Psychopharmacotherapy of Borderline Mental Disorders in Cancer Patients

Karavaeva T.A.

At present, borderline mental disorders in patients with cancer are widespread, aggravating the course and prognosis of the underlying disease and significantly worsening the quality of life of the patient and of the members of their family. Timely and adequate psychological and medical intervention and the prescription of psychotropic drugs provide a therapeutic effect in patients with such disturbances; however, without treatment, anxiety, phobic, panic, depressive, hypochondriacal, asthenic, insomnia-related, and other manifestations can lead to unfavorable medical, psychological, and social consequences [3, 9, 18].

Adequate use of psychotropic drugs possessing anxiolytic, antipanic, and antidepressant activity as part of combination therapy contributes to a significant reduction in the level of anxiety, to the relief of panic states, to the creation of conditions for overcoming phobias, to the normalization of mood, to the restoration of sleep, and to increased activity in patients with cancer [2, 7, 17]. The choice of the class of the base drug and its combination with other medications are determined by a number of factors, among which are the severity of clinical manifestations, the time of onset of the treatment result, the expected side effects, possible complications of the therapy administered, concerns about the development of withdrawal syndromes, the conditions of medical care delivery, the characteristics of the cancer disease, the relationship with the main antitumor treatment, and the general

somatic condition of the patient's body, the presence and severity of pain syndrome, and others [6, 23].

An important aspect of organizing medical care for cancer patients with comorbid mental disorders is the identification and observance of a number of principles that make it possible to take into account both the clinical, psychological, and social characteristics of the diseases (oncological and mental) and the organizational aspects and the conditions of conducting various types and stages of therapy [4, 8, 26].

The principle of staged care provides for the continuous management of patients in accordance with the indications at the outpatient and inpatient levels of oncological care delivery. Psychotropic therapy prescribed at one of the levels should subsequently be maintained and adjusted depending on the condition of the cancer patient and the specific objectives of the antitumor treatment. The abrupt discontinuation of psychotropic drugs upon hospitalization or the interruption of therapy while the patient is at home is contraindicated. In a number of cases the patient may require hospitalization in a psychiatric inpatient facility. The determination of indications for hospitalization is based on an assessment of the severity of the clinical psychopathological manifestations, the degree of impairment of functioning, the possibility of being in a specialized institution given the general condition, consistency with the main courses of treatment of the oncological pathology, as well as the need to isolate the patient and to select adequate psychotropic therapy.

It is advisable to be guided by the following indications for the choice of organizational conditions when selecting psychotropic therapy for cancer patients with borderline mental disorders

[22].

Indications for inpatient treatment:

Pronounced psychopathological symptoms – substantial asthenia, intense anxiety, deep depressive disturbances, suicidal risk.

The impossibility of selecting drug therapy on an outpatient basis due to the resistance of the condition, poor tolerability of the therapy, or the severity of the oncological manifestations.

The need to reduce the risk of crisis situations that may arise during treatment.

The symptom-related impossibility of outpatient treatment in cases of phobia, restrictive behavior, frequent panic attacks, or vital depression.

The need for isolation from the current life-threatening psychotraumatic circumstances.

Indications for outpatient treatment:

The absence of pronounced psychopathological symptoms.

The ability to remain in society and the desire (motivation) to acquire skills for coping with the psychotraumatic situation and the cancer disease, the need to preserve the existing level of adaptation, and the possibility of using psychological correction and psychotherapeutic methods of treatment.

The possibility of selecting drug therapy on an outpatient basis.

The possibility of overcoming restrictive behavior.

The principle of comprehensiveness in implementing psychopharmacological,

psychotherapeutic, and rehabilitative strategies in cancer patients may be considered in several aspects [1, 8].

First, the organization of a comprehensive examination of patients, combining a general clinical and specialized oncological, psychological, and social approach. In the general clinical

examination, the use of modern diagnostic methods contributes to a finer differential diagnosis, to the delimitation of symptoms caused by neoplasms from the manifestations of mental illness, and to the determination of the role of each disease in the course and severity of the patient's condition.

The plan of psychological diagnostic measures includes determining the characteristics of personality functioning, the presence and degree of severity of character accentuations and characterological features, the type of internal picture of the illness, the specifics of the mechanisms of psychological adaptation, the psychological mechanisms of the onset and development of the disease, symptom formation, and the nature of motivation for participation in treatment and rehabilitation work.

In assessing the patient's condition and determining the prognosis of therapy, social, occupational and labor-related (degree of work capacity, employment, level of disability, etc.), and social and everyday (degree of adaptation and current situation in the familial and extrafamilial spheres of communication) factors are significant.

Second, the principle of comprehensiveness is implemented taking into account the biopsychosocial model in the treatment of borderline mental disorders in patients with cancer under conditions of the combined interaction of various specialists (oncologists, psychotherapists, psychologists, social workers, and others). In the comprehensive form of work, the participants in the treatment and rehabilitation process consider the clinical and therapeutic phenomena from different points of view from the standpoint of their specialties, cooperating and mutually complementing one another in solving the main therapeutic tasks.

The team method makes it possible to develop an individual treatment plan specific to each patient, including the entire necessary set of medical, psychological, and social rehabilitation measures

ultimately aimed at the maximum restoration of the patient's level of functioning and the improvement of their quality of life.

The oncologist organizes the treatment process and the interaction of the specialists participating in the provision of specialized medical care, determines the plan of examination and management of the patient, and prescribes therapy. The psychotherapist prescribes psychopharmacotherapy, coordinates the conduct of psychotherapy, and introduces modern methods of treatment, psychoprophylaxis, and psychohygiene into practice.

The clinical (medical) psychologist conducts psychodiagnostic examination, including over the course of treatment, assessing the influence of the tumor process on the patient's psyche and adaptive resources. Together with the psychotherapist, they develop therapeutic, rehabilitative, and psychocorrectional programs taking into account individual psychological, sex-related, and age-related factors, the course

and prognosis of the cancer disease, and the attitude toward and tolerability of the treatment of the underlying pathology. They carry out measures for psychoprophylaxis, psychocorrection, and psychological counseling, providing help to patients and their relatives in resolving the psychological

and social problems caused by the cancer disease. Together with the psychotherapist, they assess the effectiveness of the psychological, therapeutic, and preventive measures being carried out, taking into account the general condition of the patient.

The social work specialist, on the referral of the physician, organizes individual, family, and group work with patients with the aim of improving their social adaptation, achieving fuller recovery, and enabling rehabilitation in the professional sphere during the period of remission of the underlying disease; they ensure the conduct of measures for the social and legal protection of patients and organize interaction with institutions providing social assistance. Together with the physician, they develop individual plans for the social rehabilitation of patients with

cancer; they organize a therapeutic environment in the treatment and prevention institution and create a therapeutic community of patients.

Third, the principle of comprehensiveness in psychotherapeutic and rehabilitative strategies in cancer patients with borderline mental disorders is implemented in the combined use of pharmacological (psychopharmacotherapy) and non-pharmacological (psychotherapy, psychological correction) methods of therapy.

The principle of differentiation presupposes the targeted application of therapeutic methods for a specific patient that is congruent with the main clinical manifestations of the psychopathological disturbances and that corresponds to the nature, course, and treatment strategies of the tumor disease. Depending on the clinical characteristics of the borderline mental pathology in the patient with cancer, the patient's personality features, the organizational conditions, the manifestations of the tumor process, its stage and prognosis, the general somatic condition, the patient's life and social situation, the presence of complications, and the features of the specialized therapy, the targets and goals of the treatment being carried out are assessed individually, the combined pharmacotherapy is selected, and the content and nature of the psychotherapy, as well as the scope, timing, stages, and order of provision of the entire set of therapeutic and rehabilitative measures, are determined.

The principle of integrativeness represents the well-grounded, interconnected use of oncological treatment, psychopharmacotherapy, and psychotherapeutic methods and techniques aimed at a more intensive and effective impact in order to create conditions for optimal rehabilitation and for the recovery or relief of the patient's condition. The use of psychopharmacotherapy in borderline mental disorders in cancer patients determines the vector of biological impact, whereas psychotherapy makes it possible to resolve

the psychological and social difficulties associated with the patient's personality and their underlying disease. In forming an integrative therapeutic strategy, there are methods that determine the direction, effectiveness, and prognosis and that play a strategic role, and other methods that resolve particular tactical tasks, making it possible to increase the effectiveness of treatment and rehabilitation as a whole.

Over the past decades, approaches to understanding the relationship of biological, psychological, and social factors in the pathogenesis of borderline mental disorders and cancer diseases, both as independent nosologies and in their comorbid combination, have changed substantially. Both in the global and in the domestic theory and practice of health care, a biopsychosocial paradigm of understanding disorders has taken shape, based on a holistic, systemic, and personalized approach to the assessment of the person and their functioning as a whole; new views on the relationship and content of various types of treatment, organizational forms, and medical directions have become established.

The development of the pharmaceutical industry, the creation of new drugs, and their introduction into modern therapeutic treatment strategies have made it possible not only to achieve faster symptomatic improvement but also to build trusting relationships with the patient, to enhance the effectiveness of psychotherapeutic interventions, to shorten the duration of inpatient treatment, and to make wider use of economically preferable outpatient methods of therapy in borderline mental disorders in patients with cancer.

The ratio of psychotherapy and pharmacotherapy in the treatment process is flexibly determined in each specific case. On the one hand, it depends on individual parameters (the patient's personality, their adaptive resources, the nature of social interaction, life circumstances); on the other hand – on the characteristics of the mental disorders (pathogenesis,

symptoms, the readiness for psychotherapy and psychopharmacotherapy); and on the third hand – on the localization, extent, course, and prognosis of the tumor process, its complications and treatment (the stage of the disease, the tolerability of specialized therapy, the general condition of the patient, etc.).

The more pronounced the biological mechanisms are in the complex pathogenesis of borderline mental disorders, the more positive the effect produced by the use of drug therapy. At the same time, biological types of treatment do not always resolve the strategic tasks of achieving a long-term and stable result but only tactical ones, which is determined by the substantial role of psychogenic factors in the formation of psychopathological disturbances in oncology patients, by existential experiences, and by the attitude toward the disease process and recovery. However, with the targeted use of psychotropic agents to act on particular links of pathogenesis, the influence of pharmacological substances on individual syndromes or symptoms may approach the pathogenetic [5, 11, 15].

Principles of pharmacotherapy of mental disorders in cancer patients

The following factors influence the achievement of an optimal effect when conducting pharmacotherapy in patients with cancer:

The accuracy of the diagnosis of psychopathological disturbances. Psychopharmacotherapy is indicated for anxiety, panic, phobic, depressive, hypochondriacal, asthenic, and dyssomnic disorders in patients with various cancer diseases [7, 10, 19].

The choice of drug and of the combined treatment regimen. The selection of therapy is determined by the severity of the psychopathological symptoms, the general somatic condition of the patient, the tolerability of the therapy,

the possibilities of use together with the antitumor and other drugs prescribed to the specific patient, and the characteristics of the neoplasm. Anxiolytic drugs (benzodiazepine and non-benzodiazepine tranquilizers), mood stabilizers, and antidepressants (preferably the group of selective serotonin reuptake inhibitors – SSRIs, or selective serotonin and norepinephrine reuptake inhibitors – SNRIs), and antipsychotics (more often atypical ones) are used [1, 16, 21].

The dose of the prescribed drugs. Subtherapeutic dosages in cases of pronounced exhaustion and asthenia of the body, instability of the psychopathological manifestations or their episodic manifestation; therapeutic doses in uncomplicated clinical psychopathological disturbances; high therapeutic doses – in resistant disturbances, pronounced psychopathological manifestations, pharmacological resistance, and intense pain syndrome. The low need for agents with a powerful psychotropic action provides the possibility of the wide use of psychotropic agents with minimal side effects and a low potential for drug interactions [2, 20].

The duration of treatment. In most cases, long-term and continuous therapy is necessary, taking into account the presence of the stressful situation caused by the course and treatment of the cancer disease and their consequences, and the polymorphism of trigger factors (nosogenic, somatogenic, iatrogenic). For most psychotropic drugs, the minimum period necessary to determine their effectiveness is 2–3 weeks [25].

Taking into account the severity of possible side effects and their cumulative nature with the underlying disease, its complications, and the side effects of antitumor therapy.

Taking into account the interaction of psychopharmacotherapy and the main treatment.

The choice of drug is made on the basis of the balance of effectiveness and tolerability/safety.

Taking into account the possible severity of the placebo effect of the psychotropic therapy being conducted.

Algorithm of psychopharmacotherapy of borderline mental disorders in patients with cancer (in the text, the international nonproprietary names

of the drugs are given)

As drugs for relieving emotional tension and reducing the intensity of anxiety and phobic disturbances, benzodiazepine tranquilizers are used: clonazepam,

alprazolam, bromodihydrochlorophenylbenzodiazepine, diazepam, lorazepam, diazepam [16, 17]. They are characterized by a low level of adverse influence on the activity of the main functional systems of the body, and in some cases exhibit a positive somatotropic effect. An important advantage of theirs is the absence of interaction with somatotropic drugs, chemotherapy, and radiation therapy, and the gap between therapeutic and lethal doses. In addition to a pronounced anxiolytic (anti-anxiety) effect, they possess vegetotropic, relaxing, anticonvulsant, and hypnotic action [12]. Among their disadvantages, which it is important to take into account when forming a strategy of psychopharmacotherapeutic treatment, the risk of habituation and the formation of drug dependence must be noted, as well as possible hypersedation accompanied by daytime drowsiness, impairment of cognitive functions, dysarthria, and ataxia; and the occasionally encountered paradoxical reactions (motor

agitation, irritability, aggressiveness, increased anxiety, and perceptual disturbances, which may arise when tranquilizers are prescribed in patients who abuse alcohol,

drugs, or take medications that have a depressant effect on the CNS).

Recommendations: the anxiolytic action of benzodiazepines sets in quickly; however, the drugs are of little effectiveness with prolonged use. The duration of the course should not exceed 2–4 weeks. If more prolonged psychotropic therapy is necessary, other groups of psychotropic agents should be used in a combined regimen.

The discontinuation of therapy with benzodiazepines should be carried out gradually in order to prevent withdrawal syndrome. The clinical picture of withdrawal syndrome includes insomnia, anxiety, loss of appetite, tremor, sweating, and perceptual disturbances. Withdrawal syndrome more often develops in the 2nd–3rd week after the discontinuation of the drug, but it may also arise within a few hours.

Overdose manifests in the form of sharp inhibition, confusion of consciousness, dysarthria, clonic twitching of the limbs, vomiting, and deep sleep lasting up to 2 days.

Antidepressants from various groups are used to achieve the main therapeutic effects – antidepressant,

mood-stabilizing, and additional ones – anti-anxiety, antiphobic, and hypnotic. Most of the pharmacological effects of antidepressants develop at the level of synaptic neurotransmission. In the course of therapy with antidepressants, a gradual change in receptor sensitivity occurs, which, in particular, explains the delayed clinical effect when they are used, by 2–3 weeks [3, 24].

Recommendations: owing to the sensitivity of oncology patients to side effects, small and medium doses of antidepressants are used

and drugs with good tolerability profiles, for example, SSRIs (fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram),

SNRIs (venlafaxine, duloxetine), which have few side effects but, as a rule, possess a stimulating action, which must be taken into account at the beginning of therapy. Tricyclic antidepressants require caution in the selection of adequate doses owing to their pronounced side effects. Mirtazapine is also effective, as are the minor antidepressants (trazodone, agomelatine), which are used to reduce the level of anxiety, emotional tension,

and the intensity of phobic experiences.

The duration of therapy with antidepressants is from 2 to 12 months.

In the therapy of depressive disorders in patients with cancer, it is advisable to use combined therapy that combines rational psychopharmacotherapy, in which preference is given to drugs with a minimal risk of the development of side effects and good tolerability, with the use of psychotherapeutic techniques [4, 10]. With the use of antidepressants, a rapid reduction of depressive symptoms, a high number of responders, and the possibility of obtaining an effect with the use of minimal therapeutic doses are noted, which is associated with the predominance of mild and moderate forms and with the nosogenic nature of most depressive disorders. However, one cannot ignore the fact that in the absence of a full guarantee of definitive cure, in the case of remission after radical intervention and, all the more so, in the continuous or recurrent course of cancer diseases, the nosogenic factors do not lend themselves to full correction and, along with iatrogenic/somatogenic influences, determine the need for long-term continuous therapy with antidepressants [14]. It is also necessary, when choosing therapy, to take into account the features of the drug interactions between psychotropic drugs and the agents for treating cancer diseases, which are associated not only with the possible

aggravation of side effects but also with the influence on the effectiveness of treatment as a whole.

Taking into account the delayed effect of antidepressants, for a rapid impact on anxiety and phobic symptoms, drugs from the group of non-benzodiazepine anxiolytics are used

(hydroxyzine, buspirone, etifoxine). They do not have behavioral toxicity and do not cause dependence.

The main clinical effects of antipsychotics are antipsychotic (reduction of delusions, hallucinations), sedative (normalization of psychomotor activity – correction of agitation, aggression), anti-anxiety, and sometimes activating. Among the additional effects one can note the hypothermic (owing to action on the thermoregulatory centers of the hypothalamus and peripheral vasodilation), antiemetic (through the inhibition of the chemosensitive part of the vomiting center containing dopaminergic receptors (effective in vomiting of a toxic nature)), the central and peripheral antihistamine (used in surgery and dermatology), and the potentiation of hypnotic and narcotic action.

In the treatment of borderline mental disorders in patients with cancer, in order to act on the cognitive component of anxiety and phobic disturbances, "minor" or atypical antipsychotics in medium and small doses are more often used: sulpiride, alimemazine, chlorprothixene, thioridazine, tiapride, quetiapine, risperidone. It is necessary to pay attention to the fact that most antipsychotics actively interfere with hormonal metabolism, contribute to an increase in prolactin and to shifts in other neuroendocrine subsystems, and therefore their use in cancer patients with breast tumors and other hormone-dependent neoplasms is contraindicated [13, 18].

The main effects of drugs with a mood-stabilizing action manifest in the form of the smoothing of mood fluctuations; the reduction of psychomotor agitation; and the reduction of the saturation of overvalued and delusional ideas. As side effects there may be noted: phenomena of drowsiness, dizziness, and ataxia; sometimes nausea, vomiting, constipation, and diarrhea. In rare cases, with treatment with carbamazepine – pronounced leukopenia develops, and therefore its use in the oncology clinic should be limited. Mood stabilizers are for the most part represented by anticonvulsants, which are prescribed as thymostabilizers; valproic acid, oxcarbazepine, lamotrigine, and pregabalin are used. The anxiolytic and analgesic effects of pregabalin, its influence on the mental, somatic, and vegetative components of anxiety, as well as its good tolerability and high level of safety, have been confirmed.

The recommended duration of pharmacotherapy of borderline mental disorders in patients with tumors depends on the prevailing psychopathological disturbances, the stage and prognosis of the underlying cancer disease, and the tolerability of the therapy, and most often amounts to from 3 to 12 months after the onset of the therapeutic effect from the therapy used [4, 13, 22].

Side effects of psychopharmacotherapy of borderline mental disorders in patients with cancer are possible. With the use of psychotropic drugs, side effects are possible: drowsiness, inhibition, urinary retention, constipation or diarrhea, nausea, headaches, and dizziness. At the same time, adequate dosages and the prescription of drugs strictly according to indications significantly reduce the risk of the manifestation of side effects [18, 22].

The table presents the recommended doses of drugs for the treatment of borderline mental disorders that can be used in oncology practice (Table 2).

Table 2 – Recommended doses of drugs for the treatment of borderline mental disorders in cancer patients

Note. SNRIs – selective serotonin and norepinephrine reuptake inhibitors; SSRIs – selective serotonin reuptake inhibitors.

The high-quality organization of medical care for cancer patients with borderline mental disorders, taking into account the main trends in the changing of psychopharmacological, psychotherapeutic, and rehabilitative strategies, the use of comprehensive and integrative approaches, and the involvement of various specialists in participating in the treatment, make it possible not only to solve the tasks of increasing the effectiveness and cost-efficiency of therapy and to achieve, in favorable cases, the speediest recovery of patients, but also to create conditions for improving the quality of life and relieving the condition in cases with a progressive course of the disease [3, 7, 19].