For many, the course of major depressive disorder (MDD) is recurrent, with periods of remission between major depressive episodes (MDEs); those in remission are known to be at elevated risk of future MDEs. A common and distressing symptom of MDD is overgeneralised self-blame, and this also persists into remission. In order to study the involvement of self-blame in vulnerability to MDD, a large cohort of participants was recruited: a group with remitted MDD (rMDD) and a matched healthy control (HC) group with no personal or family history of MDD. Participants completed electrophysiological and neuropsychological tasks. The rMDD group also completed a 14-month follow-up period, during which symptoms were monitored at intervals; this was to study the predictive effects of electrophysiological and neuropsychological variables, with a view to development of a biomarker with predictive value. The main method was electroencephalography (EEG), chosen for its high temporal resolution in comparison to a commonly used technique, functional magnetic resonance imaging (fMRI). On a practical level, EEG is also more cost effective and widely available, making it more suitable for future clinical transfer of any biomarker developed. A task previously used in fMRI was adapted for EEG; in this task, short sentences designed to evoke negative feelings related to the self and others were presented. The theta signal was abnormally sustained over time during self-blame in the rMDD group relative to the HC group. Given the involvement of theta in temporal binding, this may represent a correlate of dysfunction within the neural network underpinning self-blaming emotions. Correlation of sustained theta with separately collected fMRI data indicated the dorsolateral prefrontal cortex (dlPFC) was involved in this network. In a source analysis of the EEG data, the dlPFC was identified again; it showed reduced activation in the rMDD group relative to the HC group during other-blame. In summary, activation of the dlPFC appears to be adaptive in both self- and other-blame, as the HC group showed higher activation than the rMDD group; further work is required to confirm the clinical relevance of this. For a separate study of memory overgeneralisation, a known feature of MDD, a novel associative memory task was designed. A loss of bias towards remembering positive memories was found in a subgroup of the rMDD cohort with early life stress (ELS). This reduced positive bias correlated with the number of past MDEs, indicating that the cumulative effect of MDEs reactivating early traumatic memories leads to selective loss of positive memory bias. In summary, although no electrophysiological or neurocognitive predictive markers of recurrence risk were found, clear effects were seen in the cross-sectional results. Importantly, EEG was also validated as a technique for detecting self-blame-selective neural correlates of depression vulnerability. There were clear effects in the temporal domain, which highlight the benefits of EEG above other imaging techniques. However, the sources identified did not correlate with parallel fMRI work, so further work is required to understand the temporal dynamics of these sources. This research provides a platform from which future EEG investigations can develop.

Major depressive disorder (MDD) is primarily characterized by prevalent sadness and anhedonia. Laboratory studies find that depression is characterized by reduced reactivity across emotional contexts, while a few studies using naturalistic designs find that depressed people show normative reactivity to negative life events and mood brightening in response to positive events. The current study was an investigation of emotional reactivity in depression through the use of experimental and naturalistic designs. This allowed for an investigation of sources of lab-life discrepancies in emotional functioning in depression, including negative affect (NA) regulation. We examined experiential reactivity across contexts and types of stimuli in 41 currently depressed (MDD) and 33 healthy controls. Results showed that overall, our groups were largely indistinguishable in NA and PA reactivity magnitude across contexts and types of stimuli, with some exceptions. When looking at sadness reactivity specifically, despite higher sadness at baseline, MDDs reported in the lab similar decreases in sadness to a humorous film as controls. In daily life, MDDs reported larger decreases in sadness in response to positive daily events, yet indistinguishable reactivity to a structured humorous film relative to controls. Analyses using HLM showed that NA response to the happy film in the acceptance condition was marginally predictive of overall NA in daily life but not of NA reactivity to positive events. Findings suggest group differences in emotional reactivity vary across contexts and stimuli, however these variations are dependent on specificity of emotion. Current results possibly highlight increased flexibility during experience of positive events in daily life in depression. Acceptance of NA may have implications for the experience of overall negative mood in depression.

Ketamine is a non-competitive NMDA antagonist that has been shown to have antidepressant properties both clinically as well as in preclinical studies when administered at a subanesthetic dose. In vivo electrophysiological recordings were carried in male Sprague Dawley rats 30 minutes following ketamine administration (10 mg/kg) to first assess its effects on monoaminergic firing. Whilst no change in the firing activity of serotonin (5-HT) neurons was observed in the dorsal raphe nucleus (DRN), an increase in the firing activity was observed for dopamine (DA) and noradrenergic (NE) neurons in the ventral tegmental area (VTA) and locus coeruleus (LC), respectively. The effect of ketamine on these electrophysiological parameters was prevented by pre-administration of the AMPA receptor antagonist NBQX 10 minutes prior to ketamine administration. In a second series of experiments, an increase in AMPA-evoked response was observed within 30 minutes in the CA3 layer of the hippocampus (HPC) following acute ketamine administration. These findings suggest that acute ketamine administration produces a prompt enhancement of AMPA transmission in the forebrain and also results in increased catecholaminergic activity. These effects may play a crucial role in the rapid antidepressant effects of ketamine observed shortly following its infusion in the clinic.

Applying pharmacoeconomic methods were compared two selected treatments of depressive disorder. Markov model was created to evaluate cost-effectiveness of the two strategies. Knowledge from the clinical practice and the clinical research findings of the author are linked with pharmacoeconomic techniques into a multidisciplinary complex. The proposed sequential therapy uses a prediction of antidepressant response by utilizing of recent quantitative electroencephalography methods. Sequential therapy is more cost-effective compared with the conventional therapeutic strategy according to clinical guidelines. The results and limitations of the study are discussed at the conclusion from clinical and economic perspective.

Over 10 million people are affected by major depressive disorder (MDD) in the U.S. annually. Unfortunately, about 1/3 of these people do not achieve adequate remission of symptoms with current antidepressant drugs. It is expected that an improved understanding of the pathobiology of depression will result in the development of more effective antidepressant treatments. Research by this lab in recent years has provided evidence of elevated DNA damage in brain white matter in MDD, discovered by studying brain tissues from human brain donors that had an active diagnosis of MDD at the time of death and age-matched control donors who had no psychiatric illness. Accompanying this DNA damage was an elevation of gene expression of DNA base excision repair enzymes in white matter oligodendrocytes, a major cell type in brain white matter. In addition, gene expression of antioxidant genes in these oligodendrocytes was significantly lower in MDD than in control donors, suggesting that these cells were especially susceptible to the damaging effects of oxidative stress in MDD. This initial data was generated by measuring gene expressions in oligodendrocytes captured from two specific regions of white matter in the brain, the frontal cortex, and amygdala. In the present study, we designed experiments to determine whether these effects are found in oligodendrocytes in other areas of the brain in MDD and to determine whether another cell type in the brain, neurons, are similarly affected. Towards these aims, oligodendrocytes from two other brain regions (occipital cortical white matter and brainstem locus coeruleus) were captured by laser microdissection from MDD and control donors. In addition, CA1 pyramidal neurons were captured from the anterior hippocampus of MDD and control donors. We chose to specifically study hippocampal CA1 pyramidal neurons because these neurons are normally sensitive to oxidative stress, and reasoned that these cells would be among brain neurons most likely affected by conditions of elevated oxidative stress in MDD. Approximately 500 cells were captured from each brain area using immunohistochemically-guided laser capture microdissection. RNA isolated from these cells was converted to cDNA by reverse transcription and subjected to quantitative polymerase chain reactions (PCR). Statistically significant reductions in antioxidant gene expression was observed in oligodendrocytes from MDD donors as compared to control donors regardless of the brain area from which the cells were captured. In contrast, no significant changes in antioxidant gene expression were observed in CA1 pyramidal neurons from MDD donors. Additionally in contrast to findings in oligodendrocytes, levels of gene expression of the DNA repair enzyme, poly(ADP-ribose) polymerase 1 (PARP1) in hippocampal CA1 pyramidal neurons from MDD donors was similar to that from control donors. These findings demonstrate that pathological DNA damage and repair mechanisms occur in brain oligodendrocytes throughout the brain, and similar mechanisms do not appear to affect hippocampal neurons. A better understanding of the cellular systems engaged by oxidative damage to oligodendrocytes in MDD has the potential to lead to the identification of unique targets for the development of novel antidepressant drugs.

Indiana University-Purdue University Indianapolis (IUPUI) / Major Depressive Disorder is a prevalent and pervasive problem in the United States, and this mental disorder disproportionately affects adolescents of color. In particular, there is little research understanding how Hispanic/Latinx adolescents utilize and engage with mental health services, such as psychotherapy, to reduce their symptoms of depression, including factors that are positively and negatively related to engagement. As such, the aims of this study were to understand whether there were any relationships between presenting characteristics of adolescents seeking therapy for depression and their subsequent engagement with therapeutic services, with a focus on analyses examining trends in Hispanic/Latinx adolescents. To investigate these aims, we utilized data from a pilot study in which adolescents (n=42) received a mind-body intervention for depression called Mind-Body Skills Groups. We examined possible relationships between depression severity, age, Hispanic/Latinx background, and their interactions with engagement, as measured by attendance rates, self-reported motivation, and at-home skills practice. We hypothesized that high depression severity, high age, and being Hispanic/Latinx would all negatively influence engagement; we also hypothesized the depression-engagement and age-engagement relationships would be moderated by Hispanic/Latinx background. Results revealed initial relationships between lower age and being Hispanic/Latinx with higher attendance rates; depression severity was not related to attendance. When these relationships were further analyzed using hierarchical regression, no significant relationships between predictor and outcomes variables, as well as their interactions, were discovered. In an exploratory analysis investigating factors of adolescent depression using subscales, greater interpersonal problems predicted higher attendance rates. Results are interpreted relative to limitations of the small sample size and possible measurement concerns within this study, including a discussion of possible ways to improve related studies on Hispanic/Latinx youth in the future.

Background: Norepinephrine and glutamate are among several neurotransmitters implicated in the neuropathology of major depressive disorder (MDD). Glia deficits have also been demonstrated in people with MDD, and glia are critical modulators of central glutamatergic transmission. We studied glia in men with MDD in the region of the brain (locus coeruleus; LC) where noradrenergic neuronal cell bodies reside and receive glutamatergic input. Methods: The expression of 3 glutamate-related genes (SLC1A3, SLC1A2, GLUL) concentrated in glia and a glia gene (GFAP) were measured in postmortem tissues from men with MDD and from paired psychiatrically healthy controls. Initial gene expression analysis of RNA isolated from homogenized tissue (n = 9-10 pairs) containing the LC were followed by detailed analysis of gene expressions in astrocytes and oligodendrocytes (n = 6-7 pairs) laser captured from the LC region. We assessed protein changes in GFAP using immunohistochemistry and immunoblotting (n = 7-14 pairs). Results: Astrocytes, but not oligodendrocytes, demonstrated robust reductions in the expression of SLC1A3 and SLC1A2, whereas GLUL expression was unchanged. GFAP expression was lower in astrocytes, and we confirmed reduced GFAP protein in the LC using immunostaining methods. Limitations: Reduced expression of protein products of SLC1A3 and SLC1A2 could not be confirmed because of insufficient amounts of LC tissue for these assays. Whether gene expression abnormalities were associated with only MDD and not with suicide could not be confirmed because most of the decedents who had MDD died by suicide. Conclusion: Major depressive disorder is associated with unhealthy astrocytes in the noradrenergic LC, characterized here by a reduction in astrocyte glutamate transporter expression. These findings suggest that increased glutamatergic activity in the LC occurs in men with MDD.

The current study examined the relationships between Major Depressive Disorder, negative life events, perceived parenting style, perceived family environment and Disruptive Behavior Disorders, specifically Conduct Disorder, Oppositional Defiant Disorder, and Attention-Deficit/Hyperactivity Disorder, in adolescent participants, (N = 381). Results indicated that those factors, with the exception of authoritarian parenting, correlated positively with symptoms consistent with Disruptive Behavior Disorders. In addition, the overall effect of those factors predicted symptoms consistent with Disruptive Behavior Disorders more strongly than each risk factor in isolation. In conclusion, results indicated that negative life events and symptoms consistent with Major Depressive Disorder mediated the effects of perceived parenting and perceived family environment on symptoms consistent with Disruptive Behavior Disorders.

Major depression disorder is increasing globally, causing great personal suffering and economic burdens to society. Current antidepressant medications are not sufficiently able to treat all cases of depression and are often associated with troubling side effects. There is a great need for the development of novel treatments, and classic psychedelic drugs are currently being investigated with new interest. The legal status has hindered research, but promising results from pioneering studies on the antidepressant effect of psilocybin have recently given psilocybin breakthrough therapy status, allowing further research to occur more freely. This systematic review aims to investigate the literature available on psilocybin’s effect on major depressive disorder. Five studies were selected according to set inclusion and exclusion criteria. Results are suggesting that psilocybin combined with psychological support is a fast-acting antidepressant agent, able to produce a sustained decrease in symptoms of depression with minimal side effects. However, current studies come with several limitations and further research is needed before the antidepressant effect of psilocybin can be stated as a fact.

<p> Major Depressive Disorder (MDD) is a common affective disorder associated with persistent states of negative mood and selective cognitive impairments. Fronto-temporal dysregulation in MDD patients is thought to contribute to the symptoms seen in these patients.</p> <p> Based on prior evidence of structural and functional alterations in the hippocampus (Hc) and prefrontal cortex (PFC) in MDD patients, we were interested in examining the changes in cerebral function that underlie the cognitive dysfunction seen in two different MDD populations. We studied psychotropically naïve depressed patients experiencing their first treated episode (FTE) of depression, MDD patients who had experienced multiple past treated episodes (MTE) of MDD and healthy controls.</p> <p> Two functional magnetic resonance imaging studies (fMRI) were conducted. The first study used an Hc dependent process dissociation task to examine Hc activation during recollection memory. The second fMRI study examined the activation in the PFC during reward and punishment conditions of a reversal-learning paradigm. Finally, we conducted magnetic resonance spectroscopy scans to measure levels of metabolites indicative of neuronal and glial cell integrity in the Hc of depressed patients and controls. </p> <p> We observed differing results across all three studies in our FTE and MTE depression groups. Our studies examining the Hc suggest that MTE patients have decreased activation in this region as well as corresponding memory errors during recollection memory. Additionally, these patients have smaller Hc volume and signs of increased neuronal membrane turnover. Conversely, our FTE patients displayed heightened Hc activation without memory deficits. Moreover, FTE patients had signs of increased glial cell density in the Hc without volumetric differences in this region. Our examination of reward processing revealed several health-to-illness gradients of activation in areas as the nucleus accumbens, anterior cingulate and ventral prefrontal cortices during the processing of rewards and punishers. </p> <p> These findings suggest that several regions in the brain may be sensitive to the impact of disease burden and repeated episodes of MDD. In the Hc, first treatment patients may engage in compensatory processes during the early stages of illness that are attenuated with repeated episodes of illness. Moreover, reward processing may be affected in the early course of the disorder, however with a protracted course of illness these regional alterations in activation become more pronounced.</p> / Thesis / Doctor of Philosophy (PhD)