A naturalistic study comparing the efficacy of unilateral and bilateral sequential theta burst stimulation in treating major depression - the U-B-D study protocol.

BACKGROUND: Major depressive disorder (MDD) is a prevalent mental health condition affecting millions worldwide, leading to disability and reduced quality of life. MDD poses a global health priority due to its early onset and association with other disabling conditions. Available treatments for MDD exhibit varying effectiveness, and a substantial portion of individuals remain resistant to treatment. Repetitive transcranial magnetic stimulation (rTMS), applied to the left and/or right dorsolateral prefrontal cortex (DLPFC), is an alternative treatment strategy for those experiencing treatment-resistant MDD. The objective of this study is to investigate whether this newer form of rTMS, namely theta burst stimulation (TBS), when performed unilaterally or bilaterally, is efficacious in treatment-resistant MDD. METHODS: In this naturalistic, randomized double-blinded non-inferiority trial, participants with a major depressive episode will be randomized to receive either unilateral (i.e., continuous TBS [cTBS] to the right and sham TBS to the left DLPFC) or bilateral sequential TBS (i.e., cTBS to the right and intermittent TBS [iTBS] to the left DLPFC) delivered 5 days a week for 4-6 weeks. Responders will move onto a 6-month flexible maintenance phase where TBS treatment will be delivered at a decreasing frequency depending on degree of symptom mitigation. Several clinical assessments and neuroimaging and neurophysiological biomarkers will be collected to investigate treatment response and potential associated biomarkers. A non-inferiority analysis will investigate whether bilateral sequential TBS is non-inferior to unilateral TBS and regression analyses will investigate biomarkers of treatment response. We expect to recruit a maximal of 256 participants. This trial is approved by the Research Ethics Board of The Royal's Institute of Mental Health Research (REB# 2,019,071) and will follow the Declaration of Helsinki. Findings will be published in peer-reviewed journals. DISCUSSION: Comprehensive assessment of symptoms and neurophysiological biomarkers will contribute to understanding the differential efficacy of the tested treatment protocols, identifying biomarkers for treatment response, and shedding light into underlying mechanisms of TBS. Our findings will inform future clinical trials and aid in personalizing treatment selection and scheduling for individuals with MDD. TRIAL REGISTRATION: The trial is registered on https://clinicaltrials.gov/ct2/home (#NCT04142996).

Restoration of serotonin neuronal firing following long-term administration of bupropion but not paroxetine in olfactory bulbectomized rats.

BACKGROUND: Olfactory bulbectomized rats generally manifest many of the neurochemical, physiological, and behavioral features of major depressive disorder in humans. Another interesting feature of this model is that it responds to chronic but not acute antidepressant treatments, including selective serotonin reuptake inhibitors. The purpose of the present study was first to characterize the firing activity of dorsal raphe serotonin neurons in olfactory bulbectomized rats and then examine the effects of 2 antidepressants, bupropion and paroxetine. METHODS: Olfactory bulbectomy was performed by aspirating olfactory bulbs in anesthetized rats. Vehicle and drugs were delivered for 2 and 14 days via subcutaneously implanted minipumps. In vivo electrophysiological recordings were carried out in male anesthetized Sprague-Dawley rats. RESULTS: Following ablation of olfactory bulbs, the firing rate of serotonin neurons was decreased by 36%, leaving those of norepinephrine and dopamine neurons unchanged. In olfactory bulbectomized rats, bupropion (30 mg/kg/d) restored the firing rate of serotonin neurons to the control level following 2- and 14-day administration and also induced an increase in the tonic activation of serotonin(1A) receptors; paroxetine (10 mg/kg/d) did not result in a return to normal of the attenuated firing of serotonin neurons in olfactory bulbectomized rats. In the hippocampus, although at a higher dose of WAY 100635 than that required in bupropion-treated animals, paroxetine administration also resulted in an increase in the tonic activation of serotonin(1A) receptors. CONCLUSIONS: The present results indicate that unlike paroxetine, bupropion administration normalized serotonin neuronal activity and increased tonic activation of the serotonin(1A) receptors in hippocampus.

Optimizing antidepressant benefits: Effect of theta burst stimulation treatment in physically active people with treatment-resistant depression.

Theta burst stimulation (TBS) is a promising therapy for treatment-resistant major depressive disorder (MDD), but a significant proportion of individuals do not respond adequately, necessitating alternative approaches. This study explores whether individuals meeting minimum recommended physical activity levels demonstrate better responses to TBS compared to physically inactive individuals. Using data from a randomized controlled trial (n = 43), participants were categorized as physically active or inactive based on baseline International Physical Activity Questionnaire (IPAQ) scores. Depression scores (Hamilton Rating Scale for Depression, 17-item; HRSD-17) were assessed at baseline, 4, and 6 weeks of TBS treatment. A significant Time X Group effect adjusted for age and baseline depression was observed. Physically active individuals consistently exhibited lower depression scores across time points. At 4 and 6 weeks, there was a significant increase in between-group differences, indicating that the physically active group derived greater benefits from treatment. At 6 weeks, a significantly higher proportion of responders (≥50 % HRSD-17 reduction) were observed in the physically active compared to inactive group. Physical activity significantly contributed to regression and logistic models predicting treatment response. These findings support the potential role of baseline physical activity in enhancing TBS therapy for MDD.

Modulation of the antidepressant-like effects of sustained administration of carisbamate and lamotrigine on monoaminergic systems: electrophysiological studies in the rat brain.

Carisbamate and lamotrigine are anticonvulsants that act on neuronal voltage-gated sodium channels. Carisbamate has shown antidepressant-like effects in animal models of depression, and lamotrigine is a mood stabilizer with a therapeutic effect in depressive episodes of patients with bipolar disorder. This study examined the effects of carisbamate and lamotrigine on monoaminergic transmission in rodents, which could contribute to their antidepressant action. In vivo electrophysiological recordings were carried out in rats after 2 and 14 days administration of vehicle, carisbamate (60 mg/kg daily), or lamotrigine (25 mg/kg daily). Overall firing activity of the dorsal raphe nucleus (DRN) serotonin (5-HT), locus coeruleus norepinephrine, and ventral tegmental area dopamine (DA) neurons was decreased with carisbamate. Lamotrigine also decreased 5-HT neuronal firing, and this effect was abolished by lesion of the prefrontal cortex. Despite these decreases in firing activity after their prolonged administration, both anticonvulsants exhibited a significant increase in tonic activation of hippocampus 5-HT1A receptors, as shown by a disinhibition of the firing activity of pyramidal neurons in response to the selective antagonist WAY-100635 (N-{2-[4(2-methoxyphenyl)-1-piperazinyl] ethyl}-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride). This finding reveals an increase in the 5-HT level that may be attributed to a desensitization of the terminal 5-HT1B autoreceptors. This study demonstrates that sustained carisbamate and lamotrigine administration decreases 5-HT firing in the DRN but nevertheless enhances 5-HT transmission in the forebrain. This serotonergic effect may be associated with an antiglutamatergic action and may contribute to the antidepressant-like effect of carisbamate in the forced swim test and the antidepressant properties of lamotrigine.

Role of melatonin, serotonin 2B, and serotonin 2C receptors in modulating the firing activity of rat dopamine neurons.

Melatonin has been widely used for the management of insomnia, but is devoid of antidepressant effect in the clinic. In contrast, agomelatine which is a potent melatonin receptor agonist is an effective antidepressant. It is, however, a potent serotonin 2B (5-HT(2B)) and serotonin 2C (5-HT(2C)) receptor antagonist as well. The present study was aimed at investigating the in vivo effects of repeated administration of melatonin (40 mg/kg/day), the 5-HT(2C) receptor antagonist SB 242084 (0.5 mg/kg/day), the selective 5-HT(2B) receptor antagonist LY 266097 (0.6 mg/kg/day) and their combination on ventral tegmental area (VTA) dopamine (DA), locus coeruleus (LC) norepinephrine (NE), and dorsal raphe nucleus (DRN) serotonin (5-HT) firing activity. Administration of melatonin twice daily increased the number of spontaneously active DA neurons but left the firing of NE neurons unaltered. Long-term administration of melatonin and SB 242084, by themselves, had no effect on the firing rate and burst parameters of 5-HT and DA neurons. Their combination, however, enhanced only the number of spontaneously active DA neurons, while leaving the firing of 5-HT neurons unchanged. The addition of LY 266097, which by itself is devoid of effect, to the previous regimen increased for DA neurons the number of bursts per minute and the percentage of spikes occurring in bursts. In conclusion, the combination of melatonin receptor activation as well as 5-HT(2C) receptor blockade resulted in a disinhibition of DA neurons. When 5-HT(2B) receptors were also blocked, the firing and the bursting activity of DA neurons were both enhanced, thus reproducing the effect of agomelatine.