnings include adaptations in the hypothalamic–pituitary–adrenal (HPA) axis and the serotonergic system. Due to the clinical and diagnostic challenges imposed by the emergence of tolerance to antidepressants, there is an urgent need for upcoming international guidelines to reach a consensus on operational definitions for this complex clinical phenomenon, thus enabling a more precise appreciation of the incidence and correlates of tolerance to antidepressants. Taken together, the present review underscores the need to cautiously weight benefits and risks prior to considering long-term antidepressant treatment for patients with MDD as tolerance may emerge in a subset of patients. © 2018 Elsevier Ltd

Background COVID-19-associated acute respiratory distress syndrome (ARDS) is associated with significant morbidity and high levels of mortality. This paper describes the processes involved in the pathophysiology of COVID-19 from the initial infection and subsequent destruction of type II alveolar epithelial cells by SARS-CoV-2 and culminating in the development of ARDS. Main body The activation of alveolar cells and alveolar macrophages leads to the release of large quantities of proinflammatory cytokines and chemokines and their translocation into the pulmonary vasculature. The presence of these inflammatory mediators in the vascular compartment leads to the activation of vascular endothelial cells platelets and neutrophils and the subsequent formation of platelet neutrophil complexes. These complexes in concert with activated endothelial cells interact to create a state of immunothrombosis. The consequence of immunothrombosis include hypercoagulation, accelerating inflammation, fibrin deposition, migration of neutrophil extracellular traps (NETs) producing neutrophils into the alveolar apace, activation of the NLRP3 inflammazome, increased alveolar macrophage destruction and massive tissue damage by pyroptosis and necroptosis Therapeutic combinations aimed at ameliorating immunothrombosis and preventing the development of severe COVID-19 are discussed in detail., Graphical abstract Unlabelled Image

In this paper, a model is proposed of the pathophysiological processes of COVID-19 starting from the infection of human type II alveolar epithelial cells (pneumocytes) by SARS-CoV-2 and culminating in the development of ARDS. The innate immune response to infection of type II alveolar epithelial cells leads both to their death by apoptosis and pyroptosis and to alveolar macrophage activation. Activated macrophages secrete proinflammatory cytokines and chemokines and tend to polarise into the inflammatory M1 phenotype. These changes are associated with activation of vascular endothelial cells and thence the recruitment of highly toxic neutrophils and inflammatory activated platelets into the alveolar space. Activated vascular endothelial cells become a source of proinflammatory cytokines and reactive oxygen species (ROS) and contribute to the development of coagulopathy, systemic sepsis, a cytokine storm and ARDS. Pulmonary activated platelets are also an important source of proinflammatory cytokines and ROS, as well as exacerbating pulmonary neutrophil-mediated inflammatory responses and contributing to systemic sepsis by binding to neutrophils to form platelet-neutrophil complexes (PNCs). PNC formation increases neutrophil recruitment, activation priming and extraversion of these immune cells into inflamed pulmonary tissue, thereby contributing to ARDS. Sequestered PNCs cause the development of a procoagulant and proinflammatory environment. The contribution to ARDS of increased extracellular histone levels, circulating mitochondrial DNA, the chromatin protein HMGB1, decreased neutrophil apoptosis, impaired macrophage efferocytosis, the cytokine storm, the toll-like receptor radical cycle, pyroptosis, necroinflammation, lymphopenia and a high Th17 to regulatory T lymphocyte ratio are detailed., Graphical abstract Unlabelled Image

Androgens such as testosterone and dihydrotestosterone are a critical driver of prostate cancer progression. Cancer resistance to androgen deprivation therapies ensues when tumors engage metabolic processes that produce sustained androgen levels in the tissue. However, the molecular mechanisms involved in this resistance process are unclear, and functional imaging modalities that predict impending resistance are lacking. Here, using the human LNCaP and C4-2 cell line models of prostate cancer, we show that castration treatment–sensitive prostate cancer cells that normally have an intact glucuronidation pathway that rapidly conjugates and inactivates dihydrotestosterone and thereby limits androgen signaling, become glucuronidation deficient and resistant to androgen deprivation. Mechanistically, using CRISPR/Cas9-mediated gene ablation, we found that loss of UDP glucuronosyltransferase family 2 member B15 (UGT2B15) and UGT2B17 is sufficient to restore free dihydrotestosterone, sustained androgen signaling, and development of castration resistance. Furthermore, loss of glucuronidation enzymatic activity was also detectable with a nonsteroid glucuronidation substrate. Of note, glucuronidation-incompetent cells and the resultant loss of intracellular conjugated dihydrotestosterone were detectable in vivo by (18)F-dihydrotestosterone PET. Together, these findings couple a mechanism with a functional imaging modality to identify impending castration resistance in prostate cancers.

The immuno-inflammatory origin of schizophrenia in a subset of patients is viewed as a key element of an overarching etiological construct. Despite substantial research, the immune components exerting major effect are yet to be fully clarified. Disrupted T cell networks have consistently been linked to the pathogenesis of schizophrenia. Amongst the Th cell subsets, the Th17 cells have emerged as a paradigmatic lineage with significant functional implications in a vast number of immune mediated diseases including brain disorders such as schizophrenia. The present study was aimed at examining the functional role of the Th17 pathway in schizophrenia. To address this, genotyping of IL17A (rs2275913; G197A) Single Nucleotide Polymorphism was carried out by the PCR-RFLP method in 221 schizophrenia patients and 223 healthy control subjects. Gene expression of two transcription factors STAT3 and RORC was quantified in a subset of drug naive schizophrenia patients (n = 56) and healthy controls (n = 52) by TaqMan assay. The plasma levels of fifteen cytokines belonging to Th17 pathway were estimated in a subset of drug naive schizophrenia patients (n = 61) and healthy controls (n = 50) by using Bio-Plex Pro Human Th17 cytokine assays. The AA genotype was associated with higher total score of bizarre behaviour and apathy in female schizophrenia patients. A high gene expression level of RORC was observed in drug naive schizophrenia patients. In addition, significantly elevated plasma levels of IL-6 and IL-22, and reduced levels of IL-1β and IL-17F were noted in schizophrenia patients. Taken together, these findings indicate a dysregulated Th17 pathway in schizophrenia patients.

There has been increasing interest in nutraceutical augmentation strategies to boost the efficacy of antidepressants. This study assessed whether S-adenosylmethionine (SAMe), a methyl donor that occurs naturally in the body, may be of such benefit. We conducted an 8-week, double-blind RCT in which 107 treatment non-remittent outpatients with DSM-5 diagnosed Major Depressive Disorder (MDD) were randomized to either SAMe or placebo adjunctively to antidepressants. One-carbon cycle nutrients, pertinent single nucleotide polymorphisms (SNPs), and BDNF were also analysed as potential moderators of response. A linear mixed-effects model revealed a significant overall reduction in Montgomery-Asberg Depression Rating Scale (MADRS) score across time, however there was no significant between-group difference observed (p = 0.51). Response rates at Week 8 were 54.3% in the SAMe group and 50.0% in the placebo group, with remission rates 43.5% for SAMe and 38.3% for placebo (all results NS). No effect of SAMe was found on any secondary outcome. Differential response to SAMe was not modified by a range of key genotypes (e.g. COMT), nor reflected in a change of homocysteine, red cell folate, or BDNF. Use of SAMe elicited no significant adverse effects beyond placebo, however it was implicated in one case of serotonin syndrome-like symptoms. This study concludes that 800 mg/day of SAMe is not an effective adjunctive treatment in MDD, and no obvious biomarker reflected any differential response to treatment. Due to such a distinctly high placebo-response (despite rigorous screening), future studies should employ a placebo run-in period and other strategies to minimize placebo response.

Disruptions of bioenergetic signaling and neurogenesis are hallmarks of depression physiology and are often the product of dysregulation of the inflammatory, stress-response, and metabolic systems. These systems are extensively interrelated at the physiological level, yet the bulk of the literature to date addresses pathophysiological mechanisms in isolation. A more integrated understanding of the etiology, progression, and treatment response profiles of depression is possible through wider consideration of relevant preclinical and clinical studies that examine the result of disruptions in these systems. Here, we review recent data demonstrating the critical effects of bioenergetic disruption on neuroplasticity and the development and progression of depressive illness. We further highlight the interactive and dynamic nature of the inflammatory and stress response systems and how disruption of these systems influences bioenergetic signaling pathways critical to treatment outcomes. In so doing, we underscore the pressing need to reconsider the implications of treatment resistance and present a framework for developing novel, personalized treatment approaches for depression.