ISSN 03621197, Human Physiology, 2015, Vol. 41, No. 5, pp. 503–509. © Pleiades Publishing, Inc., 2015. Original Russian Text © A.F. Iznak, E.V. Iznak, E.V. Damyanovich, I.V. Oleichik, P.V. Bologov, I.I. Kazachinskaya, T.I. Medvedeva, 2015, published in Fiziologiya Cheloveka, 2015, Vol. 41, No. 5, pp. 57–65.
Transcranial Magnetic Stimulation in Combined Treatment of Pharmacoresistant Depression: Dynamics of Clinical, Psychological, and EEG Parameters A. F. Iznak, E. V. Iznak, E. V. Damyanovich, I. V. Oleichik, P. V. Bologov, I. I. Kazachinskaya, and T. I. Medvedeva Mental Health Research Center, Moscow, Russia email:
[email protected] Received March 26, 2015
Abstract—To study the mechanism of the therapeutic effect of transcranial magnetic stimulation (TMS) of the left dorsolateral prefrontal cortex in patients with depression, the dynamics of clinical scores, certain cog nitive functions, and the spectral structure of a resting EEG were analyzed in 20 patients with pharmacore sistant depression during combined treatment including TMS. A short TMS course (ten sessions) signifi cantly enhanced and accelerated the effect of antidepressants. TMS contributed to reducing depressive symp toms, improving the general condition, and recovering some of the impaired cognitive functions. The therapeutic effect of TMS was related to activation of the prefrontal cortex and closely linked subcortical structures. TMS was assumed to provide a promising nondrug method to treat the clinical conditions and symptoms of depression and to correct the functional state of the brain in depressive patients and can be employed in combined treatment of pharmacoresistant depression. Keywords: depression, pharmacoresistance, treatment, transcranial magnetic stimulation, quantitative EEG, psychological testing DOI: 10.1134/S0362119715050059
INTRODUCTION Depression is one of the most common mental dis orders, affecting more than 120 million people in the global population according to the World Health Organization [1]. Depression is the first most impor tant cause of incapacity, disability, and mortality among mental disorders and is second in frequency to cardiovascular disorders among all diseases [2–4]. Hence, effective treatment of depression is a challeng ing and pressing medicosocial problem. The problem is difficult to solve in spite of the intense development of new antidepressants varying in mechanism of action and therapeutic profile because a substantial portion (30–60% according to different estimates [2–5]) of the patients are nonresponders; i.e., the clinical efficacy of antidepressive medications is insufficient in such cases. Lack of response occurs as incomplete remission, when symptoms are reduced by less than 50% as measured by quantitative clinical scales such as the Hamilton Depression Rating Scale (HDRS) or Montgomery–Asberg Depression Rating Scale (MADRS) after an antidepressant treatment course adequate in terms of drug choice, dosage, and duration, or as multiple relapses (exacerbations) of the disease and its conversion to a chronic form. The phe nomenon is known as pharmacoresistance [5–8].
Moreover, concomitant administration of several anti depressants with different mechanisms of action to overcome resistance increases the risk of adverse side effects. It is still unclear why modern antidepressants lack efficacy and what mechanisms underlie lingering and pharmacoresistant depressive disorders. This is explained to a great extent by the fact that the disor ders are multifactorial with several brain mechanisms being involved in their pathogenesis [6, 9, 10]. The effect of a psychopharmacological drug on one target, even be it a major one, is insufficient for eliminating or alleviating the disease symptoms; i.e., pharmacoresis tance is observed. The high portion of nonresponders requires new approaches to be developed for optimizing therapy of depressive disorders; this is now one of the most press ing problems in modern psychiatry [2–7]. The nondrug therapeutic method of rhythmic tran scranial magnetic stimulation (TMS) provides an alternative means to solve the problem of pharmacore sistant depression [6, 7, 11–15]. TMS seems to be the best in terms of efficacy and safety among all nondrug methods to treat depressive disorders [6]. TMS has been shown not only to eliminate the depression
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symptoms, but also to improve cognitive functions [14]. At the same time, the neurobiological mechanisms underlying the therapeutic effect of TMS are still poorly understood. It has only been noted in the majority of studies that the dorsolateral prefrontal cor tex of the left hemisphere provides an optimal target for TMS in depression [6, 12–15], a decrease in its function being associated with depressionrelated affective conditions [16–19]. It is still an open ques tion as to what mechanisms sustain the TMSinduced improvement of the clinical condition and the func tional state of the brain in depressive patients: direct excitation of the dorsolateral prefrontal cortex, excita tion of other brain structures connected with the dor solateral prefrontal cortex, or an improvement of gen eral or local cerebral circulation upon exposure to a magnetic field. To better understand the mechanisms of the thera peutic effect of TMS, the objective of this work was to study the changes in EEG spectral structure and cog nitive functions in the course of combined therapy including highfrequency rhythmic TMS of the dorso lateral prefrontal cortex of the left hemisphere in phar macoresistant depressive disorders. METHODS This clinical–psychological–neurophysiological multidisciplinary study was performed at the Labora tory of Neurophysiology, Medical Psychology Divi sion, and Division of Endogenous Mental Disorders and Affective Conditions of the Mental Health Research Center. The study was performed with due regard to current ethical principles and biomedical research guidelines as adopted in the World Medical Association’s Declaration of Helsinki in 1964. The study included 20 inpatients treated at the Mental Health Research Center. The patients were all females aged 18–56 years (mean age 36.3 ± 3.9 years) with mild to moderate depressive disorders, which corresponded to F31.3, F33.0, F33.1, and F43.21 according to the International Classification of Dis eases, 10th revision (ICD10). Clinically, the patients displayed a set of depressive symptoms, including low moods, pessimistic views of life situations, anxiety, irritation, emotional lability, slowed movements and thinking, sleep disorders, and a lower working ability (both at work and in daily life). The clinical efficacy of antidepressive therapy was insufficient in the patients during previous hospitalizations, consistent with pharmacoresistant depression according to commonly accepted criteria [5, 7]. During the study, the patients received complex symptomoriented antidepressive therapy, which included antidepressants (mostly, selective serotonin reuptake inhibitors) and a course of highfrequency rhythmic TMS of the dorsolateral prefrontal cortex of the left hemisphere.
Clinicopsychological evaluation of the condition in dynamics. The clinical effect of therapy was evaluated using HDRS17; the test was performed twice, prior to therapy (at Visit 1) and after a TMS course (at Visit 3). In addition to the total HDRS17 score, we consid ered the total depression cluster score (DEPR, the sum of scores on items 1, 2, 3, 7, and 8 of HDRS17) and the total anxiety cluster score (ANX, the sum of scores on items 9, 10, and 11 of HDRS17). A psychological testing was performed similarly before therapy (at Visit 1) and after a TMS course (at Visit 3), using the Symptom Check List 90 Revised (SCL90R) questionnaire [20]. The SCL90R ques tionnaire includes 90 items, which are grouped in sev eral scales including depression, anxiety, and hostility, and provides the global severity index, positive symp tom distress index, and the number of selfreported symptoms. Transcranial magnetic stimulation. TMS sessions were performed daily for two weeks (ten sessions in total), using a NeuroMS/D magnetic stimulator (Neurosoft, Ivanovo, Russia) with an 8shaped coil. A patient sat in a comfortable armchair during a session. Each series of TMS of the dorsolateral prefrontal cor tex of the left hemisphere included 40 series with 40 rectangular magnetic pulses at a frequency of 20 Hz per series (1600 pulses in total) and 14s intervals between series. The intensity of pulses delivered to the projection area of the left dorsolateral prefrontal cor tex (EEG leads Fp1, F3, and F7) was set at 60–80% of the motor threshold, which was determined prelimi narily for each patient. The motor threshold was determined as the intensity of a single magnetic pulse that evoked a motor response (moving of the thumb) when applied over the right hand cortical projection of the left hemisphere (a site 5–7 cm lateral of the vertex, in the region of the EEG lead С3) and was adjusted to prevent face muscle contractions during a rhythmic TMS session. Neurophysiological testing (EEG). To study the time course of the functional state of the brain during ther apy, a multichannel resting EEG was recorded before therapy (at Visit 1), immediately (20–30 min) after the first session of TMS of the dorsolateral prefrontal cor tex of the left hemisphere (at Visit 2), and immediately (20–30 min) after the tenth TMS session (at Visit 3), using a NeuroKM topographic mapping system with BrainSys software (designed by A.A. Mitrofanov) [21]. A EEG was recorded from 16 electrodes (F7, F3, F4, F8, T3, C3, Cz, C4, T4, T5, P3, Pz, P4, T6, O1, and O2) with ipsilateral earlobe reference electrodes А1 and А2 according to the 10–20 international system with a passband up to 35 Hz, a time constant of 0.1 s, and a sampling rate of 200 Hz. The patient sat in a comfort able armchair in the state of calm waking with the eyes closed. A spectral analysis and topographic mapping of spectral power were performed using artifactfree EEG fragments (at least 30 4s epochs) in narrow fre HUMAN PHYSIOLOGY
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Table 1. SCL90R scores before and after a TMS course SCL90R parameter
Before therapy
After TMS course
p
