Pharmacotherapy for depression

The increase in the number of patients with depressive disorders significantly affected the structure of neurological morbidity. It is well known that the bulk of patients with affective disorders are in general medical, including neurological practice. So, approximately 60-80% of patients with depression do not fall into the field of vision of psychiatrists and are treated by internists, since among them patients with mild atypical forms predominate. And a large proportion of these patients are found in the practice of neurologists. Meanwhile, only a very small percentage of patients complain of mental disorders, and the majority have purely somatic complaints. And in practice, it is very difficult to isolate a mental or somatic radical, since they are always clinically linked. From a practical point of view, the identification of atypical latent forms of depression is important, since it significantly modifies the tactics of managing such patients, and the correct use of thymoanaleptic therapy predetermines the success of treatment in many cases.

Alexithymia is a person’s inability to describe their emotional state in verbal form. This violation is considered by a number of specialists not as a disease, but rather as a separate characteristic of a person. 

Pharmacotherapy has the largest share in the treatment of depression, especially on an outpatient basis, since, in comparison with other methods, along with direct effectiveness (69% on average), it also has the greatest stability of long-term results.

The range of clinical forms in which the justification of thymoanaleptic therapy has been proven and which practical neurologists have to deal with is extremely wide: chronic pain syndromes of different localization (back pain, diffuse muscle pain, various forms of headaches, cardialgia, etc.), depression in organic diseases nervous system (parkinsonism, dementia, strokes, tumors, post-traumatic disorders, etc.), eating disorders, sleep disorders, psychosomatic and psycho-vegetative disorders. A significant dominance of atypical depression among these categories should be noted. In general, about 30% of all chronic patients suffer from masked larvae forms of depression. Not being a nosologically independent unit, masked depression is a clinical phenomenon that demonstrates a high clinical relationship with the main clinically obvious somatic, autonomic, algic, anxious, motor, sensory and other neurological phenomena. In general, the main direction of the therapeutic tactics of neurologists is the relief of both depressive symptoms and pathogenetically associated somatic and neurological disorders. Another direction, justified from a pathogenetic point of view, is the use in some cases of the targeted effect of antidepressants on a specific biochemical defect (for example, the use of tricyclic antidepressants in Parkinson’s disease).

Actually, the beginning of the pharmacological treatment of depression is attributed to the accidental discovery of the antidepressant effect of iproniazide, which was used in the treatment of tuberculosis. And since that time, the pharmacological treatment of depression included the use of drugs of two classes – monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs). The further development of pharmacotherapy for depression is associated with the creation of drugs, the therapeutic effect of which is due to the ability to block the reuptake of neurotransmitters. Antidepressants of other classes also appeared – four-cyclic, atypical, and others. A significant advance in terms of the possibilities of a targeted effect was the creation in the late 1980s of selective inhibitors of the serotonin re-drink (fluoxetine, sertraline, paroxetine), dopamine (bupropion). From a practical point of view, these drugs have a number of advantages: safety, better tolerance, and the possibility of targeted action. And from a research point of view, it is important for the identification of a specific biochemical defect in the pathophysiological structure of mental disorders due to their specific affinity for certain biochemical systems. This allows you to assess the functional state of this system. Currently, interest in the clinical application of MAO inhibitors is renewed in connection with the creation of a new class – selective MAO-A inhibitors of reversible action, which also have certain advantages. Moreover, the previously generally accepted position of assessing the effectiveness of the standard antidepressants of the tricyclic structure (amitriptyline, imipramine) has undergone a significant transformation. This happened, on the one hand, due to the many side effects, the development in a large percentage of cases of resistance to such therapy, and on the other hand, due to the development of psychopharmacology and the creation of new selective and safe drugs.
Clinical classification of antidepressants

The choice of a specific type of thymoanaleptic therapy is determined by the nature of the leading psychopathological syndrome and, accordingly, the predominant direction of the psychotropic action of the antidepressant. In practical terms, it is important to subdivide antidepressants into drugs of predominantly sedative, stimulating and balanced action. The group of sedative antidepressants includes amitriptyline, doxepin, mianserin (lerivon), azafen; to the group of antidepressants-stimulants – moclobemide (auroriks) nortriptyline, imipramine, bupropion, fluoxetine; antidepressants with a balanced action – maprotiline (ludiomil), pyrazidol, tianeptine (coaxil, stablon), clomipramine (anafranil).

No less interesting from a practical point of view can be the analysis of depression, based on the ratio in its structure of two polar categories – positive (melancholy, anxiety, low self-esteem) and negative (apathy, alexithymia, anhedonia), and the associated therapeutic strategy for choosing an antidepressant. Possible different types of correlations of positive and negative affective symptoms are important from the point of view of compliance with the therapeutic characteristics of antidepressants with different neurochemical mechanisms of action. In cases where these phenomena are presented in the clinical picture as isolated persistent forms, drugs with a powerful indiscriminate neurochemical effect (for example, typical TCAs) are indicated. Much more often in the clinical field of depression there is an overlap of disorders of positive and negative affectivity, and especially often neurological disorders are combined with depressions that occur in erased atypical forms. In these cases, the use of selective antidepressants is shown and the main criterion for selection is not the strength of the antidepressant effect, but safety, the minimum severity of side effects.
Principles of antidepressant therapy

Based on the observance of the general principles of psychopharmacotherapy, when choosing a specific antidepressant, it is advisable to limit ourselves to monotherapy using convenient drugs (simplicity of the treatment regimen and dose titration). Taking into account the potential for increased sensitivity and side effects, psychotropic drugs are prescribed in small (compared to those used in “big” psychiatry) doses. Taking into account the nature of the main types of depressive disorders in neurological patients and the high representation of atypical erased forms, when choosing an effective dose of TCA at the initial stages, small doses can be used, gradually increasing them to medium therapeutic ones. Meanwhile, it should be remembered that for neurological patients, one of the reasons for the ineffectiveness of therapy is the low doses of antidepressants used. On average, by the 2-3rd week of therapy, an antidepressant effect occurs . Serotonergic antidepressants are immediately prescribed in a standard fixed dose for the entire course. A clear improvement is usually achieved after 3-4 weeks of therapy. No less important is the question of the duration of thymoanaleptic therapy. Premature withdrawal of the antidepressant can lead to a sharp exacerbation of symptoms. Therefore, the drug is withdrawn gradually.
Major classes of antidepressants used in neurological practice

Despite the fact that TCAs are the first generation drugs, they have not lost their clinical significance. Their main mechanism of action is to block the presynaptic uptake of both norepinephrine and serotonin. As a result of the blockade of monoamine reuptake, their free content in the synaptic cleft increases and, accordingly, the duration of exposure to the receptors of the postsynaptic membrane increases, which leads to an improvement in synaptic transmission. However, TCAs also have the ability to block a-adrenergic and H-1 histamine receptors. Therefore, TCAs are classified as non-selective, broad-spectrum antidepressants, and their side effects are associated with this. Along with the general side effects, TCAs have pronounced anticholinergic effects in the form of dryness of the oral mucosa, decreased sweating, tachycardia, difficulty urinating, blurred vision, constipation, tremor, and cardiac conduction disorders. This spectrum of side effects introduces significant limitations in long-term TCA therapy, especially in elderly patients. The limiting factor for TCAs is the unsafe drug interaction, which excludes the possibility of combining TCAs with a number of drugs (opiate analgesics, antiarrhythmics, indirect anticoagulants, irreversible MAOIs). Their combined use with antihistamines and antiparkinsonian drugs is also limited.

Tetracyclic antidepressants (maprotiline or ludiomil, mianserin or lerivon) are classified as second generation drugs. Ludiomil mainly blocks the reuptake of norepinephrine, has a slight anticholinergic activity. The mechanism of action of lerivon is not clear enough. It has a broad spectrum of action and belongs to norepinephrine agonists.

The main representatives of dopaminergic antidepressants amineptin (survector), bupropion block neuronal dopamine uptake, thereby exerting a predominantly stimulating effect on the dopaminergic systems.

Interest in antidepressants from the selective serotonin reuptake inhibitor (SSRI) group is associated with the serotonin model of depression. Moreover, the drugs of this group are generally addressed to the depressive states of the neurotic circle. SSRIs have a wide range of clinical effects with pronounced analgesic, anxiolytic, antipanic effects, and are successfully used in the treatment of obsessive-phobic and aggressive syndromes. The range of clinical syndromes in which clinical efficacy has been proven is quite wide: chronic pain syndrome, bulimia, obesity, alcoholism, obsessive-compulsive disorders, attention deficit hyperactivity disorder, panic disorder, etc. Along with high antidepressant activity, a significant advantage of antidepressants of this class is low representation of own side effects. Agitation, insomnia – the most common of them, can be stopped without discontinuing the drug by prescribing tranquilizers. At the same time, this class of drugs can cause specific side effects associated with hyperstimulation of the serotonin system: gastrointestinal disorders, decreased appetite, sexual disorders, tremors and increased sweating. The most serious complication of antidepressant therapy, including SSRIs, is a rather rare so-called serotonin syndrome, which manifests itself in a number of symptoms: dizziness, arterial hypertension, visual impairment, cardiovascular failure, nausea, psychomotor activation, agitation, myoclonus, hyperreflexia, sweating tremor, diarrhea, changes in mental status. The severity of complications ranges from mild forms that stop within 24 hours after discontinuation of therapy to severe.

One of the most developing areas of thymoanaleptic therapy is the return of interest in MAO inhibitors in connection with the creation of new selective drugs – MAOIs of type A of reversible action (“reverse inhibitors”), which differ from the traditional ones in less toxicity. These include pyrazidol, moclobemide (aurorix). MAOI-A are more effective against atypical depression with anxiety-vegetative symptoms, panic attacks with agoraphobia. At the same time, the positive effect of MAOIs of reversible action is observed at earlier stages of therapy compared to TCA. Their other advantage is the low risk of addiction. The main prospects for the use of reversible MAOIs are associated with the possibility of treating disorders that are comorbid with depression, primarily anxiety with panic disorder with agoraphobia.
Clinical use of antidepressants in chronic pain syndromes

Patients with chronic pain syndromes constitute one of the most difficult categories from a therapeutic standpoint. And almost all patients with chronic pain have affective disorders, among which depression occupies a dominant position. The range of ratios of various forms of chronic pain syndromes and depression is extremely variable. In this case, in fact, depressive symptoms can be dominant. However, more often we are talking about a significant predominance of algic phenomena masking depressive disorders. The close relationship of these phenomena is based, in particular, on serotonergic deficiency, with which the pathophysiological justification of treatment with antidepressants for almost any form of chronic pain is associated. In general, the effectiveness of antidepressant treatment for chronic pain reaches 75%. Practical experience with the use of antidepressants of different classes indicates their effectiveness in a variety of forms of pain syndromes: tension headaches, migraines, myofascial pains, radiculopathy and peripheral neuropathies, fibromyalgia, complex regional pain syndrome, post-stroke pain, cardialgia, abdominalgia. The choice of a specific antidepressant in each case is determined individually. However, some peculiarities should be noted here. Thus, the experience of thymoanaleptic therapy in the treatment of chronic pain is available with respect to TCAs (amitriptyline, clomipramine), SSRIs (fluoxetine). At the same time, the therapeutic doses of TCAs required to relieve pain symptoms are used 2-3 times lower than to achieve an antidepressant effect. And SSRIs are usually used in a standard dose. As a rule, the analgesic effect of antidepressants is achieved in time much faster (by 1-2 weeks), i.e. outstrips the antidepressant effect.

The specific mechanisms of action of antidepressants in chronic pain are not fully understood. Along with the indirect influence on the mechanisms of pain formation following the thymoanaleptic effect, the antinociceptive effect of antidepressants is also assumed.

The range of indications for the use of antidepressants in chronic pain syndromes has recently expanded in connection with the development of the concept of “drug-induced” or “analgesic-induced” headaches (“abusal” headaches), which constitute the bulk of chronic daily headaches (HEG) … The origin of this type of cephalalgia is associated with the daily uncontrolled and, as a rule, unjustified intake of analgesics or, less often, other drugs in order to stop, and more often to prevent headaches. As a result, under the influence of chronic administration of analgesics, the primary headaches present in patients (migraine, episodic tension headache, etc.) are transformed clinically into daily chronic cephalalgia. Moreover, one of the prerequisites for this transformation is the presence of depressive disorders. Among all forms of headaches, HEG is the leader in terms of the representation of emotional-affective, including depressive disorders, as well as comorbid disorders. Based on these ideas, along with the abolition of the drug, which is an “abusus” factor, the main share in the treatment of these patients falls on thymoanaleptic therapy. In this case, the choice, as a rule, falls on TCAs and SSRIs, and the rules for conducting therapy are the same as in the treatment of chronic pain syndromes in general.
Clinical use of antidepressants in organic and psychogenic diseases of the nervous system

Parkinsonism is the most frequent form of organic depression in neurological pathology, and along with its clinical evidence (depression occurs in 30-90% of patients with parkinsonism), a pathogenetic relationship between these conditions has also been proven. Associated with this fact is a separate aspect of the therapy of parkinsonism, namely the use of antidepressants. The use of TCAs is based on their ability to block the reuptake of dopamine at dopaminergic synapses in the brain and thereby promote dopaminergic transmission. Traditional for the treatment of parkinsonism is the use of another class of antidepressants – MAOIs, among which deprenyl (Yumex), a selective MAOI of type B, has recently been widely used. Yumex promotes selective enhancement of only dopaminergic activity in the brain, without affecting noradrenergic mechanisms, which is why its lower antiparkinsonian activity. Despite this, Yumex is widely used in the treatment of parkinsonism, rather due to its neuroprotective properties and clinically significant ability to improve mood, which is an important component of the effectiveness of therapy.

In recent years, the clinical significance of depression has been shown in a number of organic diseases of the nervous system, which are based on qualitatively different pathogenetic mechanisms: multiple sclerosis, degenerative diseases (olivoponto-cerebellar degeneration, progressive supranuclear palsy, strionigral degeneration), amyotrophic lateral sclerosis, chorea Huntington’s, hepatolenticular degeneration, etc. The justification for the use of antidepressants in organic depression is due not only to their ability to influence the depressive symptomatology itself, but in some cases also to the neurological manifestations of the disease – motor, dystonic. When choosing an antidepressant in these cases, preference is given to new generation drugs with selective mechanisms of action.

Depressive symptoms often develop in patients with cerebrovascular accident. Therapy of post-stroke depression involves the complex use of drugs of nootropic action, tranquilizers. Prescription of antidepressants in these cases is carried out in more distant stages of the disease, when, along with regression of the neurological defect, the patients have clinically significant depressive symptoms. In these cases, the use of small antidepressants with a balanced or sedative effect (pyrazidol, mianserin, azafen) is justified.

A particular therapeutic problem is the treatment of depression in elderly patients. Since such manifestations as impaired concentration, apathy and memory impairment are the main ones for primary depression in later life. These depressions are called pseudodement. In addition, they are characterized by a wide variety of somatic disorders, the predominance of anxiety-hypochondriac symptoms. On the other hand, depression often accompanies various types of dementia, both Alzheimer’s type and vascular. Considering that with age the frequency of Alzheimer’s disease, as well as multi-infarction dementia, increases several times, differential diagnosis of depression in these forms becomes extremely difficult. If for primary depressions of the elderly it is possible to use small doses of TCAs, the justification for their use in dementia, especially of the degenerative type, is doubtful due to the fact that the development of a gross cholinergic defect is at the heart of the pathogenesis of the latter. Therefore, for the treatment of depression in Alzheimer’s disease, the use of reversible MAOIs (pyrazidol, moclobemide) or SSRIs (sertraline, paroxetine) is recommended. And in these cases, the therapy is based on the effect on the main pathogenetic factors (for example, acetylcholinesterase inhibitors in Alzheimer’s disease).

Depressive disorders are often observed in the clinical picture of patients with epilepsy. The clinical efficacy of carbamazepine and sodium valproate indicates a certain pathogenetic affinity for these conditions. Nevertheless, the therapy of depressive disorders proper causes serious difficulties, since most antidepressants are capable of increasing the threshold of paroxysmal activity.

An example of the widespread use of different classes of antidepressants in neurological practice is psychovegetative disorders, in the therapy of which antidepressants are currently considered basic drugs. So, on the model of panic disorders, the antipanic effect of various representatives of TCAs, SSRIs, OIMAO-A is shown.

Eating disorders in the form of increased appetite (bulimia) are one of the most common combinations of motivational and depressive disorders. The revealed serotonergic deficiency in patients with obesity and eating disorders served as the basis for the possible use of serotonergic antidepressants for the treatment of obesity. Thus, the first attempts to use fluoxetane in obese patients indicate that fluoxetane not only normalizes the emotional state and eating behavior, but also contributes to a decrease in body weight and a decrease in psychovegetative and algic manifestations associated with these disorders.

The pathogenetic commonality of the formation of depression and a number of clinical phenomena, which are often dominant in the structure and neurological disorders, justifies the widespread use of antidepressants in neurological practice. Thanks to the successes of psychopharmacology and the creation of new drugs with targeted selective mechanisms of action, the possibilities for effective treatment of neurological patients are also significantly expanded.

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