[Biological aspects of treatment resistance in psychiatry and pharmacodynamic approaches to its management]. / Biologicheskie predposylki formirovaniya lekarstvennoi rezistentnosti v psikhiatrii i farmakodinamicheskie podkhody k ee preodoleniyu.

Treatment resistance is a persistent neurochemical condition characterized by the presence of «hybrid¼ metabolism, which combines both pathological and drug-dependent metabolisms. The difficulties in management and prevention of treatment resistance are associated with a lack of understanding of neurochemical aspects of the development of higher mental functions. The authors suggest that the basic types of species-preserving behavior are associated with the activity of monoaminergic systems while the modulation of their activity is predetermined by local neuronal networks in the rostral parts of the brain, where a variety of co-transmitters play an important role. It is emphasized that the mechanisms of the development of resistance after previous treatment with agonists (antidepressants, anxiolytics) or antagonists (antipsychotics) are different. Depending on drug actions on synaptic transmission, methodological aspects of treatment resistance management by means of «polar therapy¼, «sensitization¼ and combination strategies are considered.

[Non-drug methods in the treatment of resistant mental pathology (a neurophysiological approach)]. / Nelekarstvennye metody preodoleniia rezistentnoi psikhicheskoi patologii (neirofiziologicheskii podkhod).

The author considers the drug resistance in therapy of mental diseases of the brain within the neurophysiological concept of N.P. Behtereva about stable pathological state. Interneuronal interaction mechanisms in neuronal networks have the same type in pathological conditions and physiological activity of the brain. Methods of overcoming the sustainable functional state are aimed at the destruction of formed interneuronal networks and subsequent restructuring interneuronal interactions de novo. Search for endogenous biochemical markers of pathology under the condition of functional stability of interneuronal interactions can not be considered as a perspective direction for the detection of a pathognomonic sign of a specific brain pathology. The author argues that all known methods of non-drug exposure used today (magnetic and electrical stimulation, neurotransplantants, deafferentation, etc.) and methods with historical significance (comatose therapy, pyrotherapy) have a similar effect aimed at the destruction of pathological interneuronal interactions.

[Nosospecific anxiety and a spectrum of anxiolytic activity of psychotropic drugs]. / Nozospetsificheskaia trevoga i spektr anksioliticheskoi aktivnosti psikhotropnykh preparatov.

The article discusses the pathogenetic mechanisms of anxiety in different psychiatric disorders. The influence of anxiety on the course, pharmacotherapeutic treatment with respect to the pathogenesis and the possible neurochemical imbalance in the definite type of anxiety are discussed. An anti-anxiety effect in the action of psychotropic drugs is described. It is proposed that neurochemical disturbances are not the same with the various types of anxiety, which requires using drugs from various groups to achieve treatment of the symptom on the pathogenetic level. The various roles of anxiety in the course of different mental disorders is suggested.

[Evolutionary aspects of psychopathology and perspectives of psychopharmacology].

The authors consider the general conception of the pathogenesis of mental diseases based on the disruption of interactions between local neuronal networks. The development of mental disorders provoked by environmental factors is thought to disturb the activity of small groups of neurons with genetically determined module activity. It is hypothesized that the interaction of modules determines the forms of this activity that are of evolutionary origin predicting behavioral programs of familial inheritance and "personified" behavioral response. In this case, possibilities of pharmacological treatment of mental disorders are limited by the modulation of neurochemical processes controlling more simple fragments of behavioral response. This should be taken into consideration in the development of new psychopharmacological medications.

[Pharmacogenetic aspects of the activity of cytochromes P450 in the metabolism of antipsychotics].

Pharmacogenetic tests that allow the clinician to individualize dosage to the patient according to the activity of their metabolism are described. Pharmacogenetic aspects of the oxidative phase of antipsychotic biotransformation are reviewed. Depending on the rate of metabolism and enzyme activity of cytochrome (CYP) family (especially, CYP1 A2, CYP2D6 and CYP3A4) people can be divided into three groups: poor, rapid and ultrarapid metabolizers. Pharmacogenetic testing before the administration of therapy can be useful for choosing the optimal drug and its effective and acceptable dose for the individual patient. Along with the advantages and possibilities of pharmacogenetic testing, its difficulties and pitfalls are discussed. The authors emphasized that the investigation of cytochrome-based metabolism is only one of the components of individualized medicine.

[Studying the development of imipramine tolerance and prospects of its overcoming with the aid of tianeptine].

Reaction of two groups of mice to sub-chronic imipramine administration has been studied in a series of experiments, where one (control) group received physiological saline instead of imipramine. Then, both groups were randomly divided to receive either tianeptine (two groups) or physiological saline (two groups) for three days. After this period, the reaction of mice to imipramine was assessed again by measuring the immobilization duration in the tail suspension test. It was found that sub-chronic administration of imipramine (6 days) did not reduce sensitivity of the mice to this medication. Tianeptine showed "pro-depressive" action in the tail suspension test, but the administration of tianeptine increased the sensitivity of rodents to imipramine.

[Effect of haloperidol on changes in development of spontaneous catalepsy during subchronic injections of dopamine agonists and antagonists].

The influence of haloperidol intracutaneous injections on the development of spontaneous catalepsy phenomenon in SHR mice which received intraperitoneal injections of d,l-amphetamine (10 mg/kg) and haloperidol (5 mg/kg) alternately during 12 days, was studied ("neurochemical aggression"). It was demonstrated that alternating injections of d,l-amphetamine and haloperidol decrease the spontaneous catalepsy duration. Daily intracutaneous injections of haloperidol (0,25 mg/kg) prevented these changes but disrupted the spontaneous catalepsy phenomenon recovery by the 10-th day of measurements. A lower dosage (0,1 mg/kg) of haloperidol did not affect the results of the research. A conclusion was made that subchronic injections of haloperidol might have a protective effect in acute period of "neurochemical aggression" but slow down brain functioning recovery.

[Effect of nifedipine on the effectiveness of antipsychotic therapy in schizophrenia].

An aim of the study was to assess an influence of nifedipine in combination with haloperidol on antipsychotic activity and cognitive disturbances in comparison to the monotherapy with haloperidol and quetiapine. Sixty-two patients with ICD-10 diagnosis of paranoid schizophrenia, chronic course, and undiffirentiates schizophrenia have been studied. Patients have been stratified into 3 groups each treated during 10 weeks. Patients of the 1st group (20) received haloperidol in combination with nifedipine, 2nd group (21 patients) received haloperidol and 3rd group (21) were treated with quetiapine. Effectiveness of therapy was assessed by PANSS, CGI and a battery of neuropsychological tests including the scale of cognitive functions. The total effectiveness of the combination of haloperidol with nifedipine did not differ from that of the monotherapy with haloperidol though was some more effective relatively to negative symptoms. The positive effect of this combination on thinking and cognitive functioning was comparable to that of quetiapine.

[Experimental study of the effects of citalopram, olanzapine, and their combinations in tests for antipsychotic, antidepressant and anxiolytic activities of drugs].

The effects of citalopram, olanzapine and their combinations were studied in tests on outbred SHR male mice. The locomotor activity was determined in the open field, the antidepressant effects - in the tail suspension test, the anxiety-like behavior- in the light-dark transition test; in addition, the antidopaminergic effects of drugs and their combination were evaluated using the apomorphine-induced stereotypy. The results indicate that olanzapine inhibits locomotor activity in all behavioral tests, whereas citalopram alone has no significant effect and does not modify the action of olanzapine. An antagonistic interaction between drugs was revealed in tests for the specific antidepressant-like and antidopaminergic activity when citalopram/olanzapine combinations were used. No significant drug influence was observed on the anxiety-related mice behavior in the light/dark test.

Changes in anxiety levels are followed by changes in behavioral strategy in mice subjected to stress and in the extent of stress-induced analgesia.

The experiments reported here demonstrated that corasol increased the extent of analgesia induced by stress and decreased the duration of immobility in mice in a forced swimming test in cold water. Administration of diazepam led to the opposite changes and counteracted the actions of the anxiogen. The effects of the anxiolytic were more apparent in NMRI than mongrel mice, while in mongrel mice the effects of the anxiogen were more marked. Changes in measures following administration of agents were reciprocal in nature. These results lead to the conclusion that that these changes are determined by the level of anxiety, and that the strain differences between mongrel and NMRI mice are also linked with this factor.

[Effects of subchronic introduction of phenamine and haloperidol on development of spontaneous catalepsy in mice].

The development of spontaneous and haloperidol-provoked catalepsy was investigated in more than 200 mice. It was found that spontaneous and haloperidolic catalepsies have the same mechanism of development. Injections of amphetamine followed by injections of haloperidol led to persistent changes of cateleptogenic behavior in mice. Less duration of spontaneous catalepsy may reflect functional condition of catecholaminergic brain systems similar to that of patients with psychotic disorder.

[Does the catalepsy phenomenon reflect the functional dopaminergic activity in pharmacological investigations?]. / Iavliaetsia li fenomen katalepsii otrazheniem funktsional'noi aktivnosti dofaminergicheskoi peredachi v farmakologicheskikh issledovaniiakh?

The dynamics of spontaneous and haloperidol-induced catalepsy in mice has been studied. It is established that the degree of manifestation of the spontaneous catalepsy is directly related to the number of manipulations (mice standings in the "lector position"). At the same time, the intensity of catalepsy (both spontaneous and haloperidol-induced) was not related to the mice response to apomorphine injections. It is concluded that spontaneous catalepsy rather insignificantly influences the results of pharmacological tests, but this factor has to be taken into account in the study of physiological mechanisms. The absence of correlations between catalepsy manifestations and the apomorphine test results is indicative of complexity of the mechanism of this disorder and cannot be attributed entirely to the violation of dopaminergic processes in CNS.

[The influence of calcium channel blockers on the effects of anxiogenic preparations]. / Vliianie blokatorov kal'tsievykh kanalov na éffekty anksiogennykh preparatov.

The effect of anxiogenic drugs (caffeine, pentilentetrazole, phenilethylamine, strophantine, BAY K 8644) on SHR mice' behavior was studied in the dark-light chamber test. All these drugs have diminished the number of transitions between the chambers. Pretreatment with verapamil, nifedipine, cinnarizine and fendilin have not altered the effect of relevant anxiogenic drugs. Diltiazem prevented the effect of stophantine. It is suggested that the lack of the effect of calcium channel blockers on the action of anxiogens is related to peculiarities of formation of anxiety in this test.

[Clinical effect and tolerance of paxil (paroxetine) in management of panic disorders]. / Klinicheskaia éffektivnost' i perenosimost' paksila (paroksetina) pri lechenii panicheskogo rasstroistva.

AIM: To determine clinical efficiency and tolerance of paxil (paroxetin) in the treatment of panic disorders. MATERIAL AND METHODS: An open, non-comparative 7 week study entered 60 patients (mean age 36.6 +/- 3.22 years) with panic disorders and agoraphobias with panic disorders. Paroxetin was given in a single daily dose 20-60 mg/day in the morning. The results were assessed by Hamilton and Sihan scales, scale of clinical impression, by reduction of panic attacks. RESULTS: In 72.2% of patients panic attacks ceased or occurred less frequently (by 50%). Anxiety relieved by 67 +/- 4.6%. The number of the responders was greater while the effect occurred faster in patients with panic disorders. The drug was well tolerated, side effects occurred in 43.3% of cases. They were mild or moderate. CONCLUSION: Paroxetin has a prominent anxiolytic and antiphobic action, is well tolerated and is effective in panic disorders and agoraphobia with panic disorders.

[The anxiolytic activity of calcium-channel blockers in tests of anxious behavior in mice and rats]. / Anksioliticheskaia aktivnost' blokatorov kal'tsievykh kanalov v testakh trevozhnogo povedeniia u myshei i krys.

The evidence obtained from the studies of the anxiolytic activity of calcium channel blockers in the tests for anxiety: dark-light chamber, elevated plus-maze, social interaction, incomplete sensory deprivation, and change in the excitability of the CNS is analyzed. Methodological aspects of studying the anxiolytic activity of drugs in these tests are discussed. The problems are considered related with simulation of the normal situational anxiety and pathological anxiety as well as the prospects of using the calcium channels blockers as anxiolytics. In view of these aspects, the problem of search for an "ideal" anxiolytic and possible results of revealing its activity in the tests for the normal and pathological anxiety are discussed.

[Effect of calcium channel blockers on temperature in mice]. / Vliianie blokatorov kal'tsievykh kanalov na temperaturu u myshei.

In the experiments on SHR mice, verapamil, nifedipine, cinnarizin, fendilin, diltiazem, and nimodipine were tested for their effects on changes in rectal temperatures after intraperitoneal and intracerebroventricular injections. Intraperitoneal nifedipine (2 and 10 mg/kg), fendilin (5 and 20 mg/kg), and cinnarizin (5 and 50 mg/kg) lowered rectal temperatures. The similar effects were shown by nimodipine (2.4 micrograms), diltiazem (100 micrograms), and verapamil (100 micrograms) after their intracerebroventricular injections. It is concluded that the hypothermal effect of calcium antagonists is based on their central and hemodynamic mechanisms.

[The effect of calcium channel blockers on anxiety evoked by amputation of the vibrissae in rats]. / Vliianie blokatorov kal'tsievykh kanalov na trevogu, vyzvannuiu amputatsiei vibriss u krys.

The effect of diazepam (0.5 mg/kg) and calcium channel blockers on the behavior of rats in an "open field" was studied on a model of incomplete amputation of vibrissae. Diazepam, diltiazem (1 mg/kg), fendiline (1 mg/kg), and cinnarizine (1 mg/kg) stimulated motor activity of animals with amputated vibrissae. Nifedipine (0.5-5 mg/kg) and verapamil (0.5-5 mg/kg) were practically inactive in these tests. It is concluded that diltiazem, fendiline, and cinnarizine possess anxiolytic activity in this model. On the basis of the results obtained, the methods for studying the anxiolytic activity on animals are discussed.

[The relationship between anticonvulsant and anti-anxiety effects of calcium channel blockers]. / O sviazi mezhdu protivosudorozhnym i anksioliticheskim deistviem blokatorov kal'tsievykh kanalov.

The effect of calcium channel blockers on the development of convulsive and anxiogenic actions of corasole and caffeine was studied on mice. Verapamil, nifedipine, cinnarizine, and fendilin attenuated corasole-induced convulsions were attenuated by convulsions. Nifedipine also weakened while fendilin increased the course of convulsions induced by caffeine. All calcium antagonists did not change the effects of corasole and caffeine in the dark-light chamber test and the test in an elevated plus maze (anxiogens shortened the time that the mice stayed in the open sections of the maze). It is concluded that there are no relations between the anticonvulsive and anxiolytic effects of calcium antagonists.