Reducing Addiction in Bipolar Disorder via Hacking the Dopaminergic System

The dopaminergic system plays a central and decisive role in substance use disorder (SUD), bipolar disorder (BD), and possibly in a subgroup of patients with refractory depression. Common genetic markers and underlying cellular processes, such as kindling, support the close link between these disorders, which is also expressed by the high rate of comorbidity. Although partial dopamine agonists/antagonists acting on D2 and D3 receptors have an established role in treating BD, their usefulness in SUD is less clear. However, dopamine D3 receptors were shown to play a central role in SUD and BD, making D2/D3 partial agonists/antagonists a potential target for both disorders. This narrative review examines whether these substances bear the promise of a future therapeutic approach especially in patients with comorbid BD and SUD.

Association of VEGF With Antianhedonic Effects of Repeated-Dose Intravenous Ketamine in Treatment-Refractory Depression

Objectives: To first explore the role of plasma vascular endothelial growth factor (VEGF) concentrations in ketamine's antianhedonic effects, focusing on Chinese patients with treatment-refractory depression (TRD).Methods: Seventy-eight patients with treatment-refractory major depressive disorder (MDD) or bipolar disorder (BD) were treated with six ketamine infusions (0.5 mg/kg). Levels of anhedonia were measured using the Montgomery–Åsberg Depression Rating Scale (MADRS) anhedonia item at baseline, day 13 and 26. Plasma VEGF concentrations were examined at the same time points as the MADRS.Results: Despite a significant reduction in anhedonia symptoms in individuals with treatment-refractory MDD (n = 59) or BD (n = 19) after they received repeated-dose ketamine infusions (p < 0.05), no significant changes in plasma VEGF concentrations were found at day 13 when compared to baseline (p > 0.05). The alteration of plasma VEGF concentrations did not differ between antianhedonic responders and non-responders at days 13 and 26 (all ps > 0.05). Additionally, no significant correlations were observed between the antianhedonic response to ketamine and plasma VEGF concentrations (all ps > 0.05).Conclusion: This preliminary study suggests that the antianhedonic effects of ketamine are not mediated by VEGF.

Lithium augmentation of ketamine increases insulin signaling and antidepressant-like active stress coping in a rodent model of treatment-resistant depression

Lithium, a mood stabilizer and common adjunctive treatment for refractory depression, shares overlapping mechanisms of action with ketamine and enhances the duration of ketamine’s antidepressant actions in rodent models at sub-therapeutic doses. Yet, in a recent clinical trial, lithium co-treatment with ketamine failed to improve antidepressant outcomes in subjects previously shown to respond to ketamine alone. The potential for lithium augmentation to improve antidepressant outcomes in ketamine nonresponders, however, has not been explored. The current study examined the behavioral, molecular and metabolic actions of lithium and ketamine co-treatment in a rodent model of antidepressant resistance. Male Wistar rats were administered adrenocorticotropic hormone (ACTH; 100 µg/day, i.p. over 14 days) and subsequently treated with ketamine (10 mg/kg; 2 days; n = 12), lithium (37 mg/kg; 2 days; n = 12), ketamine + lithium (10 mg/kg + 37 mg/kg; 2 days; n = 12), or vehicle saline (0.9%; n = 12). Rats were subjected to open field (6 min) and forced swim tests (6 min). Peripheral blood and brain prefrontal cortical (PFC) tissue was collected one hour following stress exposure. Western blotting was used to determine the effects of treatment on extracellular signal-regulated kinase (ERK); mammalian target of rapamycin (mTOR), phospho kinase B (Akt), and glycogen synthase kinase-3ß (GSK3ß) protein levels in the infralimbic (IL) and prelimbic (PL) subregions of the PFC. Prefrontal oxygen consumption rate (OCR) and extracellular acidification rates (ECAR) were also determined in anterior PFC tissue at rest and following stimulation with brain-derived neurotrophic factor (BDNF) and tumor necrosis factor α (TNFα). Blood plasma levels of mTOR and insulin were determined using enzyme-linked immunosorbent assays (ELISAs). Overall, rats receiving ketamine+lithium displayed a robust antidepressant response to the combined treatment as demonstrated through significant reductions in immobility time (p < 0.05) and latency to immobility (p < 0.01). These animals also had higher expression of plasma mTOR (p < 0.01) and insulin (p < 0.001). Tissue bioenergetics analyses revealed that combined ketamine+lithium treatment did not significantly alter the respiratory response to BDNF or TNFα. Animals receiving both ketamine and lithium had significantly higher phosphorylation (p)-to-total expression ratios of mTOR (p < 0.001) and Akt (p < 0.01), and lower ERK in the IL compared to control animals. In contrast, pmTOR/mTOR levels were reduced in the PL of ketamine+lithium treated animals, while pERK/ERK expression levels were elevated. Taken together, these data demonstrate that lithium augmentation of ketamine in antidepressant nonresponsive animals improves antidepressant-like behavioral responses under stress, together with peripheral insulin efflux and region-specific PFC insulin signaling.

Optimal dose of aripiprazole for augmentation therapy of antidepressant-refractory depression: preliminary findings based on a systematic review and dose–effect meta-analysis

Background Aripiprazole augmentation is proven effective for antidepressant-refractory depression, but its licensed dose range is wide and optimal dosage remains unclear. Aims To find the optimal dosage of aripiprazole augmentation. Method Multiple electronic databases were searched (from inception to 16 February 2021) to identify all assessor-masked randomised controlled trials evaluating aripiprazole augmentation therapy in adults (≥18 years old, both genders) with major depressive disorder showing inadequate response to at least one antidepressant treatment. A random-effects, one-stage dose–effect meta-analysis with restricted cubic splines was conducted. Outcomes were efficacy (treatment response: ≥50% reduction in depression severity), tolerability (drop-out due to adverse effects) and acceptability (drop-out for any reason) after 8 weeks of treatment (range 4–12 weeks). Results Ten studies met the inclusion criteria. All were individually randomised, placebo-controlled, multi-centre, parallel studies including 2625 participants in total. The maximum target dose–efficacy curve showed an increase up to doses between 2 mg (odds ratio OR = 1.46, 95% CI 1.15–1.85) and 5 mg (OR = 1.93, 95% CI 1.33–2.81), and then a non-increasing trend through the higher licensed doses up to 20 mg (OR = 1.90, 95% CI 1.52–2.37). Tolerability showed a similar trend with greater uncertainty. Acceptability showed no significant difference through the examined dose range. Certainty of evidence was low to moderate. Conclusions Low-dose aripiprazole as augmentation treatment might achieve the optimal balance between efficacy, tolerability and acceptability in the acute treatment of antidepressant-refractory depression. However, the small number of included studies and the overall moderate to high risk of bias seriously compromise the reliability of the results. Further research is required to investigate the benefits of low versus high dose.

Hemorrhagic angiomatous meningioma: what we know. Case report and review of the literature

Meningiomas are the most common benign intracranial tumors and rarely present with spontaneous bleeding. We report on a case of hemorrhagic angiomatous meningioma that was treated surgically (the first case described in Brazil) and present a review of the literature. The patient wasa 38-year-old female with progressive headache and vomiting. She also had a previous history ofchronic headaches and refractory depression. Imaging studies showed a large left frontal extra-axialtumor, with intense contrast enhancement and hyperperfusion/hypervascularization. There was anextensive intratumoral and pericapsular hemorrhagic region, with dilation of the middle meningealarteries and falx cerebri vessels. The lesion was compatible with hemorrhagic meningioma. Thepatient underwent bifrontal craniotomy and tumor devascularization, followed by total resection.Histopathological and immunohistochemical analyses led us to conclude that this was a case of angiomatous meningioma. Subsequently, the patient’s headaches and depression improved. Noresidual or recurrent neoplastic lesion was observed during the follow-up.

A case study and practitioner perspective on the application of Radically Open Dialectical Behaviour Therapy (RO DBT)

Radically Open Dialectical Behaviour Therapy (RO DBT) is a new treatment for overcontrolled mental health disorders, including refractory depression. This case study provides the therapist's description of delivering RO DBT to a client who took part in a randomised controlled trial of RO DBT. It describes novel treatment strategies and their implementation. Sam attended weekly individual sessions and group skills training sessions over 7 months. The treatment involved collaboratively explaining the RO DBT model whilst linking it to Sam's history and experiences. Coping styles that served to keep Sam isolated from others were identified with a focus on social signalling. RO DBT skills were introduced to activate her social safety system and enhance connectedness. Percentage improvement in depression scores from baseline was 50% at 7 months (end of treatment) and 65% at 18 months.Sam was in full remission at 12 and 18 months. Subjective feedback from Sam was that she felt happier in her marriage, had started voluntary work and made friends locally. She reported being more compassionate to herself and having increased flexibility in adapting to situations.The therapist reported using the RO DBT skills herself and finding them useful, both in learning the new therapy and in the therapy sessions. RO DBT's focus on the overcontrolled coping style and teaching of new strategies to address social signalling and enhance connectedness is a novel treatment approach. It offers promise as an intervention for those with depression.