Major Depressive Disorder - Case Study Example

Major Depressive Disorder Definition and diagnosis Major depression disorder or MDD is a common mental illness that falls into the category of mood disorders. According to the Diagnostic and Statistical Manual of Mental Disorders (DSM) IV, 2000, diagnosis of MDD is made as in table-1. Table-1: Diagnosis of MDD (Nestler et al, 2002) When a certain number of depression symptoms (as below) are reported for longer than 2 week period of time, and when the symptoms disrupt normal social and occupational functioning. Symptoms of Depression Depressed mood, irritability, low self esteem, feelings of hopelessness, worthlessness, and guilt, decreased ability to concentrate and think, decreased or increased appetite, weight loss or weight gain, insomnia or hypersomnia, low energy, fatigue, or increased agitation, decreased interest in pleasurable stimuli (e.g., sex, food, social interactions) and recurrent thoughts of death and suicide The importance of MDD lies in the fact that it causes considerable impairment in social functioning, role functioning, employment and physical health of the afflicted person (Wells et al, 1989). Experts are of the opinion that depression is actually a heterogeneous syndrome comprised of numerous diseases of distinct causes and pathophysiologies (Nestler et al, 2002). MDD is also known as clinical depression or unipolar depression. Incidence and prevalence According to the National Comorbidity Survey Replication (NCS-R), which studied the epidemiology of MDD across the United States, the prevalence of MDD for lifetime was estimated as 16.2% and that for 12-month was estimated as 6.6% (Kessler et al, 2003). There are very few studies which relate the prevalence of MDD to race or ethnicity (table-2). Table-2: Lifetime and 12 month MDD prevalence (Williams et al, 2007) Lifetime MDD prevalence in the whites was 17.9%, followed by Caribbean blacks (12.9%) and African Americans (10.4%) 12-month MDD estimates across these groups were similar Infact, severe forms of depression affect 2-5% of the US population (Nestler et al, 2002). As far as age is considered, the risk is fairly low in the younger age groups (Figure-1). While major depressive disorder can develop at any age, the median age at onset is 32 (Kessler et al, 2005). It is more prevalent in women than in men (Kessler et al, 2003). MDD is comorbid with anxiety and substance use disorders (Kessler et al, 2003). Studies have shown that MDD with anger attacks are significantly associated with increased cholesterol levels and years of smoking (Fraquas et al, 2007). Figure-1: Age related incidence of MDD (Kessker et al, 2003) Aetiology and pathogenesis MDD is a debilitating and complex psychiatric disorder that involves multiple neural circuits and genetic and non-genetic risk factors (Sahay et al, 2007). Whether environmental factors or genetic factors play a major role in the pathogenesis of MDD is still debated. Exaggerated early error-detection processes have been incriminated in the etiology and maintenance of major depressive disorder and thus such processes may then recruit excessive neural and cognitive resources that manifest as symptoms of depression (Chiu and Deldin, 2007). Neuroanatomical (physical) changes Studies have shown that there are significant changes in the brains of those animal models afflicted with psychiatric illness. These changes include differences in the sizes of specific brain regions, alterations in the morphology of subpopulations of neurons, neurochemical changes at the synaptic cleft, alterations in intracellular signalling and changes in the regulation of gene expression (Tsankova et al, 2007). The specific brain regions which have been implicated in the pathogenesis of MDD are hippocampus (Tsankova et al, 2007) which is the center for mood and memory; and prefrontal cortex/ anterior cingulated region (Schatzberg, 2002) which are centers for cognition. The pathology in these regions contributes to the somatic and cognitive symptoms of the disorder (Schatzberg, 2002). Infact, the hippocampal volumes are decreased in patients with MDD and this has been attributed to the excessive glucocorticoid activity (Schatzberg, 2002). Drevets (2000) studied neuroimaging in mood disorders and proved the association between certain symptoms of MDD like cognitive deficits, psychomotor retardation, anhedonia, and lowered mood with specific focal abnormalities of regional cerebral blood flow. He demonstrated involvement of multiple areas of the orbital and medial prefrontal cortex, the amygdala, and related parts of the striatum and thalamus in MDD. In these areas, low glial density and reduced glia/neuron ratio have been demonstrated, especially in the amygdala (Bowley et al, 2002). It has also been proved that cerebral blood flow before anti depressant therapy (ADT) increases in brain areas like right temporal gyrus, left amygdale, right anterior cingulated cortex, bilateral medial frontal gyrus, bilateral insula, lingual gyrus, right precentral gyrus and left postcentral gyrus.related with the affective and cognitive components of pain; in contrast, after ADT increases only in cognitive pain related areas (Graff et al, 2007). Hypothalamus and nucleus accumbens have also been shown to be involved in the pathogenesis (Nestler et al, 2002) and probably cause symptoms associated with appetite, sleep and circadian rhythm. The neural circuits between these pathological areas in the brain is said to contribute to the symptoms. Affectation of dopaminergic neurons in the ventral tegmental area and nucleus acumens is said to cause anhedonia and decreased motivation (Berton and Nestley, 2006). Neurochemical changes: It has been proposed that certain chemical imbalances in the brain cause clinical symptoms in MDD. These imbalances are said to occur in certain neurotransmitters like serotonin and noradrenaline. Even imbalances in dopamine have been noted in MDD (Bourin et al, 2002). Positron Emission (PET) studies have proved the relationship of altered glucose metabolism with respect to serotonin imbalances in MDD (Anderson et al, 2003). Infact, lower levels of glucose metabolism and cerebral blood flow in neocortical and subcortical regions in elderly patients with MDD has also been demonstated with PET (Kumar et al, 1993 and Sackeim et al, 1993). However, recent evidence has proved that it is the problem in information processing within neural networks, rather than changes in chemical balance that causes symptoms (Castren, 2005). Neuroendocrine changes: In prolonged conditions of stress, the levels of glucocorticoids are elevated for a long time and may damage hippocampal neurons especially the CA3 pyramidal neurons (Nestler et al, 2002). This reduces the inhibitory control of hippocampus on the Hypothalamic-Pituitary-Adrenal axis leading to further increase in glucocorticoid levels and further hippocampus damage. There may also be a component of glucocorticoid resistance related in part to impaired functioning of the glucocorticoid receptor, which, in turn, may contribute to excessive inflammation as well as hyperactivity of corticotropin releasing hormone and sympathetic nervous system pathways, which are known to contribute to a variety of diseases as well as behavioral alterations. The glucocorticoid receptor function impairment may be secondary to chronic exposure to inflammatory cytokines as may occur during chronic medical illness or chronic stress (Pace et al, 2007). At this juncture, it is worth mentioning that hypercortisolemia is not universal in depression, but among those depressed subjects with hypercortisolemia, these physiological abnormalities can disappear after successful clinical intervention (Sheps and Rozanski, 2005). Holsboer et al (2001) have further reinforced the mechanism of hippocampal neurogenesis. Other hypothesis that has been proposed to hippocampal pathology is the deficiency in neurotropic support. Neurotropic support is essential for neural growth and development and currently neurotropic factors are considered as potent regulators of plasticity and survival of adult neurons and glia (Nestler et al, 2002). Depression is also associated with stimulation of the sympathetic nervous system resulting in elevated levels of circulating plasma norepinephrine levels.  Depressed subjects generally manifest increases in resting heart rates compared with nondepressed controls (Sheps and Rozanski, 2005). Figure-2: Neuroanatomical abnormalities in major depression (Hasler et al, 2004). Figure-3: Neurochemical abnormalities in major depression (Hasler et al, 2004). Environmental factors: The environmental factors which are implicated in the etiology of depression are viral infections, reduced omega-2 fatty acids in diet, stress, reduced sleep, emotions and insults during brain development (Nestle et al, 2002) and sometimes even trivial brain injury (Rapoport et al, 2003). There are many medical conditions which contribute to the development of depression and these include endocrine disorders, collagen vascular diseases, Parkinson’s disease, head injury, certain cancers, asthma, diabetes and stroke (Nestle et al, 2002). Exposure to marijuana (Leech et al, 2006) and smoking (Gray at al, 2005) during gestation can also lead to depressive symptoms later in life. Also, mass disaster can cause MDD, especially in those who have witnessed it or have gone through it (Person et al, 2006). Genetic factors: Studies have shown that 40-50% of the risk for depression is genetic (Nestler et al, 2002). However, no single gene has been attributed to this so far probably because of the possibility of many genes involved in a complex manner (Nestler et al, 2002). Though studies have shown changes in mRNA levels in specific brain regions in both animal models and diseased human brains, no stability has been noted in these aspects (Tsankova et al, 2007). In certain families, there is preliminary evidence that recurrent, early-onset major depression is linked to a region containing the CREB1 gene (Hasler et al, 2004). CREB1 plays major roles in neuronal plasticity, cognition, and memory. Also, the intermediate levels of recurrence of depressive episodes and recurrent thoughts of death and suicide have been associated with high genetic liability of MDD and appeared to be a specific characteristic of familial MDD (Kendler et al, 1999). It has been reported that CAG repeats length and alleles distributions in the androgen receptor gene in men with MDD are different from those without MDD; hence there is a possibility that AR gene might be involved in the depressive upset in adolescents (Su et al, 2007). Epigenetic factors: Recent research has prompted the possibility of epigenetic mechanisms exerting lasting control over gene expression without altering the genetic code by means of  enzyme modifications to chromatin structure that can upregulate or downregulate gene expression in a manner that is transmissible to daughter cells and also regulate gene expression in neurons making chromatin modifications sustain within individual cells (Tsankova et al, 2007). Studies have proposed that depression in humans alters chromatin regulation of brain-derived neurotrophic factor (Tsankova et al, 2007). In the process of establishing this mechanism, the term endophyte was proposed which can be described as an internal phenotype that fills the gap between available descriptors and between the gene and the elusive disease process and therefore may help to resolve questions about etiological models (Hasler et al, 2004). The methods available to identify endophenotypes include neuropsychological, cognitive, neurophysiological, neuroanatomical, and biochemical measures as elicited in figures 2& 3. Treatment aspects The drugs which are used in the treatment of MDD are called anti-depressants. All anti-depressants act via monoamine neurotransmitters serotonin or noradrenaline. They down-regulate (decrease or desensitize) some receptors in a delayed time course, which is reflected by the time to onset of therapeutic effects (Stahl et al, 1996). Antidepressant drugs actually induce plastic changes in neuronal connectivity, which gradually lead to improvements in neuronal information processing and recovery of mood (Castren, 2005). The currently available drugs are elaborated in table-3. There are both pharmaco therapies and psychotherapies available. The efficacy of depression-targeted, time-limited psychotherapies as acute phase treatments for mild-to-moderately depressed outpatients with MDD is clear and is preferred in milder, uncomplicated, non-chronic cases. The most effective approach would be to convert medication responders into remitters with psychotherapy (Rush and Thase, 2001). Type of treatment Mode of action Examples Medication Tricyclics Selective serotonin reuptake inhibitors (SSRIs) Noradrenaline reuptake inhibitors (NRIs) Serotonin and noradrenaline reuptake inhibitors (SNRIs) Monoamine oxidase inhibitors MAOIs) Lithium Atypical antidepressants Inhibition of mixed noradrenaline and serotonin reuptake Inhibition of serotonin-selective reuptake Inhibition of noradrenaline-selective reuptake Inhibition of mixed noradrenaline and serotonin reuptake Inhibition of monoamine oxidase A (MAOA). Inhibition of MAOB does not have antidepressant effects Lithium has many molecular actions (for example, inhibition of phosphatidylinositol phosphatases, adenylyl cyclases, glycogen synthase kinase (and G proteins) but which of its actions is responsible for its antimanic and antidepressant effects is unknown Unknown. Although these drugs have purported monoamine-based mechanisms (for example, bupropion inhibits dopamine reuptake, mirtazapine is an 2-adrenergic receptor antagonist and tianeptine an activator of monoamine reuptake), these actions are not necessarily the mechanisms that underlie the drugs’ therapeutic benefit Imipramine, desipramine Fluoxetine, citalopram Atomoxetine, reboxetine Venlafaxine, duloxetine Tranylcypromine, phenelzine Bupropion, mirtazapine, tianeptine Non-medication Electroconvulsive therapy (ECT) Magnetic stimulation Vagal nerve stimulation (VNS) Psychotherapies Deep brain stimulation General brain stimulation General brain stimulation? A magnetic field is thought to affect the brain by inducing electric currents and neuronal depolarization Unknown Exact mechanism is uncertain, but is thought to involve learning new ways of coping with problems In severely ill patients, stimulation of a region of the cingulate cortex found to function abnormally in brain imaging scans reportedly has antidepressant effects84 Cognitive-behavioural therapy, interpersonal therapy Table 3: Current treatments in MDD (Bertono & Nestler,2006). Antidepressant drugs are classified according to their ability to improve monoaminergic transmission. These medications need to be given for several weeks for effectiveness and in the course, there is high potential for side effects like serotonin syndrome and over dose deaths (Kapur et al, 1992) and with all these the remission rate is only 50% (Berteno and Nestler, 2006). Many of the unwanted side effects are due to the fact that the drugs, especially the tricyclic anti-depressants and monoamine oxidase inhibitors also block histaminic, cholinergic, and alpha1-adrenergic receptor sites which lead to side effects such as weight gain, dry mouth, constipation, drowsiness, and dizziness (Feighner, 1999). Also, they need to be continued for about 1 to 5 years after remission has been achieved (Nemeroff, 1994). Hence it can be said that there is a great need for faster acting, safer and more effective treatments as far as depression is concerned (Berteno and Nestler, 2006). The newer antidepressants are no more powerful than older types, but they have fewer side effects and are better tolerated and safer (Morrant, 1997). The newer ones are either selective serotonin reuptake inhibitors, selective nor-epinephrine reuptake inhibitors or both (Westenberg, 1999 and Bourin, 2002). Research is on the way to discover drugs which act via non-monoamine systems. However there is a struggle to get funds and animal models for this research. Also, so far no depression-like syndrome that fully capitulates the human form of depression has been established in animal models (Berteno and Nestler, 2006). Other new drugs which are being considered are, opioid receptor antagonists, CB-I cannabinoid receptor agonists or antagonists, cytokines, melatonin receptor agonists, galanin, neuropeptide Y, histone deacetylase inhibitors (Berteno and Nestler, 2006). Studies have shown that psychostimulants also have a role in the treatment of certain categories of MDD (Warneke, 1990). Emerging treatments Though monoamine reuptake inhibitors are the most widely used antidepressants, their delayed onset of action and considerable non-response rate remain problematic. Hence there is a dire need for novel antidepressants (table-4). Table-4: Novel antidepressant compounds (Bosker, 2004) Categorized into four groups depending on their target monoamine receptors non-monoamine receptors neuropeptide receptors hormone receptors Other possible targets which have not been the subject of clinical trials include components of post-receptor intracellular processes and elements of the immune system (Bosker, 2004). Studies are being done to look in to the possibility of using glucocorticoid antagonists like mifepristone to treat MDD (Nihalani et al, 2007). The differences in response to treatment to selective serotonin reuptake inhibitors have been attributed to variations in the serotonin transporter gene, SLC6A4. Studies have indeed shown that performing genetic testing before prescribing antidepressant treatment may lead to greater numbers of patients experiencing remission early in treatment (Smits at al, 2007). Neurikinin-1 receptor antagonists have been known for their analgesic effects. Animal experiments and early clinical trials have showed promise as novel antidepressants. Clinical trials are on the way to introduce them as novel antidepressants (Hafizi et al, 2007). Conclusion MDD is a common mood disorder. It is an incapacitating disease which needs appropriate treatment. The prevalence in females is twice as much in males. The etiologic factors are both genetic and environmental. It can run in families. No single gene has been identified so far which can be attributed to MDD. This probably is because of the heterogeneity and complexity in the pathogenesis of MDD. However, those propagating epigenetic factors have attributed genetic changes to ‘endophytes’ Treatment induces remission in only 50% of cases. The treatment is either pharmacological or in the form of psychotherapy or both. The pharmacology treatment is mainly based on amine-hypothesis. Research is still warranted for better treatment strategies with less side effects. 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