OPEN Foundation

Menu
Search
Close this search box.

Depressive Disorders

Type A monoamine oxidase and serotonin are coordinately involved in depressive disorders: from neurotransmitter imbalance to impaired neurogenesis

March 14, 2017 / Ayahuasca, Depressive Disorders, Neuroscience, Papers / By / , ,

Abstract

Type A monoamine oxidase (MAOA) catabolizes monoamine transmitters, serotonin, norepinephrine and dopamine, and plays a major role in the onset, progression and therapy of neuropsychiatric disorders. In depressive disorders, increase in MAOA expression and decrease in brain levels of serotonin and norepinephrine are proposed as the major pathogenic factors. The functional polymorphism of MAOA gene and genes in serotonin signal pathway are associated with depression. This review presents recent advance in studies on the role of MAOA in major depressive disorder and related emotional disorders. MAOA and serotonin regulate the prenatal development and postnatal maintenance of brain architecture and neurocircuit, as shown by MAOA-deficient humans and MAO knockout animal models. Impaired neurogenesis in the mature hippocampus has been proposed as “adult neurogenesis” hypothesis of depression. MAOA modulates the sensitivity to stress in the stages of brain development and maturation, and the interaction of gene–environmental factors in the early stage regulates the onset of depressive behaviors in adulthood. Vice versa environmental factors affect MAOAexpression by epigenetic regulation. MAO inhibitors not only restore compromised neurotransmitters, but also protect neurons from cell death in depression through induction of anti-apoptotic Bcl-2 and prosurvival neurotrophic factors, especially brain-derived neurotrophic factor, the deficiency of which is detected in depression. This review discusses novel role of MAOA and serotonin in the pathogenesis and therapy of depressive disorders.

Naoi, M., Maruyama, W., & Shamoto-Nagai, M. (2017). Type A monoamine oxidase and serotonin are coordinately involved in depressive disorders: from neurotransmitter imbalance to impaired neurogenesis. Journal of Neural Transmission, 1-14. 10.1007/s0070
Link to full text

The Nucleus Accumbens and Ketamine Treatment in Major Depressive Disorder

March 8, 2017 / Depressive Disorders, Ketamine, Neuroscience, Papers / By / , , , , , ,

Abstract

Animal models of depression repeatedly showed stress-induced nucleus accumbens (NAc) hypertrophy. Recently, ketamine was found to normalize this stress-induced NAc structural growth. Here, we investigated NAc structural abnormalities in major depressive disorder (MDD) in two cohorts. Cohort A included a cross-sectional sample of 34 MDD and 26 healthy control (HC) subjects, with high-resolution magnetic resonance imaging (MRI) to estimate NAc volumes. Proton MR spectroscopy (1H MRS) was used to divide MDD subjects into two subgroups: glutamate-based depression (GBD) and non-GBD. A separate longitudinal sample (cohort B) included 16 MDD patients who underwent MRI at baseline then 24 h following intravenous infusion of ketamine (0.5 mg/kg). In cohort A, we found larger left NAc volume in MDD compared to controls (Cohen’s d=1.05), but no significant enlargement in the right NAc (d=0.44). Follow-up analyses revealed significant subgrouping effects on the left (d⩾1.48) and right NAc (d⩾0.95) with larger bilateral NAc in non-GBD compared to GBD and HC. NAc volumes were not different between GBD and HC. In cohort B, ketamine treatment reduced left NAc, but increased left hippocampal, volumes in patients achieving remission. The cross-sectional data provided the first evidence of enlarged NAc in patients with MDD. These NAc abnormalities were limited to patients with non-GBD. The pilot longitudinal data revealed a pattern of normalization of left NAc and hippocampal volumes particularly in patients who achieved remission following ketamine treatment, an intriguing preliminary finding that awaits replication.
Abdallah, C. G., Jackowski, A., Salas, R., Gupta, S., Sato, J. R., Mao, X., … & Mathew, S. J. (2017). The nucleus accumbens and ketamine treatment in major depressive disorder. Neuropsychopharmacology, 1, 8. 10.1038/npp.2017.49
Link to full text

Ketamine as a Rapid-Acting Antidepressant: Promising Clinical and Basic Research

March 8, 2017 / Depressive Disorders, Ketamine, Neuroscience, Papers, Psychology / By / ,

Abstract

Suicidal ideation and attempts are a common medical emergency, accounting for about 650,000 adult evaluations per year in emergency settings (1). Depressive disorders are a major driving force behind this, but first-line antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), can take months to work, making them of limited use in acutely suicidal patients. Potentially safe and fast-acting interventions would be invaluable in acute situations until standard antidepressants have time to take effect.
Ketamine, best known as an N-methyl-d-aspartate receptor (NMDAR) antagonist commonly used as an anesthetic, has recently drawn attention for possibly filling the role. At lower doses it exhibits strong antidepressant effects in many patients, and it acts on the order of minutes. Despite these promising effects, its use as an antidepressant has been controversial, as ketamine is also a Schedule III controlled substance that is used recreationally for its dissociative and hallucinogenic effects. Furthermore, the full mechanism of action regarding its antidepressant effects has long remained unclear.
In the present article, we review research surrounding ketamine’s potential as a fast-acting antidepressant from a “two-pronged” approach: first, summarizing established and new knowledge on its mechanism of action and second, reviewing clinical research addressing its potential to quickly reduce depression and suicidality.
Tuck, A. N., & Ghazali, D. H. (2017). Ketamine as a Rapid-Acting Antidepressant: Promising Clinical and Basic Research. American Journal of Psychiatry Residents’ Journal, 12(3), 3-5. 10.1176/appi.ajp-rj.2017.120302
Link to full text

Indole Alkaloids from Plants as Potential Leads for Antidepressant Drugs: A Mini Review

February 28, 2017 / Ayahuasca, Biology & Ethnobotany, Depressive Disorders, Neuroscience, Papers, Psychology, Publications / By / , ,

Abstract

Depression is the most common illness observed in the elderly, adults, and children. Antidepressants prescribed are usually synthetic drugs and these can sometimes cause a wide range of unpleasant side effects. Current research is focussed on natural products from plants as they are a rich source of potent new drug leads. Besides Hypericum perforatum (St. John’s wort), the plants studied include Passiflora incarnata L. (passion flower), Mitragyna speciosa (kratom), Piper methysticum G. Forst (kava) and Valeriana officinalis L. Harman, harmol, harmine, harmalol and harmaline are indole alkaloids isolated from P. incarnata, while mitragynine is isolated from M. speciosa. The structure of isolated compounds from P. methysticum G. Forst and V. officinalis L. contains an indole moiety. The indole moiety is related to the neurotransmitter serotonin which is widely implicated for brain function and cognition as the endogenous receptor agonist. An imbalance in serotonin levels may influence mood in a way that leads to depression. The moiety is present in a number of antidepressants already on the market. Hence, the objective of this review is to discuss bioactive compounds containing the indole moiety from plants that can serve as potent antidepressants.

Hamid, H. A., Ramli, A. N., & Yusoff, M. M. (2017). Indole Alkaloids from Plants as Potential Leads for Antidepressant Drugs: A Mini Review. Frontiers in Pharmacology, 8, 96. 10.3389/fphar.2017.00096
Link to full text

22-azidosalvinorin A exhibits antidepressant-like effect in mice

February 17, 2017 / Depressive Disorders, Neuroscience, Papers, Psychology, Publications, Salvia / Salvinorin A / By / , , , ,

Abstract

The increasing cases of depression has made the searches for new drugs and understanding of the underligning neurobiology of this psychiatric disorder a necessity. Here, we modified the structure of salvinorin A (a known halucinogen) and investigated antidepressant-like activity of its four derivatives; 22-methylsulfanylsalvinorin A(SA1), 2-O-cinnamoylsalvinorin B (CSB), 22-azidosalvinorin A (SA2), and 2-O-(4’-azidophenylsulfonyl)salvinorin B (SA3). Prior to behavioural tests (Irwin test, open field test – OFT, forced swimming test – FST and tail suspension test – TST), SA1 was prepared by reacting salvinorin B and methylthioacetic acid with 89% yield; CSB was obtained from the reaction of salvinorin B and cinnamic acid with 92% yield; SA2 was obtained from the reaction of salvinorin B and azidoacetic acid with 81% yield; and SA3 was prepared by reacting salvinorin B with 4-azidophenylsulfonyl chloride with 80% yield. Oral treatment of mice with these derivatives (1–1000 mg/kg) did not elicit toxic sign or death. Unlike SA, SA1, CSB and SA3, treatment with SA2 (5, 10 and 20 mg/kg) decreased the immobility (TST and FST) and swimming time (FST) without altering locomotor activity in OFT. A decrease in the immobility time in TST and FST confirmed antidepressant-like property of SA2. Although p-chlorophenylalanine (serotonin depletor) or WAY100635 (selective 5-HT1A receptor antagonist) did not attenuate effect of SA2, alpha-methyl-para-tyrosine (catecholamine depletor) and prazosin (selective α1-receptor antagonist) attenuated this effect. SA2 mildly inhibited monoamine oxidase and showed affinity for α1A, α1B, α1D and κ-opioid receptor subtypes. In summary, SA2 induced monoamine-mediated antidepressant-like effect.

Fajemiroye, J. O., Prabhakar, P. R., da Cunha, C. L., Costa, E. A., & Zjawiony, J. K. (2017). 22-Azidosalvinorin A exhibits antidepressant-like effect in mice. European Journal of Pharmacology. 10.1016/j.ejphar.2017.02.031
Link to full text

Rapid antidepressant effect of ketamine correlates with astroglial plasticity in the hippocampus

February 8, 2017 / Depressive Disorders, Ketamine, Neuroscience, Papers, Psychology, Publications / By / , , ,

Abstract

BACKGROUND AND PURPOSE: Astroglia contribute to the pathophysiology of major depression and antidepressant drugs act by modulating synaptic plasticity; therefore, the present study investigated whether the fast antidepressant action of ketamine is reflected in a rapid alteration of the astrocytes’ morphology in a genetic animal model of depression.

EXPERIMENTAL APPROACH: S-Ketamine (15 mg·kg-1 ) or saline was administered as a single injection to Flinders Line (FSL/ FRL) rats. Twenty-four hours after the treatment, perfusion fixation was carried out and the morphology of glial fibrillary acid protein (GFAP)-positive astrocytes in the CA1 stratum radiatum (CA1.SR) and the molecular layer of the dentate gyrus (GCL) of the hippocampus was investigated by applying stereological techniques and analysis with Imaris software. The depressive-like behaviour of animals was also evaluated using forced swim test.

KEY RESULTS: FSL rats treated with ketamine exhibited a significant reduction in immobility time in comparison with the FSL-vehicle group. The volumes of the hippocampal CA1.SR and GCL regions were significantly increased 1 day after ketamine treatment in the FSL rats. The size of astrocytes in the ketamine-treated FSL rats was larger than those in the FSL-vehicle group. Additionally, the number and length of the astrocytic processes in the CA1.SR region were significantly increased 1 day following ketamine treatment.

CONCLUSIONS AND IMPLICATIONS: Our results support the hypothesis that astroglial atrophy contributes to the pathophysiology of depression and a morphological modification of astrocytes could be one mechanism by which ketamine rapidly improves depressive behaviour.

Ardalan, M., Rafati, A. H., Nyengaard, J. R., & Wegener, G. (2017). Rapid antidepressant effect of ketamine correlates with astroglial plasticity in the hippocampus. British Journal of Pharmacology, 174(6), 483-492. 10.1111/bph.13714
Link to full text

Sub-anesthetic doses of ketamine exert antidepressant-like effects and upregulate the expression of glutamate transporters in the hippocampus of rats

February 3, 2017 / Depressive Disorders, Ketamine, Neuroscience, Papers, Psychology, Publications / By / , , ,

Abstract

Clinical studies on the role of the glutamatergic system in the pathogenesis of depression found that ketamine induces an antidepressant response, but the molecular mechanisms remain unclear. The present study investigated the effects of sub-anesthetic doses of ketamine on the glutamate reuptake function in the rat hippocampus. Chronic unpredictable mild stress (CUMS) was applied to construct animal models of depression. Sixty adult male Sprague-Dawley rats were randomly assigned to 5 groups and received a different regimen of CUMS and ketamine (10, 25, and 50 mg/kg) treatment. The sucrose preference test and open-field test were used to assess behavioral changes. The expression levels of excitatory amino acid transporters (EAATs) were measured by western blot. Microdialysis and high-performance liquid chromatography (HPLC) were used to detect hippocampal glutamate concentrations. We found that the expression of EAAT2 and EAAT3 were obviously downregulated, and extracellular concentrations of glutamate were significantly increased in the hippocampi of depressive-like rats. Ketamine (10, 25, and 50 mg/kg) upregulated the expression of EAAT2 and EAAT3, decreased the hippocampal concentration of extracellular glutamate, and alleviated the rats’ depressive-like behavior. The antidepressant effect of ketamine may be linked to the regulation of EAAT expression and the enhancement of glutamate uptake in the hippocampus of depressive-like rats.

Zhu, X., Ye, G., Wang, Z., Luo, J., & Hao, X. (2017). Sub-anesthetic doses of ketamine exert antidepressant-like effects and upregulate the expression of glutamate transporters in the hippocampus of rats. Neuroscience Letters, 639, 132-137. 10.1016/j.neulet.2016.12.070
Link to full text

Ketamine Therapy for Treatment-resistant Depression in a Patient with Multiple Sclerosis: A Case Report

February 1, 2017 / Depressive Disorders, Ketamine, Papers, Psychology, Publications / By / ,

Abstract

Objective: Depression is a common condition among patients with multiple sclerosis and often becomes resistant to oral antidepressants. We report a patient with multiple sclerosis who developed severe treatment-resistant depression and who was successfully treated with intravenous ketamine over the period of two years.
Methods: Ketamine treatment protocol included an initial series of six treatments administered every other day, followed by a maintenance schedule. Ketamine was administered intravenously at 0.5mg/kg of ideal body weight over 40 minutes. Depression symptoms were measured using Beck Depression Index.
Results: The patient’s Beck Depression Index score prior to initiating ketamine treatment was 38, corresponding to severe depression. Response to treatment, defined as 50-percent reduction in Beck Depression Index score, was observed after five treatments. For this patient, the maintenance schedule ranged from a weekly treatment to one treatment every three weeks. During the two-year observation period, this patient was able to maintain a stable non-depressed mood and had no worsening of her MS symptoms.
Conclusion: Ketamine may be an alternative treatment for resistant depression and may have a special use in patients with multiple sclerosis.
Messer, M. M., & Haller, I. V. (2017). Ketamine Therapy for Treatment-resistant Depression in a Patient with Multiple Sclerosis: A Case Report. Innovations in clinical neuroscience, 14(1-2), 56.
Link to full text

Ketamine decreases sensitivity of male rats to misleading negative feedback in a probabilistic reversal-learning task

February 1, 2017 / Depressive Disorders, Ketamine, Papers, Psychology, Publications / By / , ,

Abstract

RATIONALE: Depression is characterized by an excessive attribution of value to negative feedback. This imbalance in feedback sensitivity can be measured using the probabilistic reversal-learning (PRL) task. This task was initially designed for clinical research, but introduction of its rodent version provides a new and much needed translational paradigm to evaluate potential novel antidepressants.

OBJECTIVES: In the present study, we aimed at evaluating the effects of a compound showing clear antidepressant properties-ketamine (KET)-on the sensitivity of rats to positive and negative feedback in the PRL paradigm.

METHODS: We trained healthy rats in an operant version of the PRL task. For successful completion of the task, subjects had to learn to ignore infrequent and misleading feedback, arising from the probabilistic (80:20) nature of the discrimination. Subsequently, we evaluated the effect of KET (5, 10, and 20 mg/kg) on feedback sensitivity 1, 24, and 48 h after administration.

RESULTS: We report that acute administration of the highest dose of KET (20 mg/kg) rapidly and persistently decreases the proportion of lose-shift responses made by rats after receiving negative feedback.

CONCLUSION: Present results suggest that KET decreases negative feedback sensitivity and that changes in this basic neurocognitive function might be one of the factors responsible for its antidepressant action.

Rychlik, M., Bollen, E., & Rygula, R. (2016). Ketamine decreases sensitivity of male rats to misleading negative feedback in a probabilistic reversal-learning task. Psychopharmacology, 1-8. 10.1007/s00213-016-4497-1
Link to full text

Prophylactic Ketamine Attenuates Learned Fear

January 27, 2017 / Anxiety Disorders / PTSD, Depressive Disorders, Ketamine, Neuroscience, Papers, Psychology, Publications / By / , , , , , ,

Abstract

Ketamine has been reported to be an efficacious antidepressant for major depressive disorder (MDD) and posttraumatic stress disorder (PTSD). Most recently, ketamine has also been shown to be prophylactic against stress-induced depressive-like behavior in mice. It remains unknown, however, when ketamine should be administered relative to a stressor in order to maximize its antidepressant and/or prophylactic effects. Moreover, it is unknown if ketamine can be prophylactic against subsequent stressors. We systematically administered ketamine at different time points relative to a fear experience in order to determine when ketamine is most effective at reducing fear expression or preventing fear reactivation. Using a contextual fear conditioning (CFC) paradigm, mice were administered a single dose of saline or ketamine (30 mg kg−1) at varying time points before or after CFC. Mice administered prophylactic ketamine 1 week, but not 1 month or 1 h before CFC, exhibited reduced freezing behavior when compared with mice administered saline. In contrast, ketamine administration following CFC or during extinction did not alter subsequent fear expression. However, ketamine administered before reinstatement increased the number of rearing bouts in an open field, possibly suggesting an increase in attentiveness. These data indicate that ketamine can buffer a fear response when given a week before as prophylactic, but not when given immediately before or after a stress-inducing episode. Thus, ketamine may be most useful in the clinic if administered in a prophylactic fashion 1 week before a stressor in order to protect against heightened fear responses to aversive stimuli.

McGowan, J. C., LaGamma, C. T., Lim, S. C., Tsitsiklis, M., Neria, Y., Brachman, R. A., & Denny, C. A. (2017). Prophylactic Ketamine Attenuates Learned Fear. Neuropsychopharmacology. 10.1038/npp.2017.19
Link to full text

interested in becoming a trained psychedelic-assisted therapist?

Management of Psychedelic-Related Complications - Online Event - Nov 20th

REGISTER NOW