Depressive disorders: Definitions, contexts, differential diagnosis, neural correlates and clinical strategies

Starting from the categorical defi nitions of “depressive disorders”, we proceeded to list the individual forms provided by the DSM-V, with a particular focus on historical, clinical, neurobiological and therapeutic profi les, concluding the analysis of the possible strategies to be used to fi nalize the resolutions to problems arising from the disorder in question. Review Article Depressive disorders: Defi nitions, contexts, differential diagnosis, neural correlates and clinical strategies Giulio Perrotta* Psychologist sp.ing in psychotherapy with a strategic approach, Forensic Criminologist expert in sectarian cults, esoteric and security profi les, Director of the Department of Criminal and Investigative Psychology UNIFEDER, Jurist sp.ed SSPL, Lecturer, International Essayist, Italy Received: 08 June, 2019 Accepted: 26 July, 2019 Published: 27 July, 2019 *Corresponding author: Dr. Giulio Perrotta, Psychologist sp.ing in psychotherapy with a strategic approach, Forensic Criminologist expert in sectarian cults, esoteric and security profi les, Director of the Department of Criminal and Investigative Psychology UNIFEDER, Jurist sp.ed SSPL, Lecturer, International Essayist, Italy, E-mail:

underestimate the problem, especially in western and highly industrialized countries [3].

Profi li storici e classifi catori
In ancient times, the Greek physician Hippocrates of Coo described the condition of melancholia (in Greek μελαγχολία) as a distinct disease with particular mental and physical symptoms, characterizing all the "fears and discouragement, if they last long" as symptomatic of this particular disease [4]. This description among other things is very similar to the modern concept, albeit with a different content spectrum, including symptoms of sadness, discouragement and discouragement, often fear, anger, delusions and obsessions [5].
The term "depression" comes from the Latin verb "deprimere", which means "press down" [6] and was used since the 14th century, even by great authors of English literature [7]. A fi rst use instead as a reference to a psychiatric symptom was made by the French psychiatrist Louis Delasiauve in 1856; from that moment, and particularly from 1860, the term began to appear in medical dictionaries as a reference to a lowering of emotional function with pathological features [8].
Even though "melancholy" remained the predominant term in diagnostics, the term "depression" grew from the studies of the German psychiatrist Emil Kraepelin who used it as a general term to refer to the different types of depressive melancholy [9]. Sigmund Freud then compared the state of melancholy to mourning, in his paper "Lutto e melanconia" (1917), theorizing the loss of an "object" (eg the loss of a relationship due to death or interruption of a loving relationship), in relation to the loss of the "subject": in essence, the depressed individual, according to the author, identifi es with the object of affection, according to an unconscious process of narcissistic matrix (called "libidinal investment") ego "). The result of this loss involves severe melancholic symptoms deeper than mourning, not only is the outside world seen negatively, but the ego itself is compromised [10]. The patient's decline in self-perception is revealed in the conviction of his guilt and his inferiority and unworthiness [11], exactly as it happens in the fi rst life experiences, which then will mark us for the whole existence [12].
More recently, the fi rst version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-I, 1952) spoke of "depressive reaction", while DSM-II (1968) of "depressive neurosis", defi ned as an overreaction to internal confl ict or an identifi able event. It also included manic-depressive psychosis among the major affective disorders [12]. In the mid-twentieth century, researchers hypothesized that depression was caused by a chemical imbalance in brain neurotransmitters: a theory based on observations made in the 1950s on the effects of reserpine and isoniazid in modifying the levels of family neurotransmitters of monoamines concerning depressive symptoms [13].
The term "major depressive disorder" was instead introduced by a group of US doctors in the mid-1970s as part of the proposed diagnostic criteria based on symptom patterns (called "Research Diagnostic Criteria", structured on the basis of previous "criteria"). Feighner ") [14], which then formed the DSM-III of 1980 [15]. To maintain consistency, the ICD-10 uses the same criteria, with only minor changes [15,16]. Indeed, the ICD-10, simplifying the previous ICD-9, lists the depressive episode, persistent mood disorders (dysthymia), other mood disorders and unspecifi ed disorders; similar to the previous version, it distinguishes different subclasses of depressive episode: the mild and moderate form of depression, the severe depressive episode without or with psychotic symptoms, atypical depression and "masked" depression, and again the unspecifi ed depressive episode (Table 1).

Clinical contention and categorical classifi cations
There are several clinical "forms" on a depressive basis, categorized according to the symptoms; for this it is necessary to demarcate the boundaries in a reliable way, so as to be able to deal with the theme "depressions" in a more correct manner, always bearing in mind that not all people who experience depressive symptoms actually suffer from a pathological form [3].  Depressive temperament is characterized by a tendency to sadness, low self-esteem, pessimism, isolation: the subject appears predominantly gloomy, introverted, solitary and incapable of having fun, tending to brooding. He has concerns about his own inadequacies and failures, presenting an ease in feeling guilty [2].
In the second place of the imaginary scale we fi nd the "physiological depressive reactions": the "sadness", the "blues" and the "mourning". Sadness is one of the primary emotions and consists of a universal response to adversity, which in the ethological meaning of the term demonstrates its important adaptive function. By blues (bad mood) we mean short-term transitory forms of depression consisting of reactions to specifi c stressful events: we distinguish for example. the holiday blues (the sadness that appears when you return from vacation); maternity or baby blues (also called third day syndrome; typically emerges 2-3 days after birth and disappears within about ten days), not to be confused with the much more severe postpartum depression; we also mention the anniversary blues (melancholy states in relation to certain recurrences) and the premenstrual blues. Mourning is an "emotional" state that appears in relation to loss experiences (death, divorce, emotional detachments, emigration, wars, etc.) [2]. As reported in the fi fth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) (APA, 2013), bereavement can present the same symptoms as a major depressive episode, such as feelings of intense sadness, rumination on loss, insomnia, poor appetite and weight loss, but there are some elements that make it possible to distinguish the two phenomena: in mourning, fi rst of all the experiences and negative thoughts appear strictly in relation to the deceased; reactivity to external stimuli is maintained, the psychomotor slowdown typical of major depression is not present, as are ideas of self-depreciation and excessive guilt or other psychotic symptoms and suicidal ideation is rare. The reaction of mourning also differs for other psychopathological signs such as "mummifi cation" (keeping the objects of the deceased as they were before death) and serious "anniversary" reactions [2].
Still in the depressive continuum, in third place, it is possible to highlight the forms that defi ne the "threshold" between "physiological reactions" and "real depressive disorders" [2]; let us say, to simplify, the "typical and atypical forms of depressive disorders" [1].  (Table 2).
Focusing attention on the DSM-V categorization (latest version), we fi nd the following forms [1]: that appears before the age of 18 (with fi rst onset between 6 and 10 years) and is characterized by persistent irritability, which involves frequent anger and aggression (at least 3 times a week). It often evolves, in adolescence or early adulthood, into an anxiety disorder or major depression. It is quite common to fi nd this disorder in children who have ADHD or anxiety disorders in developmental age.

2.
Major depressive disorder or unipolar depressive or endogenous depression. It is a depression not linked to particular events (eg grief, loss, stressful situations) and the main symptoms related to mood, vital drive, thoughts and ability to concentrate. It is characterized by depressed mood episodes mainly accompanied by low self-esteem and loss of interest or pleasure in normally pleasant activities (c.d. anedonia). A clinical investigation is suggested fi rst to exclude physical pathologies capable of favoring this condition (eg hormonal dysfunctions, systemic infectious conditions, use of drugs or drugs).
For the diagnosis of major depression, 5 or more of the following symptoms must have been present almost every day during the same 2-week period, and one of them must be a depressed mood or a loss of interest or pleasure (criterion A): • Depressed mood for most of the day; • Marked decrease in interest or pleasure for all or almost all activities for most of the day; • Signifi cant (> 5%) increase or loss of weight or decrease or increase in appetite; • Insomnia (often maintenance insomnia [central]) or hypersomnia; • Agitation or psychomotor slowing observed by others (not self-reported); • Asthenia or energy loss; • Excessive or inappropriate feelings of self-depreciation or guilt; • Decreased ability to think or concentrate or indecision; • Recurring thoughts of death or suicide, a suicide attempt, or a specifi c plan to carry it out.
Furthermore: the symptoms cause clinically signifi cant distress and impairment of functioning in the social, work or other important areas (criterion B); the episode is not attributable to the physiological effects of a substance or to another medical condition (criterion C); the occurrence of the major depressive episode is not better explained by schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional disorder or schizophrenia spectrum disorder and other psychotic disorders with other specifi cation or without specifi cation (criterion D); there has never been a manic or hypomanic episode. Note. This exclusion does not apply if all the manic-like or hypomanic-like episodes are induced by a substance or are attributable to the physiological effects of another medical condition (criterion E). c) Postpartum depressive disorder. Becoming a mother is a complex psychological process, which can offer the opportunity to review one's own childhood bonds, reworking past confl icts and prefi guring a new mature and integrated identity, but it can also deconstruct a fragile personality, exposing it to the risk of psychopathologies. If the relationship with one's mother has been positive, the pregnant woman can identify herself with an image of fertility and protection and at the same time with herself as a child, remembering the need for affection that she showed and the confi dence that she would be satisfi ed, thus succeeding to descend into the role of mother and to understand the needs of the child; instead, if the relationship with her mother was confl ictual, the woman re-experiences with her child the painful fusion experienced as a child with her mother, feeling that she has failed in her process of individuation and reducing her willingness to care for her child if not is sustained and has unsolved psychological confl icts, the intense effort of psychological, physiological and social adaptation required by motherhood can expose her to the risk of clinical pictures, especially depressive, of different intensity and severity. The fi rst and mildest of the postpartum depressive clinical pictures is the baby-blues or maternity blues, a mild transient emotional disorder that affects more than half of Western women and that occurs in the days immediately following childbirth. The "blues" is a moment of lowering the mood, with a feeling of tiredness, of sadness and distrust, crying crying, which is accentuated around the fourth or fi fth day after the birth, that is, in correspondence with the milky whipping, it lasts some hours or a few days and then resolves spontaneously. However, if it persists and worsens, it can become a real post-partum depression and, in some extreme cases, become a puerperal psychosis. The DSM reports a specifi c post-partum depression, with symptoms such as depressed mood for most of the day, sleep disorders such as insomnia or hypersomnia, agitation or psychomotor slowing, feeling of exhaustion due to lack of energy, feelings of self-depreciation or excessive and inappropriate guilt, sharp reduction in the ability to think, concentrate or make decisions. Puerperal psychosis, on the other hand, is the most serious post-partum depressive condition, since it involves a destructuring of psychic functions, an impairment of the reality test and the onset of psychotic symptoms such as delusions and hallucinations. Postpartum depression is not only a state of discomfort for the mother, but also affects the health of the child, with modalities and outcomes that cannot be accurately predicted, since the depression itself involves a fl uctuation of the maternal mood and the modalities of interaction with the child. The interactive style of depressed mothers is not uniform, however Cohn and Tronick (1989) have detected 4 main patterns: a) Intrusive mother style. The style of these mothers is intrusive, as it does not respect the child's rhythms, but tends to force them, intervening even when the child manifests the need to withdraw from interaction to regain energy. The stimulation is excessive and inopportune, it is accomplished with an irritated tone of voice, agitated and awkward maneuvers of care that arouse anger and hostility in the child; 009-033. DOI: http://doi.org/10.17352/2455-5460.000038 b) Withdrawn maternal style. These mothers show themselves unavailable to interaction, so attempts by children to engage with them generally fail, generating a sense of incompetence in the children themselves, who develop a negative affective core, dominated by sadness and resignation; c) Positive maternal style. These mothers resemble the nonpress ones, since they are suffi ciently responsive and involved in interaction, allowing the child to develop a predominantly positive affective nucleus. However, they differ from nondepressed mothers in the quantity and frequency of interactive exchanges, which is signifi cantly lower; d) Mixed maternal style. These mothers oscillate between an intrusive, withdrawn style and a positive style, based on changes in mood and contingent situations. Even in children, there is an analogous oscillation with a risk of emotional disorganization, since I cannot foresee the mother's response with stability.
The maternal depressive symptomatic picture reproduces in the child, who experiences a micro-depression, with psychomotor retardation, prevalence of melancholy moods, facial and postural inexpressiveness. In this regard, Stern (1995) identifi ed 4 types of subjective experience of the child with a depressed mother: a) Microdepression. The child fails to involve the mother, so try to get in touch with her through identifi cation and imitation. Imitation involves taking on expressions and behaviors similar to those observed in the mother: since the maternal face is inexpressive and sad, her voice has a low tone and her posture seems soft, even the child will reproduce this confi guration, becoming silent and expressionless. Then, through identifi cation, he models his state of mind on that of his mother, feeling the same feelings of suffering, loss and distrust; b) Resuscitation of the mother. The child who does not receive a response from his mother to his invitations, activates strategies that capture his attention, for example, raises his eyebrows, opens his mouth, vocalises more frequently and in a higher tone. Often, by intensifying the efforts to involve the mother, the child gets an answer, since the mother realizes her emotional unavailability and changes her attitude, approaching her son and interacting with him; c) Search for self-stimulation. If the child does not receive a reply from his mother, despite his efforts, he desists from "reviving her" and relies on the search for stimulation and gratifi cation in the external environment; d) False stimulation. When mothers notice that they have not offered stimulation to the child, they try to repair, resorting to intense and forced stimulation, which is intrusive and inappropriate. However, being the only stimulation available, the child accepts it, being content.
Si assiste, quindi, ad un'interazione forzata, dove la madre attua una falsa stimolazione e il bambino risponde con un falso sé compiacente, stando al gioco, pur di soddisfare il suo bisogno di interazione. In small children, desire can be expressed in play and behavior even through behaviors that refl ect being separated from, and even reunited with, a caregiver or another fi gure that is the object of attachment.
2. Sadness and intense emotional pain following death.
3. Concern for the deceased. 4. Concern for the circumstances of death. In children, this concern for the deceased can be expressed through the contents of the game and the behavior can extend to concern about the possible death of other close people. -Diffi culty to abandon oneself to positive memories concerning the deceased.
-Bitterness or anger in relation to the loss.
-Negative self-assessment in relation to the deceased or death (eg sense of self-guilt).
-Excessive avoidance of memories of the loss (eg avoidance of persons, places or situations associated with the deceased; in children this may include avoidance of thoughts and feelings regarding the deceased. 2) Social and identity disorder.
3) Desire to die to be close to the deceased.
4) From the moment of death, diffi culty in trusting others.

5)
From the moment of death, feeling of being alone or detached from others. 6) Feeling that life is empty or meaningless without the deceased, or thought not to succeed without the deceased. 7) Confusion about one's role in life, or diminished sense of one's own identity (eg a part of oneself is diminished along with the deceased). 8) From the moment of loss, diffi culty or reluctance to pursue one's own interests or to make plans for the future (eg friendships, activities).
d) The disorder causes clinically signifi cant distress or impairment in social, occupational or other important areas.
e) The bereavement reaction is disproportionate or inconsistent with cultural or religious or age-appropriate norms. e) Psychotic depression. A specifi c form of depressive episode is psychotic or delusional depression. Psychotic depression is characterized by false ideas and beliefs (delusions) and sometimes even by hallucinations. The disappointments are typically focused on grossly exaggerated feelings of guilt (eg "I am just a burden to my family" or "I made a terrible mistake"), on the fear of complete fi nancial ruin (disappointment of poverty) or on the exaggerated fear of a serious incurable disease (hypochondriac disappointment). The disappointments usually remain even if proof of the contrary is available (for example, having enough money). Patients with psychotic depression almost always need psychiatric treatment due to the severity of this disorder and the high risk of suicide. Psychotic depression can occur in both unipolar and bipolar depression. indicating the need to continue with a prophylactic treatment, such as at least 3 lifetime depressive episodes or 2 episodes interspersed with a free period of duration less than 5 years). In the case of bipolar depression, on the other hand, the fi rstchoice treatment consists of a mood-stabilizing drug, which will be maintained in the long term (usually for life) with the aim of preventing affective recurrences of both polarities. The correct differential diagnosis is not always easy for the clinician, especially if he is not a specialist in psychiatry, for two substantial reasons: fi rst of all, a signifi cant proportion of patients with a subsequent diagnosis of DB presents an EDM as a fi rst affective lifetime episode, which will therefore necessarily be considered as unipolar (a recent meta-analysis has estimated that 22.5% of subjects with DDM followed for 12-18 months will subsequently develop a counterstrike episode -Ratheesh et al., Acta Psychiatr Scand 2017; the conversion risk is maximal in the fi rst year , and then decreases -Kessing et al., Bipolar Disord 2017); secondly, patients, especially in the case of a Type II DB, will report recurrent EDM in their medical histories while they will tend to consider the short hypomanic phases as physiological well-being periods, especially when accompanied by symptoms such as mild euphoria and increased energy and activities aimed at , thus denying its belonging to the sphere of the disorder and thus preventing a correct longitudinal diagnosis. It is therefore necessary to recall the importance of an adequate longitudinal anamnesis, conducted where possible with the help of family members (...): the recent literature evidences, in fact, underline the relationship between the number of affective episodes and the increase in the risk of subsequent recurrence, the reduction of the probability of response / remission of the episode, the severity of subsequent episodes, the reduction of the threshold for the development of subsequent affective episodes (initially associated with stressful events and subsequently independent of them), and fi nally the progression towards a cognitive impairment (Kapczinski et al., Expert Rev Neurother 2017). Beyond the possible use of assessment scales and / or self-administered questionnaires (such as: Mood Disorders Questionnaire, Bipolar Spectrum Diagnostic Scale, Bipolar Disorder Screening Scale, Hypomania Checklist) that can help identify bipolar depression, the only really effective strategy consists in focusing attention on the longitudinal dimension of the disease (we return to the kraepelininani teachings), thus avoiding to base the diagnosis exclusively on the transversal approach. A correct and innovative approach to the diagnosis of bipolar depression consists in considering a cumulative risk index that derives from the sum of the genetic risk (familiarity for DB) with intraepisode or longitudinal clinical elements that are mainly associated with bipolar depression. (...) A useful tool, expression of the same probabilistic approach and which represents a summation of many of the bipolar predictor clinical elements already mentioned, is the Bipolarity Index, proposed by Sachs in 2004, which recently confi rmed its predictive ability with high sensitivity and specifi city (Aiken et al., J Affect Disord 2017) (…)>> [17].
A useful summary scheme of the main aspects is reported by the Australian and New Zealand guidelines for the treatment of affective disorders (Malhi et al., Aust N Z J Psychiatry 2015) (Table 3).  (…)>>. [17] Correlation between depressive disorders and suicide The theme of suidicio, in depressive disorders, is of central  b) The individual is involved in self-injuring activities with one or more of the following expectations: 1. Get relief from a negative feeling or cognitive state; 2. Solving an interpersonal diffi culty; 3. Induce a positive feeling. c) Self-harm is associated with at least one of the following symptoms: 1. Interpersonal diffi culties or negative feelings or thoughts, such as depression, anxiety, tension, anger, generalized discomfort, self-criticism, which occur in the period immediately preceding the self-injurious act; 2. Before making the gesture, there is a period of concern that is diffi cult to control with regard to the gesture that the individual intends to make; 3. Thoughts of self-harm frequently, even when the behavior is not implemented.

Correlation between depressive disorder and anxiety [19]
<<  These data account for the considerable socio-economic impact, as well as the important consequences in terms of "loss of health" caused by these disorders. It has been estimated that currently depression is the fourth cause of

Depressive disorders in children and adolescents [20-25]
<<(…) The basic manifestations of depressive disorders in children and adolescents are similar to those of adults but are associated with concerns typical of children, such as homework and play. Children may not be able to explain feelings or internal experiences. Depression must be considered when a young person, who fi rst behaved adequately, starts going wrong at school, isolates himself or commits delinquent actions. In some children with a major depressive disorder, the predominant mood is irritability rather than sadness (an important difference between infantile form and adult forms). The irritability associated with childhood depression can manifest itself as hyperactivity and aggressive, antisocial behavior. In children with intellectual disabilities, depression or other mood disorders may manifest as somatic symptoms and behavioral disorders.
(…) Disruptive mood dysregulation disorder results in persistent irritability and frequent episodes of behavior that is very out of control, with onset at 6 years to 10 years. Many children also have other disorders, particular oppositional defi ant disorder, attention defi cit / hyperactivity disorder, or anxiety disorder. Diagnosis is not made before 6 years or after 18 years. As adults, patients may develop unipolar (rather than bipolar) depression or anxiety disorder. The events include the presence of the following for ≥ 12 months (without any period ≥ 3 months without all of them): a) Serious outbursts of recurrent anger (eg, verbal anger and / or physical assault against persons or property) that are grossly disproportionate to the situation and that occur on average ≥ 3 times / week; b) Outbreaks of anger that are not consistent with the level of development; c) An irritable state of mind, angry present every day for most of the day and observed by others (eg, parents, teachers, peers).
Anger outbursts and angry moods must occur in 2 of the 3 living environments (at home or at school, with peers).
(…) Major depressive disorder is a discrete depressive episode lasting ≥ 2 weeks. It is found in 2% of children and in 5% of adolescents. Major depressive disorder can occur at any age but is more common after puberty. If left untreated, major depression can regress spontaneously in 6-12 months. The risk of recurrence is greater in patients who have severe episodes, who are younger, or who have had more episodes. The persistence of depressive symptoms, even mild during remission is a strong predictor of recurrence. For the diagnosis, 1 or both of the following criteria must be present for most of the day almost every day during the same 2-week period: The symptoms may be more or less intense than those of a major depressive disorder.
A major depressive episode may occur before or during the fi rst year (ie, before the duration criterion is satisfi ed for persistent depressive disorder). It is interesting to note that neurogenesis appears to be associated with the ability of the brain of mammals, including humans, to memorize recent memories, a phenomenon that is signifi cantly reduced in the aging brain in which the process of neurogenesis is greatly reduced. and clinical neurobiology of affective disorders is to understand how a depressive disorder is capable, if not treated in a timely and adequate manner (appropriate and prolonged dosage) of altering the homeostasis of the neurons, particularly in brain areas such as the hippocampus, the amygdala and the cingulate cortex whose morphology and function are altered by this pathology. In depressed subjects, in whom the treatment is not continued for long enough, the number of relapses in the months following the cessation of therapy is always markedly higher than that of patients treated for at least 2 years. Furthermore, in patients with repeated relapses, the hippocampal volume is signifi cantly reduced compared to the values obtained in the same patients at the beginning of therapy. These results suggest that timely treatment is needed to protect the depressed brain and adequate dosages and times that go far beyond simple remission of symptoms. The extraordinary images obtained, at an experimental level, with high-resolution supermicroscopes and at the clinical level through the studies of "Brain Imaging", have allowed us to demonstrate that a chronic stress in animals and depressive pathology in humans determine a reduction in capacity functional neurons associated with a loss of trophism,

Clinical strategies for the management of the pathological conditions
Pharmacological therapies: <<(…) Depression, in its various forms, is the most widespread mental disorder on a global level. It is a chronic recurrent pathology that manifests itself with somatic, affective and vegetative symptoms and has a greater prevalence in women and in the elderly population.
Depression is characterized by a very high comorbidity with other psychiatric disorders, including anxiety disorder, substance abuse, and impulse control disorder. Until the 1950s it was thought to be an exclusive pathology of the psychic sphere and, as such, had to be treated with psychotherapy and psychoanalysis. The discovery of the antidepressant action of some drugs arises by chance with the use of the isoniazid that in 1952 Hoffmann-La Roche, introduced into the market as an antibiotic for the treatment of tuberculosis. In 1953, a similar analogue, iproniazid, was developed for the same purpose.
However, its use was associated with numerous unexpected effects, including euphoria, psychostimulant action, increased appetite and improved sleep. These observations led to the hyproniazide becoming a widely used drug for the treatment of major depression in just a few years. Subsequently it was discovered that the action of this molecule depended on its ability to inhibit the Mono-Amino-Oxidase (MAO), the main enzyme system responsible for the degradation of catecholamines (noradrenaline, dopamine and serotonin).
Another historic step in the development of antidepressants was the discovery of tricycle compounds. The fi rst drug of this class to be introduced into therapy was imipramine. Also in this case the discovery was causal since, being a chlorpromazine analogue, it was developed as an antipsychotic. As a neuroleptic it proved to be of modest effi cacy while a remarkable ability to improve symptoms of depression was observed. Imipramine also demonstrated less adverse effects than the MAO inhibitor iproniazide. In the following years numerous other tricylclic molecules were developed and it was discovered that the main mechanism of their action was the blocking of catecholamine reuptake with the consequent increase in synaptic availability. reuptake of serotonin (but to a lesser extent than the SSRIs) act as agonists on the 5-HT1A receptor and antagonists on the 5HT2A and 5HT2C and 2-adrenergic. The use of these drugs is usually accompanied by sedation. They fi nd utility in inducing or improving sleep in patients whose depressive state is accompanied by diffi culty sleeping.
Clinical studies have suggested that in patients with reduced adherence to treatment, treatment with two antidepressants with different mechanisms of action can often be more effective than association with other classes of drugs. Indeed, by combining two molecules capable of modulating different molecular "targets" (receptors, transport mechanisms, etc.) it is possible to obtain a better adherence to the therapy.  [30,31], vary from therapy to therapy (Table 4)   "Renunciation is a daily suicide", Honoré de Balzac.
2) Complaining: complaining is a natural human reaction.
It is necessary for survival because the lament activates the attention of others and spurs them to offer us the care we need. Just imagine how many alarm bells light up in a mother when she hears her baby crying. The problem arises when the complaining becomes continuous and constant, because the more we ask for help, the greater will be our feeling of incapacity, in fact if we were able on our own we would not have complained. Moreover, complaining constantly, we will become less and less credible in the eyes of others and our subsequent requests for help will lose value. "The complaints are anchors in the sand that prevent us from taking off.   The best treatment to date is the one combined between psychotherapy and targeted drug therapy, supplemented by somatic and nutritional therapies.  The identifying profi le of the pathology is also fundamental, to then fi nd the most suitable targeted therapy; an identifying error would de facto annul the possibility of recovery and management of the disease, as in the case of an erroneous diagnosis of bipolar disorder or personality disorders, and vice versa.
In the neurobiological fi eld, recent research shows the crucial role of reduced neuronal plasticity in the etiology of depressive pathology, and suggests that a drug therapy, especially if combined with a valid psychosocial or psychoeducational support, can guarantee a better adherence of the patient to the treatment. In fact, drug therapy can only benefi t from the association with non-pharmacological practices capable of favoring mechanisms that modulate trophism and brain plasticity. The consolidated neurobiological evidences show that the depressed subject's neurons present a loss of trophism and neuronal plasticity that limit their best adaptation to negative environmental stimuli. The same evidences show how antidepressants activate, although with non-specifi c mechanisms, the function of genes involved in the synthesis of trophic factors. The profi le linked to pharmacogenetics and drug-resistance deserves great attention. Neurostimulation is still an expanding fi eld aimed at improving the effi cacy, safety and tolerability of DRT treatments.
Major Depressive Disorder (MDD) is one of the most common but also the most debilitating mental disorders; however, its etiology remains unclear, seeking it in both neurobiological and environmental factors [38]. In recent years, several genetic and genotypic components have been found that predispose to depression; predisposition which is not in itself triggering the pathology but which would be triggered in the presence of other elements, such as environmental stresscausing and physiopathological hormones. Genetic expression would therefore predispose but would not be a trigger. Other factors related to the triadial alterations of the serotonindopamine-norepinephrine transmitters, but in recent years the patient has not completely recovered; the neurotrophic and neuroplastic factors, and also the sudden changes of sex hormones, cortisone and catecholamine, and the immune aspects treated and cytokines. Still, other profi les concern the infl ammatory profi les found in the presence of increased levels of histamine and interleukin-1 and -6 (related to the increase in hunger) and interleukin-4 (linked to the decrease in hunger) [39].
Future research perspectives must be clearly oriented in the hypothesis of correlating all these analysis profi les, reconstructing the psycho-bio-pathological path of a disorder still with an etiology that is not completely explained.