Clinical polymorphism and neurocognitive dysfunctions in treatment resistance depressions

SUMMARY

The study revealed a high frequency of cognitive dysfunction (violation of attention, difficulty in making decisions, impaired memory, and information processing deficits, psychomotor disturbances, and abuse of executive functions) and set the complex nature of relationships between depressive symptoms and cognitive impairment in therapeutically resistant depression.

Key words: treatment resistant depression, cognitive dysfunction, psychopathological characteristic

The prevalence of depressive disorders in the population is a central problem of modern psychiatry, since negative impact on socio-economic indicators due to the high degree of patient’s social dysfunction and working capacity, and because a large percentage of disability caused by depression [6]. Among the depression about 30-60% is treatment resistant, that significantly enhances the importance of this nosology [16]. Cognitive functioning long been regarded as one of the markers of depressive disorders, the concept of cognitive deficits is an integral part of depression.

The symptoms of cognitive disorders are one of the diagnostic criteria for depression: decreased concentration, memory impairment, disturbance of planning activities and decision-making, slowing of speech. At the present stage cognitive impairments in depressive disorders are in the focus of researchers not only as one of the main manifestations of the disease, but also as one of the efficacy criteria of treatment and further social functioning of patients [1, 3, 4]. The quality of social functioning with reducing of affective symptoms is modern determining factor in assessing the effectiveness of antidepressant therapy [6]. According to different scientific data, cognitive disorders in a Treatment Resistant Depression (TRD) found in 94% of cases and stored as residual symptoms in remission in 44% of cases [2, 6, 9, 11].

The factors that influence the development and severity of cognitive impairment in TRD are: patient's age, educational level, age of onset, disease duration, number of episodes, clinical and psychopathological types of episodes, comorbid states (anxiety, comorbidities), methods of treatment [12, 15]. Pathomorphological substrate of cognitive disorders in TRD is a disturbance of neuroplasticity. Thanks to the latest scientific achievements by using of modern investigational methods it was found that in depressive disorders occur pronounced ultrastructural and makromorphological changes in certain brain structures [8,18].

It is known that the dorsolateral frontal cortex and striatum complex connections involved in the formation of positive emotional afforcement in process of goal achieving. Breaking of these connections due to the gap phenomenon causes failure of positive reinforcement and results the state of chronic frustration that leads to depression. Also it was shown that in patients with TRD is a reduction of the hippocampus observed [22].

Moreover, the degree of reduction of its volume correlates with the number of depressive episodes. At the same time it was found that not only the number of neuronal cells but also the number of active synapses reduced in the hippocampus also decreased of dendrites length and it’s branching and terminated of neurogenesis processes. Parallel extended reducing of the size of the prefrontal cortex because reducing the density and size of the cell cortex (both neurons and glial cells), as evidenced by histological study of biopsies. At the same time, lifetime study of patients using Positron Emission Tomography (PET) revealed reduces of blood flow and glucose metabolism in this part of the brain. Structural and functional changes have been found in corpus amygdaloideum in recent years. It was proved that in patients who suffered from TRD has an increase of blood circulation and glucose metabolism in corpus amygdaloideum, which further enhanced with increasing severity of depression. The dimensions of amygdale in these patients in the early stages of depression often increased. But over time, duration of disease is reducing its size observed [11, 12, 14].

An important discovery was to determine of glutamate as the biochemical basis of neuroplasticity. Glutamate is an excitive neurotransmitter. It is essential substance for normal brain neuronal functioning. But in case of glutamate excess in human brain it starts cascade of reactions that leads to injury and death of neurons. It is proved that by glutamate neurotoxicity it is caused listed above structural changes in the brain in patients with TRD. Thus, cognitive impairment in understanding the pathogenesis and clinics of TRD occupy a leading position, and the quality of cognitive functions is an important marker of treatment efficacy and predictor of further social rehabilitation even to a greater extent than the severity of depressive symptoms [5, 12, 16,19].

The aim of this study was to analyze the features of neurocognitive deficiency in patients with TRD in terms of their clinical polymorphism.

Materials, design and procedure

Prior to the study on the basis of informed consent 87 patients was involved, men (24) and women (63), aged 22- 40 years, with verification of diagnosis according to ICD-10 criteria: depressive episode in the structure of bipolar affective disorder of varying severity (F31. 3 - F31.5), depressive episode (F32), recurrent depressive disorder (F33), dysthymia (F34.1), with signs of resistance to treatment (depression considered resistant if during two consecutive courses (3-4 weeks) of adequate monotherapy with pharmacologically different drugs was recorded absence or lack of clinical efficacy (reduction of symptoms by the Hamilton scale was less than 50%) [21].

Organic brain diseases include brain injury, psychoactive substance abuse, metabolic disorders, drugs overdose was exclusion criteria for this study. All patients at the time of the study were treated in a Communal Institution "Lviv Regional Clinical Psychiatric Hospital". Examination was conducted at the first week of inpatient treatment. Clinical and psychopathological method based on the principles of psychiatric examination of patients according to clinical criteria of ICD-10. The survey evaluated the mental state by analyzing of patients' complaints, anamnesis, the assessing of symptoms, syndromes, their psychopathological interpretation and correlation characteristics with classification ICD-10. To assess of clinical manifestations and degree of severity for depressive disorder we used HAMD-21 scale (Hamilton M., 1960) [10].

By using HAMD-21scale were evaluated severity of TRD, in results with 7-16 points was interpreted as a mild depression, 17-27 points-as moderate, severe depression was qualified with more than 27 points. To assess the cognitive function in patients who suffered from TRD we used the MMSE - MiniMental State Examination (mental status short scale assessment). The result was obtained by summation of points (maximum can be 30). About absence of cognitive disorders indicated result in 28-30 points, cognitive impairment occurred in 24-27 points, mild cognitive dysfunction was diagnosed in 26-27 points and moderate in 24-25. Dementia found when the result was below than 24 points. As an instrument for the study of objective indicators of cognitive function we used the Montreal Cognitive Scale (called MoCA test) (Nasreddin Z., 1996) [7], which allows assessing different cognitive areas: attention and concentration, executive functions, memory, language, constructive and visual skills, abstract thinking, counting and orientation.

The time of scaling is 10 minutes. Assessment in 26-30 points indicates normal cognitive status. At 18-26 points results interpreted as mild cognitive impairment, at 10-17- as moderate. Less than 10 points is defined as a deep degree of cognitive deficit [11]. During psychological examination was also used Trail Making Test (TMT) (Reitan RM, 1958) [17] for observing of visual-motor coordination, which consists from 2 parts: part "A" evaluates eye coordination and part "B" - attention, working memory and executive function. The result is determined by the time spent on tasks both parts ("A" and "B"), but no more than 4 minutes. By Verbal Fluency Test (VFT) (Lezak MD, 1995) [13] we studied the contributions of verbal ability and executive control to verbal fluency performance. It consists from 2 subtests: Category (Semantic) Subtest and Letter (Phonetic) Subtest. To evaluate the intensity and selectivity of attention and executive functions study we used Stroop color word interference test (Stroop JR, 1935) [20].

Statistical analysis was performed using Microsoft Excel 2010.

Results and discussion

Firstly detailed analysis of patient’s sociodemographic data was conducted. The average age of the patients was 32, 2 ± 4, 7 years. By the educational level the examined group was as follows: people with basic secondary education- 7, which is 8.0%, with the secondary vocational-42 (48.3%), university degree had 38 patients (43.7%). Characteristics of employment status in the group of studied patients found that the employed was 33 people, unemployed was 28 patients, and were on disability 26 patients, which is 37.9%,32.2% and 29.9% rateably. Subgroup of employed patients was divided into 2 parts: most of them were in mental work- 24 people (27.6%), other-9 (10.3%) performed physical work.

The duration of resistant depression in a studied group was 4,4 ± 0,7 years with a total duration of disease 12,1 ± 3,4 years. The average age of manifestation of disease was 20, 3 ± 3, 4 years, manifestation of resistance was detected in 20, 6 ± 2, 7 years an average. Duration of depressive episode in TRD was 8,2 ± 1,3 months an average, the number of episodes of depression before transferred to the resistance was 3,4 ± 0,4.

By Hamilton depression scale, 21 points (HAM-D21) were performed evaluation of TRD severity. The illustration for this indicator is presented in Table 1.

Table 1- Indicators of depression’s severity in patients with TRD (by HAM-D21 scale item)

As can be seen from the above data in the majority of patients (79.4%) was recorded severe depression (more than 27 points on HAM-D21 scale). By nosological characteristics it was mainly patients with bipolar affective disorder, depressive episode (26.4%) and recurrent depressive disorder (32.2%). On the basis of the finding data were identified symptoms in structure of depressive syndrome that are typical for most patients with TRD.

These patients often demonstrated less interest for the things that were interesting before (83.9% of cases), reduced ability to experience pleasure (in 95.4% of cases), apathy (55.2%), weakness (74, 7%), increased fatigue (63.2%), anxiety, fear (in 83.9% of cases), sleep disorders (86.2%), physical complaints - in 55.2% of cases. High level of suicidality - 40.2%- was rather, patients exhibited suicidal thoughts, trends, have also been suicide attempts. Summarized data for psychopathological structures of TRD are presented in Table 2.

Table 2 - Psychopathological structures of depressive syndrome in TRD

The results of clinical and psychopathological examination of patients with TRD showed that in

86.4% of cases they expressed disturbances in the cognitive area. Most patients complained losses of confidence, lower self-esteem, pessimistic view for the future, negative retrospective analysis, impaired concentration, reduce of memory, especially short-term type, lack of the ability to understanding of information, problems with abstract thinking, violation of social relations, somatopsychic depersonalization, reduced ability to make decisions.

Considering these facts, results of clinical evaluation were supplemented by neuropsychological investigation of cognitive functioning for patient with TRD. By the criteria of MMSE scale in 12 patients (13.8%) from studied group no cognitive impairment reported. Cognitive deficit was found in 75 patients, which is 86.2%. Mild cognitive decline was found in 37 patients (42.5%), moderate cognitive dysfunction was found in 36 patients (41.4%), and in 2 cases (2.3%) reported markers specific for initial dementia.

The total score by the Montreal cognitive scale (MoCA-test) was 21 ± 2, 4. The most significant were changes of neurodynamic parameters for activity in patients with TRD- efficiency fluctuations and slowing of mental processes. Also was detected significant functional impairment of voluntary attention with increasing distraction to external stimuli that caused ease of side association’s synthesis and placed them to the current activity. Typical is the modal-nonspecific short-term memory disorders, especially in motor language and visual parts.

Trial Making Test (TMT) showed the presence of voluntary attention disorders in patients with TRD, which manifested by decreasing of the ability to switch attention in situation with changing tasks. This is primarily illustrates the neurodynamic character of attention disorders with the absence of primary regulatory violations.

After performing of Verbal Fluency Test (VFT) it was revealed a high degree of patient’s distraction from the task, rapid loss of interest, the need to re-stimulate for further test run. Significant were violations of semantic memory.

By the Stroop test in patients suffering from TRD was registered the difficulty in the crossing from verbal functions into sensory-perceptual functions, that indicating once more the difficulties with attention switching ability. Parameters of cognitive functioning summarized and illustrated in Table 3.

Table 3 - Parameters of cognitive functioning in patients with TRD.

Qualitative characteristics of cognitive disorders in TRD showed heterogeneity of their structure. Basically they have the characteristic of neurocognitive deficit and manifest by violations of executive functions, problems with attention, memory, changing of psychomotor processes flow speed and optic- spatial abilities. Also was determined the features of cognitive impairment depending on the psychopathological variant of depressive syndrome.

Thus, in patients with anxiety (agitated) depression was found significant complications in performing tasks, increase the number of errors, violations of psychomotor coordination, visual-spatial function and long-term memory. Also was observed fluctuations of mental activity efficiency, impulsivity of mental processes. Asteno-anergic variant was characterized by inhibition rate of mental activity, inertia and emptiness of mental processes. Cognitive dysfunction manifested by the violation of attention stability and decrease concentration, by both short-term and long-term memory decline.

In apathy-adynamic clinical variant of TRD phenomenology of cognitive deficits features by pronounced psychomotor inhibition, loss of ability to experience pleasure, decreased motivation, difficulty in concentrating and making decisions, disturbances of dynamic praxis, attention, visual-spatial disorders and memory reductions are dominated. In this manner affective and cognitive deformation influence on the cognitive sphere of patients with TRD that contribute to the emergence of unrealistic conception, opinions and judgments of depressive patients. Also following components of depressive syndrome such as changes of introspection, violations of self-esteem and self-regulations of mental processes (memory, thinking, attention) called as methacognitive disorders and found in TRD. Moreover, the heavier the manifestation of depressive symptoms, especially in the genesis of cognitive impairment, the more of affective and cognitive deformation and methacognitive disorders play the role.

CONCLUSIONS

Thus, our study revealed a high incidence of neurocognitive deficit (violation of attention, difficulty in making decisions, impaired memory, information processing deficit, disturbances of psychomotor functions and executive functions) and set the complex nature of relationship between depressive symptoms and cognitive disorders in patient with TRD.

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