Affective Disorder

The purpose of this study is to examine the efficacy, safety, and tolerability of CYB003 compared to matching placebo as adjunctive treatment in participants with MDD.

The investigators conduct a randomized controlled trial to evaluate the (cost-)effectiveness of ABFT compared to Treatment As Usual (TAU) on suicidality, as delivered in daily practice. The hypothesis is that, compared to TAU, ABFT will lead to a stronger reduction of suicidal ideation and suicidal behavior, and will be more cost-effective, will improve family functioning and young adult attachment, and that this effect will hold at follow-up. The primary objective is change in suicidality, that is, suicidal ideation, attempts and suicide as assessed by the Suicidal Ideation Questionnaire Junior (SIQ-JR), and as reported by therapists during treatment. Secondary objectives are cost-effectiveness, process, working alliance and adherence during treatment, and change in young adult depressive symptoms, family functioning, and young adult attachment. Attachment Based Family Therapy (ABFT): ABFT is a manualized treatment, that emerges from interpersonal theories that suggest suicide can be precipitated, exacerbated, or buffered against by the quality of family relationships. Therefore, ABFT focuses on strengthening parent-child attachment bonds to create a protective and secure base for young adult development. Sessions are scheduled weekly, and the intervention lasts on average 16 weeks. Treatment as usual (TAU): Participants in both arms will receive TAU, in the experimental condition ABFT will be delivered as an add-on. Most treatment centres' clinical practices rely heavily on the use of antidepressants and/or CBT or DBT. All regular interventions are allowed in TAU, except for systemic family therapy of more than 4 sessions in total. Parents are allowed to be involved in the treatment, which is part of treatment as usual, and can comprise for instance psycho-education or parental support or skill training.

Introduction Post-secondary students report alarming rates of feeling overwhelmed, hopeless, anxious, and depressed. To better support student mental health, there is a well-documented need to improve the range and quality of mental health services available to students. Focussing on formalized treatment approaches and strategies supporting well-being in the campus community more generally are needed. Physical activity is an alternative therapeutic approach that could be implemented as an evidence-based lifestyle intervention for supporting mental health and well-being on post-secondary campuses. Despite the growing evidence supporting physical activity for student mental health, there are significant knowledge gaps in the literature. First, research to date has predominantly been single-group designs with a lack of a control group and randomization. This contributes to limitations in the confidence and quality of the implications drawn from the synthesized studies. Indeed, within a post-secondary context, most studies are noted as poor quality and lack critical information regarding how they are designed, delivered, and made accessible to students. Second, there is a paucity of research exploring the effects of different delivery styles (i.e., one-on-one (1:1) vs. group) on primary (i.e., mental health symptomology reduction) and secondary (i.e., social support, social connectedness) outcomes. Importantly, group-based physical activity, in comparison to 1:1 delivered physical activity, may provide a less costly and less resource intensive intervention option, and may have unique benefits associated with exercising with others and peer-to-peer support (e.g., social support, a sense of belonging, expanded social networks). Third, the maintenance effects of a physical activity program on mental health or sustained physical activity behaviour change are largely unknown. As such, conclusions concerning achieving lasting change to mental health and sustained physical activity involvement are not possible. Lastly, limited research has explored contextual factors (e.g., intervention reach, adherence, and program satisfaction) that may influence the sustainability and scale-up of such programming opportunities. Examining contextual implementation factors is critical for optimizing physical activity intervention delivery and for facilitating wider dissemination of research findings into practice. Objectives and Hypotheses This randomized controlled trial study will assess the immediate (post-intervention, 6 weeks) and follow-up (4 weeks after post-intervention) maintenance effects of 1:1 supervised physical activity and group-based physical activity in comparison to a 10-week waitlist control group in reducing symptoms of poor mental health, supporting social well-being outcomes, and facilitating physical activity behaviour among post-secondary students experiencing poor mental health. The primary outcomes will be the immediate change in symptoms of poor mental health (anxiety symptoms, depression symptoms, psychological distress). The secondary outcomes will include follow-up change in symptoms of poor mental health (anxiety symptoms, depression symptoms, psychological distress) as well as the immediate and follow-up change in social well-being outcomes (social connectedness, social support), and physical activity behaviour. The aims of the study include: (1) examining group differences between 1:1 physical activity delivery, group-based physical activity delivery, and the 10-week waitlist control group on the primary and secondary outcomes; and (2) grounded in process evaluation recommendations, to explore contextual factors (e.g., intervention reach, adherence, and program satisfaction) that may be linked to variation in primary and secondary outcomes while offering insight for wider dissemination. It is hypothesized that there will be no group differences between 1:1 delivery and group-based delivery on the primary outcomes. It is also hypothesized that group-based delivery, in comparison to 1:1 delivery will achieve greater improvements and more favourable maintenance effects in the secondary outcomes. Lastly, it is hypothesized that in comparison to the control group, 1:1 delivery and group-based delivery will be more effective in achieving change in the primary and secondary outcomes. Study Setting The trial will be delivered in the post-secondary setting of a large metropolitan university. Importantly, post-secondary contexts offer natural advantages for large-scale implementation of physical activity programs for student mental health because they offer essential infrastructure (e.g., an integrated setting with access to sport and recreation facilities and mental health services) and practical support (e.g., experts in diverse fields) to develop, evaluate, and disseminate sustainable and scalable programs. Aligning with this perspective, the current study will employ a collaborative implementation approach, whereby the research team will work with on-campus sport and recreation professionals (i.e., for the provision of certified coaches with standard training in behavior change coaching and physical activity delivery) and mental health professionals in the post-secondary community (i.e., for program design, recruitment and implementation, and evaluation). In addition, purposeful efforts (e.g., through advocating for targeted referrals to the program and delivering targeted information sessions) will be made to promote the program among professionals (e.g., accessibility services, student-life services, health and wellness services) involved with providing mental health support or referrals to on-campus support services- an important approach for facilitating collaboration across disciplines and sectors in the campus community. Participant Timeline The university research ethics board (REB) has approved this study (protocol # 00045228). Students who meet eligibility and who have provided informed consent will be contacted to schedule an intake session with a program coordinator for the trial. Students who do not meet eligibility will be notified via email by the program coordinator and will be provided with a mental health resource sheet outlining alternative health and wellness programs and resources available to participate in. Intake sessions will be scheduled in-person in a private research space conveniently located in the campus athletics and recreation centre. During the intake session, participants will complete the baseline assessment (T1), and randomization will be conducted. Following completion of the intake session, participants in the experimental arms will complete the 6-week physical activity program (either 1:1 physical activity delivery or group-based physical activity delivery). In the experimental arms and control condition, study outcomes will be assessed at baseline (T1), 6-weeks post baseline (T2), and at 1-month follow-up (T3). Sample Size A 3 (group, individual, control) by 3 (T1, T2, T3) repeated measures design would require 25 participants per group assuming a moderate effect size of .30, a power level of .80, an alpha of .05, and expected correlations between timepoints of r = .50. To account for a loss to follow-up rate of 25%, the final targeted sample size is 93 post-secondary students. Participants will be randomly assigned to equal groups of approximately 31 students. Recruitment Purposive and snowball sampling procedures will be used to recruit post-secondary students who are physically inactive and experiencing poor mental health. Post-secondary students will be recruited and referred to the intervention through the team's research and professional networks (e.g., health and wellness and student support services; student life listservs; campus mental health listservs; the research team's social media platforms including Twitter and Instagram). Digital recruitment materials (including email scripts and poster advertisements) outlining the purpose of the intervention, intervention procedures, eligibility criteria, and a link to the screening questionnaire will be shared. The screening questionnaire will be administered through REDCap and allow participants to "sign up" up for the intervention through providing their email address and completing several screening questions to confirm eligibility. The program coordinator will contact eligible participants through their provided email address to confirm involvement in the study and to schedule an intake meeting. Data Collection Methods Statistical Methods Preliminary analyses will include descriptive statistics (including mean scores for study variables, standard deviations, frequency counts for categorical variables and bivariate correlations) to examine the relationships between study variables and to describe participant characteristics. A 3 (group, individual, control) by 3 (T1, T2, T3) repeated measures ANOVA will be used to examine whether there are group differences between 1:1 physical activity delivery, group-based physical activity delivery, and the 10-week waitlist control group on the primary and secondary outcomes. Lastly, the implementation process evaluation outcomes will be assessed analyzing the responses to the closed-ended and open-ended questions. Closed-ended questions will be analyzed using descriptive statistics and open-ended questions will be analyzed using inductive thematic analysis. Methods Monitoring Harms There are minimal risks or harms associated with participating in the research trial. Nonetheless, the current sample represents a population with relevant group vulnerability due to self-reported mental health concerns. There are also inherent risks associated with engaging in physical activity. First, it is possible that the self-report assessments may provoke negative emotions or may elicit uncomfortable thoughts and/or feelings. To mitigate emotional risks, participants will be informed of their right to not answer questions they feel uncomfortable answering, and all participants will be provided with a mental health resource sheet following completion of the intake meeting. Participants will also be informed of their right to withdraw from the trial without any penalty to their involvement in the 6-week physical activity intervention. Second, physical risks are rare but include cardiac events and musculoskeletal injuries. To reduce the risk of injury, the physical activity sessions will be delivered by certified sport and recreation coaches who have received standard training in behaviour change coaching and physical activity program delivery. Participants will also receive clearance for physical activity engagement using the PAR-Q+ and will be informed to refrain from engaging in any physical activity causing sharp pain, nausea, dizziness, or light-headedness. Bi-weekly meetings with the research team and sport and recreation coaches to mitigate any risks or concerns for participant vulnerability throughout the duration of the study will be held. Ethics and Dissemination Protocol Amendments Protocol amendments, including but not limited to changes in the study objectives, the eligibility criteria, samples size, the outcomes, or statistical analyses will be submitted to appropriate REB review. Substantive changes will also be documented as amendments to the published study protocol and to the trial registry. Confidentiality All information collected for this trial will be kept strictly confidential. The information will be stored electronically in secure, password-protected folders only accessible to members of the research team. All data will be collected through a secure online data capture program (REDCap), where identifying information (i.e., email address, participant name) will be removed prior to data analysis. Data will be coded by participant ID and presented as aggregate-level data to maintain confidentiality and anonymity of the data.

Major depression is a major societal challenge worldwide and a substantial proportion of patients do not attain remission. Major depressive disorder (MDD) bears several key neurobiological similarities with Alzheimer's Disease, namely cognitive deficits, impaired neuroplasticity, neurodegeneration, and neuroinflammation. Inducing neuroplasticity and reducing neuroinflammation are thought to be key cellular targets in the treatment of MDD. However, 40 Hz light stimulation research in the context of MDD is limited. In this double-blinded, randomized placebo-controlled trial the primary objective is to investigate the antidepressant effect of a non-invasive neurostimulation therapy using a 40 Hz masked flickering light. This study utilizes a novel way of masking light by alternating the spectral composition of white light, resulting in the flicker unnoticeable to human perception. The primary outcome measure of this study is the estimated difference in the Hamilton Depression Rating sub-scale (HAM-D6) scores between groups at week 6. Furthermore, investigators want to assess whether 40 Hz masked flickering light therapy produces a similar early shift in neural and cognitive response to emotional information seen with antidepressant therapy and whether this predicts treatment efficacy. Suicidal ideation, sleep patterns, and quality of life will be also investigated in order to evaluate the 40 Hz masked flickering light stimulation effects on other symptoms of depression. Explorative analysis of the EEG data will be performed from baseline to week 6 for the further development and validation of EEG-based biomarkers. A total of 60 participants will be enrolled for a six weeks treatment period followed by a two weeks follow-up period. Participants will be recruited from a psychotherapeutic outpatient unit. Medication should be unchanged for the last 4 weeks and during the study period.

SAMPLE Inward patients at Klinikum rechts der Isar, Munich, Germany diagnosed with schizophrenia (F20) or a schizoaffective disorder (F25) will be recruited. Treating physicians will screen and pre-select patients who are primarily affected by negative symptoms and on stable medication and/or psychotherapy (treatment as usual) throughout the study period. The target sample size for this pilot is at least N = 10 patients who undergo the experimental study protocol, and an equal number of patients who only complete the scales as a treatment-as-usual control group. PROTOCOL - EXPERIMENTAL GROUP The protocol for the experimental group will be as follows. After written informed consent was obtained by their treating physician, patients will undergo session 0 for pre-tests five to one day(s) before the first stimulation session. For a fair comparison with the post-tests in the last session, patients will be asked not to drink coffee in the three hours beforehand, to rest at the lab for one hour, and then to complete the mood and cognition scales (PANAS and THINC-IT). The psychiatric symptom assessment (PANSS) will be carried out by their treating physician before the first stimulation in session 1. The stimulation protocol will take place the week after, from Monday to Friday, at approximately the same time of day as session 0. Patients should again avoid consuming coffee three hours before each session start, to facilitate sleep. In session 1 (Monday), the EEG will first be set up. The session will start with a five-minute resting-state EEG recording; then, patients will lay down and undergo the visual stimulation protocol with their eyes closed for one hour. They will be encouraged to relax and fall asleep during this time. Afterward, we will inquire about adverse events and the EEG will be removed. In sessions 2 to 4 (Tuesday to Thursday), no EEG will be recorded. Patients will undergo one hour of visual stimulation and subsequently be asked about adverse events in the same way as in session 1. In the last session 5, the protocol will be the same as in session 1, including EEG, five minutes of resting-state recording, and one hour of visual stimulation. Afterward, as in session 0, patients will also complete the mood and cognition scales (PANAS and THINC-IT). The psychiatric symptom assessment (PANSS) will be carried out by their treating physician zero to three days after the last stimulation session. PROTOCOL - CONTROL GROUP As for the control group, after written informed consent was obtained by their treating physician, patients will undergo session 0 analogously to the experimental group for the pre-tests. This procedure will be repeated 7-10 days later for the post-tests. VISUAL STIMULATION Visual stimulation parameters will be analogous to a previous study (Hainke et al., 2025). A customized sleep mask with inbuilt LEDs externally linked to a microcontroller will be used to deliver visual stimuli. Its high-wavelength LEDs with a narrow spectral peak at 605 nm and an illuminance of 80 lux will flicker at 40 Hz in a square wave pattern at a 50 % duty cycle. Light will be faded in at the beginning and out at the end for 10 seconds, respectively. Patients will be asked to keep their eyes closed and encouraged to fall asleep for the full stimulation duration of 60 minutes. After every stimulation session, the experimenter will verbally inquire about adverse events, by asking the patient: "Have you experienced any undesired effects during or after the stimulation?". If the patient answers yes, they will be asked to describe the adverse event and then rate its severity as mild, moderate or severe and whether it was unlikely, likely or certainly related to the stimulation. For the resting-state measurement, the LEDs will be flickering at 40 Hz as during the stimulation, but they will be covered with black tape ("blackout"). This controls for the possibility of electrical interference from the mask on EEG data (Hainke et al., 2025). Here, patients will remain awake. EEG SETUP EEG will be measured in the experimental group at sessions 1 and 5 using the Neurofax system at the clinic's sleep laboratory, supported by Polaris.One software (Nihon Kohden Europe GmbH, Rosbach v.d.H., Germany). The sampling rate will be 1000 Hz. Gold cup electrodes will be positioned at A1, A2 (mastoids reference), FpZ (ground), left EOG, left EMG, C3, C4, O1, Oz, O2, PO3, POz, and PO4. Sleep scoring will be performed automatedly and offline using the Python library YASA based on the C4, EOG, and EMG electrodes, and participants' sex and age (Vallat \& Walker, 2021). EEG PROCESSING Data will be pre-processed using MNE Python as in Hainke et al. (2025): Band-pass filtering (0.16-300 Hz) Bad channel rejection by visual inspection Electrode averaging by Region of Interest: central (C3, C4) and occipital (O1, Oz, O2, PO3, POz, PO4) Re-referencing to the mastoid average (A1, A2) Dividing data into 30-second epochs Bad epoch rejection (\<50% sleep scoring algorithm certainty or stimulation duration \<25 seconds) For frequency domain analyses, epochs with a peak to peak amplitude \> 1 mV will be rejected. All 30-s epochs will be subjected to a Fast-Fourier Transform using a Hamming window to obtain the Power Spectral Density per epoch. For time domain analyses, data will be further divided into 25 ms segments length of one cycle of a 40 Hz oscillation); segments with a peak-to-peak amplitude \>100 μV will be rejected. 30-s epochs and 25-ms segments will be averaged by region of interest (central / occipital), condition (blackout / stimulation), session (1 / 5), and state (awake / light sleep / deep sleep). Light sleep is defined as NREM1 and NREM2; deep sleep is defined as NREM3. EEG OUTCOMES The two resulting EEG outcomes describe the Steady-State Visually Evoked Potentials (SSVEPs), i.e., the magnitude of the neuronal response to 40 Hz visual stimulation, from complementary perspectives. EEG signals can be interpreted in the time domain or the frequency domain; analysing both allows for maximal information gain about underlying neuronal processes (Hainke et al., 2025). In the time domain, SSVEP magnitude is quantified as the peak-to-peak amplitude of the 25-ms segment average in microvolts. In the frequency domain, SSVEP magnitude is quantified as the signal-to-noise ratio of power at 40 Hz, i.e., the power spectral density value at 40 Hz in dB divided by the surrounding values \[38 to 39.5 Hz\] + \[40.5 to 42 Hz\] in dB. COGNITIVE \& PSYCHIATRIC OUTCOMES The following scales will be completed by both the experimental and control group patients, in the respective first and last session. Cognition will be assessed with the THINC-integrated tool test battery (THINC-IT; Harrison et al., 2018), presented on a Windows laptop. It has previously been used to assess cognition in schizophrenia (Szmyd et al., 2023) and has five components: Spotter (Choice Reaction Time), Symbol Check (1-back test), Trails (Trails Making Test B), Codebreaker (Digit Symbol Substitution Test), and a self-reported cognitive function questionnaire (5-item Perceived Deficit Questionnaire). Mood will be measured with the Positive And Negative Affect Schedule (PANAS; Watson et al., 1988). The Positive and Negative Syndrome Scale (PANSS; Kay et al., 1987) will be administered by a trained physician to quantify schizophrenia-related psychiatric symptoms. An interim analysis will be conducted when a sample of 10 patients in the experimental group has been reached.

Major depressive disorder (MDD) has a lifetime prevalence of over 16% and is associated with reduced work productivity, disability, increased mortality, and increased rates of suicide attempts and completed suicides. Unfortunately, \~34% fail to respond to standard ADs (ADs). Environmental and patient-level factors that increase the risk of MDD could pinpoint novel mechanisms underlying the disorder. One such factor may be relative hypoxia. Persons with hypoxic medical conditions, such as asthma and chronic obstructive pulmonary disease, are at higher risk of depression and suicide compared to those with other chronic medical conditions. Smoking also promotes hypoxia and is linked to increased risks of suicide and depression. Of special relevance to this study, living at high altitude produces relative hypoxia even after months, and is linked to increased risks of suicide and depression. Hypoxia could contribute to MDD in at least two ways. First, brain bioenergetics are altered in both hypoxia and MDD. Hypoxia reduces several neurochemical markers of brain activity, including phosphocreatine (PCr) and n-acetylaspartate (NAA), and alters mitochondrial dynamics in the hippocampus. Proton magnetic resonance spectroscopy (1H-MRS) shows that high-altitude residents have altered whole brain pH and reduced inorganic phosphate to total phosphate (tP) ratios compared to persons dwelling at sea-level. In depressed patients, phosphorus MRS (31P-MRS) shows reduced nucleotide triphosphate (NTP) concentrations and decreased PCr concentrations; AD response is associated with increases in PCr and NTP. Hypoxia could also promote MDD by altering serotonin (5-HT) production. Chronic hypoxia reduces 5-HT in the forebrain and brainstem in rodents. The conversion of tryptophan to 5-hydroxytryptophan (5-HTP) by tryptophan hydroxylase is oxygen-dependent and slowed by hypoxia. Animal studies have shown that selective serotonin reuptake inhibitors (SSRIs) are not as effective at altitude, possibly because of inadequate 5-HT production. Reductions in 5-HT synthesis and inefficiencies in bioenergetics could both contribute to altered brain functional connectivity. MDD may disrupt cortical emotion regulation, and resting state functional connectivity (fcMRI) studies suggest that depression involves reduced connectivity between frontal cortical regions and the amygdala, while AD response correlates with normalization of those connections. Alterations in connectivity associated with AD response are correlated with changes in brain metabolites, suggesting a link to brain bioenergetics. This suggests two natural supplements as interventions for depression. Oral creatine monohydrate (Cr) could improve bioenergetics in MDD, as Cr alters brain tCr, PCr, and NTP levels. Moreover, Cr produces improvements in mood correlated with normalization of PCr levels and structural connectivity. Alterations in 5-HT synthesis due to hypoxia could be rectified by 5-HTP, as its conversion to 5-HT is not oxygen-dependent. 5-HTP elevates brain 5-HT levels and has AD efficacy in clinical trials. The proposed study is a two-phase, three-armed trial to evaluate whether SSRI/SNRI augmentation with the supplements Cr, 5-HTP, or their combination (5-HTP+Cr) can enhance AD response in treatment-resistant MDD. In the R61 phase, the study will assess the ability of the interventions to alter biological signatures associated with depression, as measured by 31P-MRS, fcMRI, and changes in whole blood 5-HT. In the R33 phase, the study will attempt to replicate the above findings with dose variation and evaluate their correlation with clinical outcomes. The study will have the following aims: Aim 1. Replicate the clinically meaningful changes in biological signatures (PCr:tP ratios as measured by 31P-MRS, sgACC connectivity as measured by fcMRI, and whole blood serotonin) demonstrated in the R61 phase, following the decision rule noted above. Aim 2. Demonstrate that the changes in each of the above markers that is carried over from the R61 phase are correlated with changes in depression as measured by the 17-item Hamilton Depression Rating Scale, which would be studied in a subsequent efficacy trial. Study results will help elucidate the potential efficacy of a novel combination of nutritional supplements in persons with MDD, given strong epidemiologic and physiologic evidence suggesting that relative hypoxia can contribute to depression through alterations in brain bioenergetics and 5-HT synthesis. Target engagement will be indicated by improvements in functional connectivity and frontal cortical energy metabolism.

The revolution in rheumatoid arthritis (RA) therapeutics has been transformative for many patient outcomes. Yet most patients continue to experience life disabling pain. Strikingly, even those who achieve full disease remission with state-of-the-art anti-tumour necrosis factor (TNF) treatments report substantially higher levels of pain when compared to the general population. Such disconnect presents one of the greatest contemporary challenges to the care of patients with RA. Considering the ongoing excess burden of pain in this patient population, trials of Janus kinase inhibitors (JAKinibs) present welcome data. JAKinibs deliver superior pain improvements in comparison to those receiving anti-TNF therapy. Of note, the majority of this effect has not been fully explained by markers of peripheral inflammation and remains to be understood. Moreover, JAKinibs appear to offer rapid analgesic benefit. Traditional DMARDS and modern biologics commonly take several weeks to bring relief whereas JAKinibs, such as filgotinib, begin to improve pain as early as 2 weeks, even before the observed attenuation of peripheral clinical inflammation. In light of these clinical observations, the investigators believe that RA is a mixed pain state i.e., pain pathways exist in addition to established peripheral inflammatory nociceptive mechanisms. In particular, the central nervous system (CNS) may have an important role in determining RA pain. Recently our group were the first to delineate distinct neurobiological pain signatures in the brains of RA patients by employing functional connectivity magnetic resonance imaging (fcMRI) - a recent adaptation of functional MRI data that examines the synchrony of neural activity which modulates the efficiency and extent of neuronal transmission between brain regions. Specifically, the investigators identified and replicated two distinct pain signatures: 1. enhanced functional connectivity between the Default Mode Network (DMN) and insula, which was unrelated to levels of peripheral inflammation but, intriguingly, is an established neurobiological marker of fibromyalgia (the prototypical CNS pain sensitization disorder, and 2. enhanced functional connectivity between the Dorsal Attention Network (DAN) and the left inferior parietal lobule (LIPL) which was related to levels of peripheral inflammation. Pre-clinical experiments have not only implicated the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway with peripheral immune system functioning but also the brain. In the CNS, this pathway promotes gene expression associated with inflammation which in turn generates pro-nociceptive cytokines. However, there is now also emerging evidence to support the pathway's direct role in synaptic transmission and neurotransmitter receptor modulation. Specifically, the JAK-STAT pathway appears important in N-methyl-d-aspartate (NMDA) related synaptic plasticity - a ubiquitous glutamate receptor of the human brain. Their induction is selectively blocked by JAK inhibitors. Increases in glutamate and subsequent binding to NMDA receptors cause chaotic and incoherent neuronal functional activity. Human studies of fibromyalgia have consistently evidenced both elevated glutamate levels within the insula and dysfunctional neural connectivity. Moreover, fibromyalgia pharmacotherapy (pregablin), considered to reduce neural glutamate, rectifies both insular glutamate and brain functional connectivity (DMN-insula). JAK inhibition (JAKi) may facilitate the reduction of glutamate-NMDA binding and ultimately pain alleviation by normalising the functional activity of these same neural connections.

Antidepressants typically decrease amygdala response to negative stimuli while enhancing response to positive stimuli, but it is unclear at a mechanistic level how increasing serotonin would have this opposing effect. One hypothesis is that although positive and negative cues activate the same area at a global level, more detailed characterisation may reveal key differences in processing in terms of localisation or response function. Until now, due to methodological restriction, the amygdala has been mostly studied as a single structure. It is however known that it consists of a number of subfields, which are likely to play distinct roles in emotional processing. In this study the investigators will make use of 7T fMRI scanning to study the effects of a single dose (20 mg) of citalopram (selective serotonin reuptake inhibitor, SSRI) on these subfields during emotional face processing, allowing greater precision to identify underlying neural mechanisms underpinning psychological effects.

Study Description: This study will examine whether phosphodiesterase 4B (PDE4B) can be accurately quantified in the human brain and whether it is reduced in the brain of individuals with major depressive disorder (MDD). Objectives: Primary Objective: To determine whether PDE4B is reduced in the brains of individuals with MDD experiencing a major depressive episode (MDE). Secondary Objectives: To determine the optimal length of scanning and the retest variability and reliability of \[18F\]PF-06445974, and whether PDE4B binding correlates with clinical rating scales. Endpoints: Primary Endpoint: measurement of PDE4B density (distribution volume VT) in the brains of individuals with MDD compared to healthy volunteers Secondary endpoints: 1. To determine the optimal length for PDE4B scans with \[18F\]PF-06445974 PET scans in healthy volunteers 2. To measure whole-brain VT of PDE4B in a retest setting. 3. To assess the relationship between clinical rating scales and PDE4B binding. 4. To measure the blockade of PDE4B radioligand binding in brain after oral administration of apremilast.

The investigators will conduct a pilot randomized controlled trial to evaluate the preliminary effectiveness of an adapted community health worker (CWH)-delivered positive affect counselling intervention delivered remotely via mHealth. The adapted intervention will include CHW-delivered positive affect skill-based counseling accessible through video call that will be accessible through the mHealth app. The CHW will conduct approximately 5 weekly individual 60-minute counseling sessions via a secure video call feature. If the participant does not have symptomatic improvement, the CHW will refer the participant to a licensed mental health professional. Participants will be randomized to receive access to the counselling intervention that also includes modified features of the mHealth app with increased mental health resources (intervention arm) or to current standard of mental health care that includes the unmodified version of the app (control arm). Participants allocated to the intervention arm will receive the counseling intervention approximately weekly for 5 weeks. The study will continue to abstract data from participants' EMR and mHealth app for approximately 6 months after enrollment. To assess preliminary effectiveness, the investigators will analyze differences by condition in anxiety and depression (primary outcome). Informed consent will be obtained prior to study participation.