Depressive Disorders: Clinical Symptoms and Neurobiological Theories

Depressive Disorders Overview

Depressive disorders include disruptive mood dysregulation disorder, major depressive disorder (including major depressive episode), persistent depressive disorder, premenstrual dysphoric disorder, substance/medication-induced depressive disorder, depressive disorder due to another medical condition, other specified depressive disorder, and unspecified depressive disorder. The common feature of all of these disorders is the presence of sad, empty, or irritable mood, accompanied by related changes that significantly affect the individual's capacity to function (e.g., somatic and cognitive changes in major depressive disorder and persistent depressive disorder). What differs among them are issues of duration, timing, or presumed etiology.

Major Depressive Disorders

Major depressive disorders (MDD) are also called unipolar depression disorders to be distinguished from the bipolar disorders, characterized by a shift from symptoms related to depression toward psychotic disorders. According to DMS-5 they belong to different types of disorders.

Unipolar Disorder Prevalence

Unipolar disorder affects between 3-7% of the world's population and often begins in the teens (20-30s) but can happen at any age. More precisely, age is a risk factor in developing MDDs. Clinically, women are more frequency affected. There isn't a clear molecular-based explanation, probably because they are easier diagnosed, and more treatments are provided compared to males.

Etiology of Depressive Illnesses

Both genetic and environment factors are involved in the etiology of depressive illnesses. There is evidence of genetic predisposition, like polymorphisms in growth factor genes, that seems to increase the probability to develop depressive-like behavior. Furthermore, of familiarity underlying a link between a MDD affected mother and her children affected by a similar pathology. Nonetheless, it is quite challenging to understand which component - genetic or environmental - prevails on the other. This isn't the case of other diseases, such as schizophrenia, characterized by strong evidence of genetic contribution.

Animal Studies on Depressive-like Behaviors

Some animal studies were used to induce and observe the development of depressive-like behaviors. Generally, a polymorphism that might increase the probability to develop this trait is mother-related.

Maternal Deprivation Model

MATERNAL DEPRIVATION MODEL: Researchers recreate a stress condition by taking pups (P1-5) away from the mother for several days, then give them back. This becomes a stressfully and maladaptive event, influencing the development of the brain's sons and their future behavior. Is this condition genetics dependent or environmental dependent? Any correct answer can be provided since it can be induced by the interplay between both components.

Diagnosis of Depression

According to the DSM-5, depression is currently diagnosed subjectively in terms of clinical presentation with the use of questionnaires and clinical evaluations. Questionnaires and clinical observation help defining some "objective" diagnostic criteria related to a certain disease. Describing a disease is complicated because 1) the pathology is characterized by a mixture of complex symptoms that differ among patients in terms of severity and overall manifestation, and because of 2) the enrollment of the patients.

Main Clinical Features of MDD

The main clinical features of MDD are:

• LOW MOOD characterized by subjective feeling of sadness or emptiness. Instead, depressed children and adolescents often display signs of IRRITABILITY rather than low mood, more difficult to be detected.
• ANHEDONIA is the loss of interest in most activities, loss of libido and an inability to feel pleasure in activities that were previously enjoyed.
• Reduced energy characterized by feeling of LETARGY and FATIGUE, associated with sleep disorders. More related to the physical behavior respect to the mental one that still is present in form of feeling empty (the mind isn't able to cope with the daily routine).
• Pessimistic thought, feeling of WORTHLESSNESS, low self-esteem, helplessness and guilty recollections.
• SUICIDAL IDEAS, preoccupation with death and sometimes attempts to commit suicide because of the previous points. Patients are usually refractory to any treatment.
• CHANGES in the SLEEP PATTERNS, normally characterized by insomnia with early morning waking, but sometimes characterized by hypersomnia (oversleeping).
• Loss of appetite and weight changes, which can cause some troubles with antidepressant administration bringing up some low self-esteem feelings.
• COGNITIVE SYMPTOMS, such as difficulties in focusing attention on everyday tasks, and observable deficits in memory recall.
• Changes in activity normally characterized by a slowing down or a reduction in activity. Sometimes, however, there may be psychomotor agitation.

DSM-5 Diagnostic Criteria

According to the DSM-5, at least 5 of the clinical symptoms must be present most of the day, almost every day for at least 2 weeks, and must not be a result of drug use or misuse or psychotic disorder. Indeed, drug abuse affects some of the pathways involved in behavior changes like PFC, amygdala, midbrain, hippocampus, hypothalamus.

Comorbidity with Depression

Some psychiatric conditions may be comorbid with depression, such as anxiety. Indeed, most antidepressant drugs act also as antianxiety.

Categorization of Depressive Symptoms

Depressive symptoms can be categorized as emotional (sad, irritable, apathetic), physical (tired, disrupted sleep, no motivation), mental (difficulty in concentrating, negative thoughts, suicidal ideas) and behavioral (withdrawn, no engaged in activities).

Patient Subclassification and Risk Factors

The patient subclassification is defined according to the severity of their symptoms: not all depressive patients are equal to others! Depression can be subclassified depending on the symptoms, their appearance and the driving force, taking into account also the presence of comorbidities. There are some elements that seem to increase the risk of developing or triggering depression:

• Certain personality traits, such as low self-esteem and being too dependent, self-critical or pessimistic.
• Traumatic events, such as physical or sexual abuse, the death or loss of a loved one, difficult relationship or financial problems.
• Serious or chronic illness, including cancer, stroke, chronic pain or heart disease.
• Abuse of alcohol or recreational drugs.
• Medication like high blood pressure medications or sleeping pills.
• History of other mental health disorders, like anxiety disorder, eating disorders or post- traumatic stress disorder.

Types of Depressive Illnesses

MDD with Psychotic Features

It is a distinct type of depressive illness in which mood disturbance (low mood) is accompanied by psychosis either delusion, hallucinations or both. Those are positive symptoms of psychosis that can help in diagnose, not present in normal subject are. Delusion means that the patients is not able to perceive correctly himself, he has no control; hallucination means that the patient hears some voices that are not present. Psychotic features occur in nearly 18.5% of patients who are diagnosed with MDD, and the prevalence increases with age. Geriatric patients with psychotic depression have been found to have more pronounced brain atrophy, higher relapse rates, and greater mortality compared with geriatric patients without delusions or hallucinations.

Melancholic-Type MDD

MDD include severe symptoms associated to sadness, low mood, accompanied by anhedonia with lack of reactivity to pleasurable stimuli, feelings of worthlessness, guilt and helplessness, anorexia and weight loss, insomnia and psychomotor retardation or agitation. This type of depression is usually seen in patients who have had one or two previous episodes of depression and who responded to antidepressant drugs with full or partial remission. So, in order to diagnose it there must be a sort of chronicity.

Seasonal Affective Disorder

A recurrent form of depression that occurs during a particular 60-day period of the year; full remission also occurs within a particular 60-day period of the year. For a positive diagnosis of SAD, the patient has to have had 3 episodes of depression in 3 separate years (at least two of which are concurrent) with the same temporal relationship with respect to season (that is, at the same time of year). SAD usually occurs during the wintertime or during fall and is characterized by these relapse and remission phases. It disappears with seasonal changes.

Persistent Depressive Disorder

If an episode of MDD lasts for more than 2 years, then it is classified as PDD. It is the worst one: the treatment is refractory.

Postpartum Depression

A significant number (that can be as high as 85%) of women suffer some transient mood problems following the birth of a child. In most cases, they spontaneously remit with the first 2 weeks postpartum. However about 10-15% of women will develop a depression that is indistinguishable from MDD. Postpartum depression usually develops slowly over a 3-month period after birth and is typified by increasing low mood, sadness, despair, anhedonia and anxiety. Indeed, patients are subjected to different changes not only because of the newborn, but also because of hormonal changes that determine a transition to sad mood that might became very severe. These depressive symptoms may interfere with the ability of the mother to nurse and care for her baby and there is also the possibility that the mother will become suicidal.

Treatment and Diagnosis Challenges

Symptoms differ among patients as well as the response to treatment. The identification of a specific categories may help in developing a sharper therapeutic strategy to treat them. Indeed, antidepressants are necessary but not always sufficient because other synergistic effects are needed. The DSM doesn't tell anything about predictivity vs responsiveness to treatment, and around 30% of MDD patients are refractory to all available treatments, and nowadays it is hard to identify the time of diagnosis and responsiveness.

Comparison of MDD and Type II Diabetes

Comparison of MDD and type II diabetes. Diabetes type II is a potential chronic illness. It has been compared with depression in terms of strategy to diagnosis, identification of molecular pathways, treatment option and so on. With this comparison, it is possible to underline that the difficulty in the management of a complex pathology, such as MDD, lies above all in the fact that the etiopathogenesis itself is complex. Moreover, it is difficult to measure biomarkers or have clear indications of a therapeutic effect.

Diagnosis and Monitoring Differences

They differ is the type of diagnosis and monitoring:

• MDD: it is subjective-qualitative diagnosis through clinical observation (self-reporting readout of the patients) through standardized questionnaires (DSM-5 related). The treatment isn't fast effective and not well predictive, rather it takes time to exert its effect. The challenge is trying to find a way to get it objective.
• Type II diabetes: it involves an objective-quantitative diagnosis. Considering urine analysis, it is possible to demonstrate an increased amount of glucose with classical signs or abnormal glucose tolerance, insulin insufficiency. The readout can lead to the adjustment of the insulin treatment. The same situation happens in the presence of cancer.

Systematic Comparison of Major Depression and Type 2 Diabetes

Table 1| A systematic comparison of major depression and type 2 diabetes Criterion Major depressive disorder Type 2 diabetes Lifetime risk 1 in 6 1 in 3 Diagnosis and monitoring Subiective-qualitative: patients must show a depressed mood or anhedonia, as well as assorted other symptoms, for at least 2 weeks, and these symptoms must disrupt normal social and occupational functioning Obiective-quantitative: diagnosis requires demonstration of an increased amount of serum glucose with classical signs (polyuria, polydipsia, obesity) or abnormal glucose tolerance (reflecting insulin resistance) Patients monitored through standardized questionnaires Significant increases in HbA1C, a glycosylated haemoglobin, demonstrate long-standing poor glycaemic control Aetiology and risk factors Stressful life events (such as loss of loved ones or financial or professional crises) Lifestyle factors (sedentary lifestyle, high-fat diet) Genetic risk (heritability = 35%) Genetic risk (heritability = 40%) Disease genes unknown; can be idiopathic, a side effect of a drug (such as interferon-a or isotretinoin) or secondary to systemic illness (such as Cushing's syndrome or stroke, among many others) Established disease genes (such as PPARG, TCF7L2 or KCNJ11); can be iatrogenic (such as treatment with glucocorticoids or phenytoin) Treatments Monoamine reuptake inhibitors (such as tricyclic drugs, SSRIs, NRIs or SNRIs) Insulin Sulphonylureas (such as tolbutamide) Monoamine oxidase inhibitors (such as tranylcypromine) Meglitinides (such as repaglinide) 'Atypical' agents (such as bupropion or mirtazapine) PPAR-y agonists (such as rosiglitazone) Electroconvulsive seizures Biguanides (such as metformin) Psychotherapy Glucosidase inhibitors (such as miglitol) Deep brain stimulation Incretin (GLP1) mimetics (such as exenatide) Exercise promotes recovery Lifestyle changes (such as weight loss or exercise) Pathogenesis Abnormal activity of the HPA axis (hypercortisolism or hypocortisolism)? Obesity, sedentariness and genetic predisposition promote peripheral insulin resistance leading to pancreatic ß-cell hyperplasia Alterations in neurotrophic signalling? Abnormal hippocampal neurogenesis? Deficits in brain reward processing? ß-Cell dysfunction and failure ensues, leading to impaired glucose tolerance Abnormal cognitive styles (negative thinking)? End-organ damage (nephropathy, neuropathy and angiopathy) occurs secondarily to hyperglycemia, excessive protein glycation and aberrant intracellular signalling GLP1, glucagon-like peptide 1; HbA1C, haemoglobin A1 C; HPA, hypothalamic-pituitary-adrenal axis; KCN/11, potassium inwardly rectifying channel J11 gene; NRIs, selective noradrenaline reuptake inhibitors; PPARG, peroxisome-proliferator-activated receptor-y gene; SNRI, serotonin-noradrenaline reuptake inhibitor; TCF7L2, transcription factor 7 like 2 gene.

Questionnaires for MDD Diagnosis

Questionnaires are the main tools to diagnose MDD, that can be implemented based of the knowledge present in the DSM. Types of questioners:

1. Cross-cutting symptoms measures don't specifically measure depression rather different domains of the mental health. It might give information to clinicians to go deeper into details