Antidepressant Lundbeck Cipralex (escitalopram) - reviews

Indications

◊ Recommendations of the Russian Ministry of Health

F32 Depressive episode

F33 Recurrent depressive disorder

F40.0 Agoraphobia

F41.0 Panic disorder (episodic paroxysmal anxiety)

◊ FDA recommendations

• Major depressive disorder (adults and children over 12 years of age)
• GTR

◊ Recommendations from UK Medicines and Healthcare Products Regulatory Agency

• Major depressive episode
• Panic disorder with/without agoraphobia
• Social phobia
• GTR
• OCD

◊ Using Off-label

• Vasomotor symptoms during menopause
• Insomnia
• Dysmorphophobia
• Bulimia [5].

Mechanism of action and pharmacokinetics

Escitalopram is the S-isomer of citalopram. Selectively inhibits the reuptake of serotonin, increasing the concentration of this neurotransmitter in the synaptic cleft. Escitalopram, like other antidepressants from the SSRI group, practically does not bind to dopamine (D1 and D2) receptors, α-adrenergic and m-cholinergic receptors, as well as benzodiazepine and opioid receptors [4]. Long-term use of escitalopram leads to desensitization of somatodendritic 5-HT1A and terminal autoreceptors.

• Bioavailability – 80%.
• Half-life 27-32 hours
• Stable concentration in the blood is maintained for one week
• Metabolized by CYP3A4, CYP2C19; inhibits CYP2D6

Currently, according to an analysis conducted by the Organization of Economic Cooperation and Development (OECD) in 25 countries, there is an increase in the consumption of antidepressants. Thus, in Germany, from 2012 to 2021, there was an increase in the consumption of antidepressants in the general population by 46%, and in Spain and Portugal - by 20%. As of 2021, the leaders in consumption of this group of drugs are Iceland and the USA: 10 and 11% of the population, respectively. The presented data do not fully reflect the real situation of antidepressant consumption, since the OECD analysis did not take into account the minor population [1].

One of the most widely used classes of antidepressants are selective serotonin reuptake inhibitors (SSRIs). Drugs in this group are often prescribed to patients due to their relative safety and ease of use. However, based on data from a number of studies, side effects of SSRIs have been described, such as a limited range of emotions and emotionlessness or apathy [1–8].

In the last decade, publications have appeared in the foreign literature characterizing the emotional disturbances that occur with the use of this group of antidepressants as a reversible dose-dependent side effect - “apathy syndrome with SSRIs”, or “indifference syndrome with SSRIs” [2].

Large-scale epidemiological studies on this problem are currently lacking. According to available publications, the prevalence of apathy syndrome varies from 5 to 20% [9]. M. Bolling and R. Kohlenberg [7], based on semi-structured telephone interviews with patients who underwent treatment for depression with one of the SSRI drugs, identified 29 types of undesirable effects and identified 20% of cases of apathy and 16.1% of cases of “loss of ambition.” According to M. Fava [10], every 3rd patient taking SSRIs reports apathy, of which 7.7% report severe and moderate severity; 40% of patients report a loss of motivation, of which 12% report severe or moderate severity. In pediatric practice, the incidence of apathy syndrome was 5% in patients treated with fluvoxamine [11]. There is evidence that emotional blunting (apathy) during antidepressant therapy occurred in approximately ½ of patients, somewhat more often in men (52% of cases) than in women (44%), and was associated with a low quality of remission [12].

It was noted that in patients with SSRI-induced apathy, a similar reaction was not observed in response to taking monoamine oxidase inhibitors or tricyclic antidepressants (including clomipramine) [1], which confirms the specificity of this reaction specifically to SSRIs [1, 2]. When treated with venlafaxine, the syndrome in question was manifested not only by indifference, but also by repeated daily persistent yawning (up to 80 times a day) [13].

Clinical characteristics of apathy

Apathy is widely represented in the structure of mental disorders. It can occur in the form of specific negative disorders within the framework of schizophrenia spectrum disorders, syndrome-forming affect in various types of affective disorders. Apathy is often observed in organic diseases of the brain: cerebrovascular disorders, Alzheimer's disease, dementia with Lewy bodies, frontotemporal dementia, Parkinson's disease, progressive supranuclear palsy, Huntington's disease [14-16].

In psychology, apathy is defined as a form of executive and cognitive dysfunction. Diagnostic criteria for apathetic syndrome have been developed, highlighting the structural components: decreased motivation, goal-directed behavior and cognitive activity, and emotional response [17].

According to the definition of one of the leaders in the study of apathy, R. Marin (1996), it is a primary decrease in motivation that is not associated with changes in consciousness, cognitive impairment or emotional disorders. The manifestation of apathy syndrome can be represented by a decrease in interest in the surrounding world, psychomotor retardation and deterioration in the perception of information [18]. The criteria for apathy are the presence of reduced motivation and at least 2 of the following symptoms: 1) reduced initiative (decreased motivation to act, dependence on others to create something); 2) reduced interest (decreased interest in learning new things or gaining new experiences, weakening of worries about personal problems; 3) reduced emotionality (constancy of affect, weak emotional response to positive or negative events).

The clinical manifestations of apathy can be divided into 3 main components. The first is characterized by a decrease in the productivity of activity, a weakening of the efforts applied to it, a decrease in the duration of its implementation (interest in any activity), a decrease in initiative, and the need for external stimulation of the patient’s activity. The second includes a decrease in interest in mastering new knowledge, skills, and indifference to one’s health and personal problems. The third is manifested by a decrease in emotional reactions to both positive and negative stimuli.

R. Marin suggests distinguishing between apathy as a symptom and as a syndrome [18, 19]. Apathy as a symptom may result from markedly low mood in depression, significant decline in cognitive function in dementia, changes in alertness such as marked sleepiness, and inability to concentrate in delirium. Apathy may be an independent syndrome in which the decrease in motivation is not secondary, as in depression or dementia, but primary, and has a special pathophysiological basis.

Anatomical correlates of apathy syndrome have been discovered, in particular, nonspecific changes in the structure of white and gray matter with a decrease in their volume and density [20], specific changes localized in the cingulate cortex [21, 22], frontal lobes [23, 24] and basal ganglia [25 ]. This has made it possible to view apathy as a multidimensional phenomenon secondary to dysfunction or damage to the prefrontal cortex. N. Lavretsky et al. [26] described neuroanatomical differences on magnetic resonance imaging in elderly patients with depression, apathy, anhedonia and anergy. These disorders were characterized by nonspecific changes—an increase in the total volume of postischemic lacunar changes in the brain, mainly in the white matter and putamen of the cerebral hemispheres. The specificity of the changes concerned their localization. Thus, with anhedonia, anergy and apathy, a decrease in the volume of white matter was observed, only with anergy and apathy - the volume of the cerebral cortex, and with depression, more pronounced post-ischemic lacunar changes in the thalamus were noted. In addition, in patients with anergy and anhedonia, the number of foci of hyperintense MR signal on T2-weighted images in the white matter of the brain increased. A specific neuroanatomical sign for apathy was a decrease in hippocampal volume [26]. In the work of A. Grool et al. [27] found a decrease in the density of the gray matter of the brain in the thalamus, amygdala and striatum, as well as pronounced vascular changes in the frontal lobe.

Depression and apathy

It is believed that apathy is a typical component of depression, especially in older people (74.5%) compared to depression in young people (53.5%) [28].

Sh. Ishii et al. [29] identify signs of similarities and differences between apathy and depression. Their common symptoms include decreased interest, psychomotor retardation, fatigue, and drowsiness. The most characteristic features of apathy are flattened emotional reactions, indifference, low social involvement, lack of initiative and decreased duration of activity. Distinctive signs of depression are such manifestations as suicidal thoughts, ideas of self-deprecation and guilt, pessimism, and hopelessness.

In cases of dementia, in which depression and apathy are present simultaneously, their manifestations are associated with damage to different areas of the brain, which shows differences in the pathophysiological mechanisms of these syndromes. Thus, in Alzheimer's disease, psychomotor agitation and behavioral disturbances correlate with the formation of neurofibrillary tangles in neurons of the orbitofrontal cortex, while an increase in apathy is associated with their greater severity in the anterior cingulate cortex [30, 31].

The question of whether the occurrence of apathy while taking SSRIs is a residual symptom of depression (apathy as a symptom) or is a consequence of taking an antidepressant (apathy as a syndrome) remains controversial.

In one of the studies [32], when determining the emotional side effects of SSRIs, it was found that SSRI-induced indifference/apathy is manifested by a reduction in the intensity of emotional experiences (“I think rather than feel”, “emotions are not real, they are difficult to understand”), including emotions of a higher order (conscience, sense of duty, emotions associated with hobbies and other interests, music, nature, feelings of beauty, inspiration, imagination, creativity), emotional alienation.

The structure of emotional disorders while taking SSRIs is shown in the figure

Structure and frequency (in%) of emotional disorders in patients treated with SSRIs. [7].

Thus, taking SSRIs is associated with disorders such as decreased activity in both the behavioral (decreased motivation) and emotional (blunted emotions) spheres. Although these symptoms are divided into two separate clusters, from a clinical point of view it is common to combine them and describe them as SSRI-induced apathy.

The clinical characteristics of SSRI-induced indifference/apathy (SRI-induced indifference) include the following: low motivation, especially in children and adolescents; delayed and slow onset; predisposition to the development of apathy syndrome when using high doses of SSRIs; leveling of apathy when stopping SSRI therapy or reducing their dosages[1].

SSRI-induced apathy is often associated with SSRI-induced sexual dysfunction. Thus, 80% of patients with SSRI-induced sexual dysfunction have clinically significant blunting of emotions. The results of a survey using the Laukes Emotional Intensity Scale (LEIS) showed that, compared with the control group, patients with SSRI-induced sexual dysfunction noted a significant decrease in the ability to experience erotic dreams, sexual pleasure and loss of interest in sex [33].

Diagnosis of apathy

The SSRI side effect in question is often unrecognized: missed by the attending physician or regarded as a manifestation of the patient’s existing depression [34]. For example, the anhedonia and decreased activity observed in depression and related to affective symptoms may be perceived as apathy, and vice versa. An incorrect clinical and psychopathological assessment of the patient's condition may lead to an increase in antidepressant doses, which leads to increased apathy. Thus, a kind of “vicious circle” is formed: on the one hand, taking an antidepressant from the SSRI group can help reduce the severity of depressive symptoms and its withdrawal is accompanied by its increase, and on the other hand, apathy, which was previously absent in the patient, can worsen as therapy continues and increasing drug dosages.

Other psychotropic drugs can also cause lethargy, such as antipsychotics. However, antipsychotic-induced apathy differs from SSRI-induced apathy in that, in addition to emotional flattening and decreased motivation, patients experience extrapyramidal and cognitive impairment. In addition, when apathy develops during SSRI therapy, it is necessary to carry out a differential diagnosis with similar conditions in connection with dementia, hyperthyroidism, damage to the frontal lobe, cannabinoid use, and schizophrenia spectrum diseases [35].

When psychometric instruments are used, apathy is often identified as one of the symptoms of depression, such as the Hamilton Depression Scale (HAM-D). Therefore, for the purpose of differentiated assessment of apathy, it is preferable to use a specific scale - Apathy Evaluation Scale, Clinician version (AES-C). In this regard, studies that used different scales are of interest. Thus, in a study by E. Aydemir et al. [9] showed that taking SSRIs (fluoxetine, escitalopram, paroxetine) for 6 weeks in a group of patients with major depressive disorder or anxiety disorder led to significant positive changes in the Hamilton Depression and Anxiety Scales (HAM-D and HAM-A) , at the same time, the AES scale scores significantly increased. At the same time, in patients taking selective serotonin and norepinephrine reuptake inhibitors (SSRIs; venlafaxine) for 6 weeks, there was also a significant positive change in results according to the HAM-D and HAM-A scales, but no significant changes were detected on the AES scale . This confirms the role of SSRIs as a factor in the development of apathy.

In 2021, the OQESA questionnaire (Oxford Questionnaire of Emotional Side Effects of Antidepressant Therapy) was validated [36]. This questionnaire was found to reliably capture emotional side effects during antidepressant treatment, differentiating them from depressive symptoms. The corresponding data were obtained from a survey of 669 patients who were taking antidepressants at the time of the survey; 150 were in remission, of which 46% noted emotional dulling. Among the latter, 37% of patients assessed their condition negatively, and 38% positively. Men were significantly more likely to perceive this condition negatively than women ( p

=0,008).

Possible mechanisms for the development of SSRI-induced apathy

There is no precise understanding of the mechanisms of SSRI-induced apathy yet, but there is a fairly reasonable assumption that the reason for its development in these cases is an increase in serotonergic transmission in certain neuronal structures. It is assumed that SSRI antidepressants, through the serotonin system, influence activity in the frontal lobe or, through the prefrontal cortex system, project changes in midbrain systems [1, 2, 4, 5, 35].

It is believed that SSRIs may influence the activity of the frontal lobes, potentiating their inhibitory effect. On the other hand, SSRIs may affect the serotonergic systems, which act on midbrain dopaminergic projections to the prefrontal cortex. There is a complex interaction between the serotonin, norepinephrine and dopaminergic systems, influencing each other and the release of neurotransmitters. For example, the 5-HT2C receptor plays a specific role as an inhibitor of dopaminergic neurons [37]. It is known that activation of the dopaminergic system is associated with motivation and feelings of pleasure, and the effects of serotonin through the 5-HT2C receptor may be associated with the development of SSRI-induced apathy [38]. A study by I. Callegari et al. [39] provided some evidence in favor of this mechanism of apathy. The effect of agomelatine on apathy was studied in a group of patients with frontotemporal dementia. Agomelatine is an antidepressant that stimulates melatonin receptors type 1 and 2 and exhibits antagonistic activity at 5-HT2C receptors. During the study, in the group of subjects taking agomelatine, a significant decrease in the severity of symptoms of apathy was noted compared to the group taking melatonin.

Important data were obtained using single-photon emission computed tomography in patients with SSRI-induced apathy, which showed that changes in the frontal lobes are reversible [4].

Attention is drawn to the fact that the described apathy syndrome does not occur in all patients, i.e., other factors may also play a role in its development, and this significantly complicates the understanding of its mechanisms.

Therapy for SSRI-induced apathy

Discontinuation of SSRI therapy is considered as a way to overcome SSRI-induced apathy [40]. When depression occurs in this case, three main therapeutic strategies are recommended [2].

The first strategy involves reducing (titrating) the dose of the SSRI (provided that reducing the drug dosage will not cause an exacerbation of pre-treatment symptoms). An antidepressant dosage is selected that is sufficient to correct all or part of the symptoms of depression, but less than the critical dose level that causes apathy. This strategy may be effective when using antidepressants with a shorter half-life [3]. If it is not possible to titrate the doses of the original drug, it can be replaced with an SSRI with a shorter half-life [5].

The second strategy is augmentation therapy. For example, the addition of bupropion to therapy has been shown to eliminate this side effect [41]. It must, however, be borne in mind that bupropion is not used in the Russian Federation; the drug is regarded as an ephedrone derivative and therefore falls under the List of Narcotic Drugs, Psychotropic Substances and Their Precursors Subject to Control.

The third strategy is to replace a drug from the SSRI group with an antidepressant from another group, for example, an SSRI [2]. So, Milnacipran (Ixel) may be a possible drug of choice.

Milnacipran is an antidepressant with a dual mechanism of action, the most noradrenergic (balanced) SSRI, dose-dependently increasing the levels of serotonin and norepinephrine in the hippocampus, as well as the levels of serotonin, norepinephrine and dopamine in the prefrontal cortex ( in vivo

) [42]. At low doses (25-75 mg), the noradrenergic effect is somewhat predominant, and at a dosage of 100 mg/day the effect becomes equal (in the serotonin/norepinephrine ratio) [43].

Differences in clinical response to Milnacipran and SSRIs can be seen in a French double-blind, comparative, multicenter study [44] that compared Milnacipran (100 mg) and paroxetine (20 mg). After 6 weeks of therapy, patients who had 3-4 points on item 8 of the HADRS scale (psychomotor retardation) were 2 times more likely to achieve remission when treated with Milnacipran compared with paroxetine ( n

=300,
p
<0.05). These data were confirmed by the results of another comparative study of Milnacipran (100 mg/day) and paroxetine (20-50 mg/day) [45].

From a clinical point of view, the differences in the effects of SSRIs and Milnacipran are easier to understand when assessing the effects of the drugs on the SASS (Self-Assessment Scale of Social Adjustment), which assesses leisure activities, relationships with friends, family, work, general social relationships and self-perception. In a small Japanese study [46], twice as many patients achieved SASS remission when treated with Milnacipran (mean dose 83 mg/day) compared with paroxetine. In the study by Yu.A. Alexandrovsky et al. [47] also demonstrated the effectiveness of Milnacipran in the treatment of adaptation disorders in individuals with impaired social relationships. To this we can add that Milnacipran is able to increase the level of motivation of patients for rehabilitation, in particular in patients with depression after a stroke [48].

It is possible to transfer a patient from an SSRI to Milnacipran without a washout period of the drug due to its lack of metabolism mediated by the cytochrome P-450 system. Thus, in one study [49], no differences were noted at all when switching rapidly or gradually from fluoxetine to Milnacipran [50].

As part of the second strategy to overcome apathy, combinations of SSRIs with Milnacipran can be used, which may overall improve the therapeutic response to antidepressant therapy. For example, the combination of Milnacipran with fluvoxamine resulted in a therapeutic response in 80% of patients after 3 weeks of therapy. When choosing a drug to transfer from an SSRI in the event of SSRI-induced apathy, an important factor in favor of Milnacipran is its ability to restore sexual function impaired by SSRIs, especially in women (libido, orgasm intensity). In a study by D. Baidwin et al. [51] evaluated the effect of Ixel in SSRI non-responders with SSRI-mediated sexual disorders while observing 80 patients, of whom there were 64 women, during treatment with fluoxetine 20 mg/day, paroxetine 20 mg/day and sertraline 100 mg/day. When switching to therapy with Milnacipran 100 mg/day, not only an increase in the effectiveness of antidepressant therapy was achieved (after 12 weeks, 61.3% of patients demonstrated a therapeutic response of at least 50% reduction in symptoms according to HAM-D), but also an improvement in scores on the sexual dysfunction questionnaire.

In general, it can be stated that Milnacipran is the drug of choice for most patients with depression, since, being comparable to tricyclic antidepressants in terms of effectiveness, it is superior to them in tolerability, and has greater effectiveness than SSRIs [52].

However, when using Milnacipran, one should take into account such features of the action of noradrenergic antidepressants as the effect on blood pressure (BP). In the presence of elevated blood pressure, preliminary correction is required. However, patients with apathy are characterized by a reduced blood pressure level. In addition, you need to keep in mind the possible presence of untreated adenoma in elderly men - in these cases, preliminary administration of an alpha-blocker (tamsulosin or others) is required.

Thus, SSRI-induced apathy is a clinical reality [53]. The prevalence and causes of this syndrome remain poorly understood. Considering the data from the above studies, it can be assumed that the cause of apathy syndrome during SSRI therapy is the drug itself, and not the residual symptoms of depression. Unfortunately, the level of evidence for this statement is insufficient and requires further study in large clinical samples. From a practical point of view, to improve the outcomes of SSRI antidepressant therapy, the possibility of developing such a side effect (indifference, loss of initiative) should be highlighted within the framework of psychoeducation and active monitoring of the patient’s condition during psychopharmacotherapy should be carried out.

The authors declare no conflict of interest.

The authors declare no conflicts of interest.

Information about authors

Petrova N.N. - https://orcid.org/0000-0003-4096-6208; e-mail

Markin A.V. - https://orcid.org/0000-0001-9510-4918; e-mail

Corresponding author:

Petrova Natalia Nikolaevna — e-mail

Treatment regimen

◊ Dosage and dose selection

• Optimal dose for treating depression, OCD and GAD: 10-20 mg/day
• Start with 10 mg/day, increase to 20 mg if necessary
• Take once daily, morning or evening
• 10 mg escitalopram is comparable to 40 mg citalopram, but without side effects
• A dose of 30-40 mg is suitable for some patients [1]
• To relieve vasomotor symptoms during menopause, 10 mg/day is sufficient, but if ineffective within 4 weeks, the dose may be increased to 20 mg/day
• If anxiety, insomnia, agitation, or akathisia occur at the beginning of treatment or after interruption of treatment, the possibility of bipolar disorder should be considered and switched to a mood stabilizer or an atypical antipsychotic

◊ How quickly it works

• Begins to act after 2-4 weeks
• If there is no effect after 6-8 weeks, you need to increase the dose or switch to another drug
• To prevent relapse, it can be taken for many years.

◊ Expected result

• Complete remission.
• After the symptoms of depression disappear, you should continue taking it for 1 year if this was the treatment of the first episode. If this is to treat a recurrent episode, treatment can be extended indefinitely.
• Use in the treatment of anxiety and chronic pain may be indefinite.

◊ If it doesn't work

• Change the dose, switch to another medicine or add an auxiliary drug;
• Connect psychotherapy;
• Review the diagnosis by identifying comorbid conditions;
• In patients with undiagnosed bipolar affective disorder, the effectiveness of treatment may be low, in which case it is necessary to switch to a mood stabilizer [1].
• In the acute phase of severe depressive disorder, which is accompanied by psychotic or catatonic symptoms, as well as in patients with current suicidal ideation, electroconvulsive therapy should be considered [7].

◊ How to stop taking it

It is usually not necessary to reduce gradually, but to be sure to avoid withdrawal symptoms, you can reduce it gradually. Gradual reduction scheme: dose reduced by 50% - 3 days, again reduced by 50% - 3 days, complete cessation. If withdrawal symptoms appear, increase the dose, wait for withdrawal symptoms to subside, and continue decreasing [1].

◊ Treatment combinations

• For insomnia: trazadone
• For fatigue, drowsiness, loss of concentration: modafinil [3].
• Combinations with other antidepressants may activate bipolar disorder and suicidal ideation
• For bipolar depression, psychotic depression, treatment-resistant depression, treatment-resistant anxiety disorder: mood stabilizers, atypical antipsychotics
• For anxiety disorder: gabapentin, tiagabine

The effectiveness of the drug escitalopram (Cipralex) in the treatment of panic attacks

Escitalopram (Cipralex) is a highly selective serotonin reuptake inhibitor (SSRI) with proven effectiveness against panic disorders. Due to the selectivity of their action, antidepressants of the SSRI group have a significantly lower number of side effects and the degree of their severity in comparison with drugs of the previous generation - tricyclic antidepressants. The antidepressant effect of escitalopram has been demonstrated in clinical trials, including placebo-controlled ones, mainly in patients with depressive disorders.

Table 1. Patient population

Table 2. Previous diagnoses

Table 3. Groups of drugs used as therapy

Table 4. Main complaints during an attack of PA

Table 5. First Panic Score

Table 6. What, according to the patient, is associated with the development of the disease

Table 7. Characteristics of attacks

Table 8. Dynamics of attacks

Rice. 1. Weekly self-assessment according to VAS for 10 weeks

Table 9. Dynamics of test indicators over 10 weeks

Table 10. Subjective assessment of escitalopram therapy in patients with PsA

Escitalopram is the S-enantiomer of the SSRI citalopram, a racemic compound consisting of two isomers (S- and R-). It has been established that the ability of the S-isomer to inhibit serotonin reuptake is more than 100 times higher than that of the R-isomer. S-citalopram was isolated as an independent drug, which is superior to citalopram in the speed of development of the clinical effect and the degree of its severity.

Thus, in previous studies, using escitalopram at a fixed dose of 10 mg/day, the same improvement in key parameters of antidepressant efficacy was observed as when using 40 mg citalopram. The early and persistent antidepressant effect of escitalopram is achieved using doses in the range of 10–20 mg/day. with exceptionally good tolerability [11]. According to multicenter studies conducted in the United States, escitalopram was well tolerated in 76% of cases, regardless of dose. Discontinuation of escitalopram due to side effects was recorded in 4.2% of those taking the drug at a dose of 10 mg/day. and in 10.4% - at a dose of 20 mg/day. [16]. The severity of adverse events that occurred during therapy does not exceed 2 points on the scale of side effects of therapy (UKU), which indicates the absence of a significant impact on the patient’s condition and functioning. The dynamics of adverse events are regressive in nature, i.e., by the end of the 2nd week of treatment, most manifestations are mild and lose both objective and subjective significance [3].

Panic attacks (PA) are the most severe form of anxiety disorders, leading to severe maladjustment [14], having a chronic course with exacerbations and remissions [4]. PAs are discrete periods in which there is a sudden onset of intense anxiety, fear or terror, often associated with a feeling of impending doom. These attacks are characterized by symptoms such as shortness of breath, throbbing, chest pain or discomfort, a feeling of suffocation, and fear of “going crazy” or “losing control” [5]. Diagnostic criteria for a panic attack (PA) are paroxysmalness, polysystemic vegetative symptoms, the presence of emotional disorders, the severity of which can range from “a feeling of discomfort” to “panic.”

Purpose of the study

The effectiveness and tolerability of a 10-week course of escitalopram (Lundbeck) at a dose of 5–10 mg/day were assessed. in the treatment of panic disorders according to the dynamics of clinical characteristics and psychometric indicators, as well as identifying predictors of therapy effectiveness. The main assessment of effectiveness was made by the frequency of panic attacks in the 10th week of treatment compared with baseline indicators (before the start of treatment) and the effect of the drug on comorbid conditions. The effectiveness of escitalopram was verified by a statistically significant reduction in panic attacks, a decrease in the level of anxiety, and depression.

Research material

Forty outpatients fulfilling DSM-IV (1994) and ICD-10 (1995) criteria [13, 17] for panic disorder with or without agoraphobia. All subjects had typical PAs – the typicality index was 0.68 [3]. Among the examined patients, there were 27 (67.5%) women and 13 (32.5%) men. The average age of patients in the whole group at the time of treatment was 35.9 ± 9.1 years (from 24 to 61 years). The average age of onset of PA was 33.8 ± 8.1 years (from 23 to 57 years), with 33.3% being within the age limit of 25–35 years, 33.3% within the age limit of 35–40 years, and 14 .8% – within 30–35 years. That is, all the examined persons were of active, working age. The average duration of the disease in the group was 1.1 ± 1.1 years (from 1 month to 4 years). The patient population is presented in Table 1.

Among the examined patients, 29.6% suffered from agoraphobia. These patients were unable to travel on the subway on their own or drive their own car (only when accompanied by loved ones). 25.9% had restrictive behavior, which included poor tolerance of hypermarkets, markets, and other public places that provoke attacks of PA due to “flashing before the eyes of people and a lot of goods.” Among the observed patients, 11 are car owners, but due to attacks of PA they were forced to give up driving a car independently. During therapy, patients began to drive again without any subjective difficulties, which indicates good tolerability of escitalopram against the backdrop of a pronounced effect of increasing concentration.

Professional representation

In the groups of patients there were representatives of different professions, among them 81.5% had a permanent job (manager, head of construction operation, company administrator, doctor, deputy general director of the enterprise, leading specialist in regional supplies, accountant, director of the company, economist, bank employee, businessman, pharmacist, supermarket salesman, curtain designer, personal chef) and 18.5% did not work (housewife, pensioner). Only one patient left work due to the onset of her illness, the rest - due to somatic diseases or age. 51.8% had higher education, 48.2% had specialized secondary education. As can be seen from the list of professions, the vast majority of the patients studied occupy leadership and responsible positions that require maximum internal stress.

It turned out that more than half of the patients had a combination of clinical syndromes: autonomic dysfunction, algic manifestations, motivational and insomnia disorders.

Headaches were observed in 30% of cases. The characteristics of headaches in patients with PA had some signs of tension headaches (localization in the fronto-parieto-temporal region, of a pressing nature, the average intensity on the VAS reached 4-5 points) and differed from the latter in the accompanying symptoms: a feeling of “heaviness in the head”, “ deterioration of hearing”, the feeling that “one can hear the heartbeat”, “something is tense in the head.” Since headaches occurred only in association with other symptoms, these characteristics may indicate that headache was part of a psycho-vegetative complex.

The majority of patients (63%) who sought help had previous diagnoses that either reflected failure in the somatic sphere or did not have a clear nosological focus; 37.5% had no diagnosis at all and only 15% had a corresponding diagnosis of PA (Table 2). The data obtained indicate that panic disorder is underdiagnosed in general somatic practice.

Previous treatment

All patients unsuccessfully or insufficiently effectively (the effect lasted for several days or, less often, 1 month) took a number of drugs without receiving the proper therapeutic effect.

Study design and methods

The patients were examined during the 2nd, 4th, 6th and 10th weeks of continuous therapy with escitalopram. The following methods were used to assess the status of patients:

• clinical and neurological examination according to the survey protocol for patients with PA with assessment of the panic attack typicality index [5];
• psychometric testing using the Sheehan Anxiety Scale (Sheehan, 1983), Beck Depression Inventory (Beck, 1961) [2] and quality of life for panic attacks [5], Holmes TM Life Events Scale [18], 10-point visual analogue scale (VAS) for self-assessment of general well-being (where 0 points are the worst, 10 points are the best idea of ​​the state of health) (according to S. Walker, R. Roser, 1993) [2];
• subjective assessment of the effectiveness of escitalopram therapy on a 5-point scale (where 0 points is no effect, 5 points is a pronounced effect).

Background indicators

During the initial examination, patients in the study group complained of rapid heartbeat, fluctuations in blood pressure, respiratory distress (hyperventilation, “attacks of suffocation,” “inability to inhale,” “lump in the throat”), tension-type headaches, increased anxiety and internal trembling, fixation on the state of one’s health, decreased performance and a feeling of helplessness, lipothymia (“blackout before the eyes”), sleep disturbance (difficulty falling asleep, early awakenings), “ringing in the ears.” During the attack, each patient had several symptoms. The main symptoms accompanying the attack are presented in Table 4.

At the onset, 9 patients had such severe anxiety and fear of death that they had to call an ambulance or were repeatedly hospitalized. The assessment of the “first panic” is presented in Table 5.

Neurological status

In the vast majority of patients, the following features were revealed in their neurological status: revival of tendon reflexes from the arms and legs with expansion of reflexogenic zones, with unstable pathological hand signs (Rossolimo, Hoffman rivers), dissociation of reflexes along the axis (more vividly from the legs than from hands), Khvostek's sign of I–II degree, wetness of the hands, nystagmus in the extreme abductions, slight asymmetry (smoothness) of the nasolabial folds.

An analysis of patients’ opinions regarding the provoking factor in the development of the disease showed that the majority of patients (37.5%) indicated stressful situations at home and/or at work as the main factors that provoked the development of the first attack of PA (Table 6). But it should be noted that there was often a combination of several factors.

Treatment results

The study results showed that out of 40 patients, 33 (82.5%) completed the full 10-week course of escitalopram therapy. Subjectively, the frequency (from 14 to 0–1 attacks per week) and intensity of attacks (from high, with an ambulance call, to complete absence), the duration of one episode (from 24 hours to several minutes), and the number of symptoms in an attack (from 13 to 1) at the end of the course of therapy.

At the initial stage, only a small proportion of patients used therapy correctors: anaprilin, sonopax, alprazolam, fluanxol.

We assessed the effectiveness of therapy based on the qualitative characteristics of the attack and their dynamics, using objective rating scales; we compared the effectiveness in groups of patients who had previously taken and had not taken antidepressants (Table 3). Table 7 presents the qualitative characteristics of the attack.

Noteworthy is the long duration of the attack, which in some patients reached several hours. This circumstance is due to the fact that for the duration of the attack, patients took a combination of events that included the attack itself, a post-attack state in the form of asthenia, anxiety, irritability, headaches, etc., or a series of attacks with short time intervals.

All patients (100%) had daily both full-blown and abortive attacks before starting therapy. In the process of taking the drug, there was the following dynamics: a gradual decrease in attacks and shortening their duration, a decrease in intensity until complete cessation, and an increase in self-control during an attack. The dynamics of attacks are presented in Table 8.

In the background study, all patients (100%) had both spontaneous and situational (100%) attacks of PA. At the end of therapy, spontaneous attacks were not observed in any patient, situational ones persisted in 6 patients and were abortive in nature (a single monosymptomatic attack of low intensity, quickly resolving). In connection with this circumstance, these patients continued taking escitalopram after a 10-week course of therapy.

The drug prescription regimens for those patients (n=33) who completed the full course of therapy were as follows:

1. The initial dose is 1.25 mg/day. for 10 days, the next 10 days at 2.5 mg/s, the remaining days at 5 mg/day. (n=1);
2. The initial dose is 2.5 mg/day. for 2–3 weeks, followed by a transition to a dose of 5 mg/day. (n=3);
3. The initial dose is 5 mg/day. for 3 weeks, followed by a transition to 10 mg/day. (n=2);
4. The initial dose is 5 mg/day. for 1 week, followed by a transition to 10 mg/day. (n=27).

Most patients used the 4th treatment regimen and the drug was well tolerated. However, when prescribing escitalopram, it should be taken into account that some patients require a specific individual treatment regimen 1, 2 or 3.

The reasons why non-standard treatment regimens were prescribed are as follows. In a patient treated according to regimen 1, after a single dose of 5 mg, severe weakness, dilated pupils, and increased blood pressure were observed - the dose was reduced to 2.5 mg, which also led to increased symptoms of panic. It was decided to further reduce the dose to 1.25 mg, which was well tolerated by the patient. Subsequent dose increases did not cause any side effects. Patients transferred to regimen 2 also turned out to be sensitive to a dose of 5 mg; a dose of 2.5 mg was well tolerated by them. The patient taking the drug according to regimen 3, after a week's course, was unable to switch to a dose of 10 mg; she required a longer adaptation period.

Tolerability of the drug was generally rated by patients as good. Subjectively, within 2 weeks, the following was noted: a decrease in attacks and a decrease in their intensity, an increase in self-assessment of general well-being according to VAS (Fig. 1), improved mood, and normalization of sleep. Objectively, all test indicators reliably changed for the better (Table 9).

Subjective assessment data (on a 5-point scale) of escitalopram therapy by patients who completed a 10-week course of treatment are presented in Table 10. Most patients rated the drug at 5 points. The average sum score was 4.57.

Tolerability of the drug included side effects, paradoxical reactions, and drug refusal. On days 1–3, almost all patients reported side effects of varying severity: dizziness, “drowsiness,” decreased concentration, and increased anxiety. Paradoxical reactions developed, as a rule, during the first week (on days 3-5-7 of therapy at a dose of 5 mg/day or when switching to a dose of 10 mg/day): severe weakness, rise in blood pressure, sharp worsening of all symptoms of PA, sleep disturbance (insomnia, drowsiness), leg cramps. This was the reason for refusal of escitalopram therapy in 7 (17.5%) patients (5 women, 2 men). The drug was well tolerated by most patients in the following days.

Conclusion

The study showed the high effectiveness of Escitalopram in the treatment of panic disorder over a 10-week course. Patients who completed the course of treatment subjectively highly rated both the effectiveness of the drug and its tolerability.

The anti-panic effect appears in the 2-3rd week of therapy; first of all, full-blown attacks undergo regression. The undeniable advantage of Escitalopram is its effectiveness against concomitant agoraphobic and depressive disorders. The dynamics of the reverse development of depressive symptoms and symptoms of agoraphobia correspond to the regression of panic attacks. Symptoms of agoraphobia have proven to be the most resistant to treatment. In treated patients who retained PA at the end of the treatment course, only situational PA (a marker of agoraphobia) was observed. In the presence of severe agoraphobia and severe panic disorder, longer courses of treatment may be recommended - from 3 to 5 months.

Thus, escitalopram can be recommended as monotherapy or a basic drug in polytherapy for the treatment of panic disorder.

Special patient groups

◊ Patients with kidney problems

Use caution if the patient has severe kidney disease [1].

◊ Patients with liver disease

The recommended dose is 10 mg/day [1].

◊ Patients with heart disease

There are no systematic data on the use of escitalopram in people with pathology of the cardiovascular system. Supposedly safe. Useful in recovery after a heart attack [1].

◊ Elderly patients

For elderly patients, a dose of 10 mg is recommended [1].

◊ Children and teenagers

• Recommended for the treatment of depression aged 12-17 years
• It is necessary to regularly and personally check the patient's condition, especially in the first weeks of treatment.
• Use with caution due to the risk of undiagnosed bipolar disorder and suicidality.
• Inform adults about the risks.

◊ Pregnant women

• There have been no adequate studies in pregnant women [1].
• Not recommended for pregnant women, especially in the first trimester
• All risks should be weighed and compared
• Bleeding can be expected during childbirth

◊ Breastfeeding

• The medicine passes into breast milk.
• If the infant shows signs of irritation or sedation, discontinue feeding or escitalopram
• However, treatment after childbirth may be necessary, so the risks should be weighed.

Escitalopram

Use during pregnancy and breastfeeding

Contraindicated for use during pregnancy and lactation (breastfeeding).

Use for liver dysfunction

Should be used with caution in case of liver cirrhosis.

Use for renal impairment

It should be used with caution in patients with renal failure (creatinine clearance less than 30 ml/min).

Use in children

Contraindicated in children and adolescents under 15 years of age.

Use in elderly patients

Should be used with caution in elderly patients.

special instructions

Use with caution in patients with renal failure (creatinine clearance less than 30 ml/min), hypomania, mania, pharmacologically uncontrolled epilepsy, depression with suicidal attempts, diabetes mellitus, elderly patients, cirrhosis of the liver, a tendency to bleeding, simultaneously with taking medications that reduce the threshold of convulsive readiness, causing hyponatremia, with ethanol, with drugs metabolized with the participation of isoenzymes of the CYP2C19 system.

Escitalopram should be prescribed only after 2 weeks. after discontinuation of irreversible MAO inhibitors and 24 hours after discontinuation of therapy with a reversible MAO inhibitor. Non-selective MAO inhibitors can be prescribed no earlier than 7 days after discontinuation of escitalopram.

Some patients with panic disorder may experience increased anxiety at the beginning of treatment with escitalopram, which usually disappears over the next 2 weeks. treatment. To reduce the likelihood of anxiety, low initial doses are recommended.

Escitalopram should be discontinued if epileptic seizures develop or become more frequent in pharmacologically uncontrolled epilepsy.

If a manic state develops, escitalopram should be discontinued.

Escitalopram can increase the concentration of glucose in the blood in diabetes mellitus, which may require dose adjustment of hypoglycemic drugs.

Clinical experience with escitalopram indicates a possible increase in the risk of suicide attempts in the first weeks of therapy, and therefore it is very important to carefully monitor patients during this period.

Hyponatremia associated with decreased ADH secretion occurs rarely with escitalopram and usually disappears when it is discontinued.

If serotonin syndrome develops, escitalopram should be immediately discontinued and symptomatic treatment prescribed.

Impact on the ability to drive vehicles and operate machinery

During the treatment period, patients should avoid driving vehicles and other activities that require high concentration and speed of psychomotor reactions.

Side effects and other risks

◊ Mechanism of side effects

Side effects are caused by an increase in serotonin. Most side effects occur immediately after starting treatment and go away over time.

◊ Side effects

• Gastroenterological (reduced appetite, nausea, diarrhea, constipation)
• Insomnia, sedation, agitation, tremor
• Sweating
• Urinary dysfunction
• Dry mouth
• Dangerous side effects: seizures, mania, suicidal ideation
• Weight gain: very rare
• Sedation: very rare
• Sexual dysfunction: yes

◊ What to do about side effects

1. Wait
2. Switch to another antidepressant [1].

◊ Long-term use

Safely

◊Addiction

No.

◊ Overdose

• There are very few reports of overdose.
• Very rare cases of fatal overdoses.
• Vomiting, sedation, cardiac arrhythmia, dizziness, tremor.

Expert advice

• The best antidepressant in terms of tolerability
• Lowest sexual impact compared to other SSRIs
• Lack of response to escitalopram in elderly patients may indicate Alzheimer's disease
• In postmenopausal women, escitalopram works better in combination with estrogen [1]
• Escitalopram and fluoxetine show similar effects in the treatment of depression. The only difference noted is that escitalopram significantly improves microinflammation in the patient’s body [6].