2009, volume 25, issue 3-4

Only for Pharmacotherapy in Psychiatry and Neurology

Omega-3 polyunsaturated fatty acids: biochemical, functional and practical aspects

Jerzy Z. Nowak
Farmakoterapia w Psychiatrii i Neurologii, 2009, 3-4, 127–146

Fatty acids comprise a large family of compounds possessing diverse chemical structures and biological activities. Among various fatty acids, omega-3 and omega-6 ones are necessary for human function and they should be supplemented, particularly omega-3 acids, because of their insufficient synthesis in an organism. The characteristics of such compounds, including their chemical structure and function, will be discussed, taking into account the presence or absence of double bond/s localized to specific place/s of fatty acid carbon chain, which determines their unsaturated or saturated nature. A focus will be given to docosahexaenoic acid (DHA) – a polyunsaturated fatty acid that is an indispensable building and functional element of the central nervous system. Insufficient supply of DHA, as well as another omega-3 fatty acid – eicosapentaenoic acid (EPA), may contribute to various membrane and cell dysfunctions and pathologies, including inflammation and neurodegeneration. These fatty acids, especially DHA, are crucial for early development, e.g. neurogenesis and synaptogenesis, and later processes such as cognitive brain development. On the other side, DHA and EPA, possessing in their structures respectively 6 and 5 intracarbon double bonds, are particularly sensitive – especially under insufficient antioxidant defense – to peroxidation and generation of reactive oxygen species, structural defragmentation, and formation of immunogenic conjugates with proteins. Analysis of possible „pros” and „cons” related to supplementation with omega-3 fatty acids (diet, pharmaceuticals) indicates a clear advantage of the former, which suggests that intake with either food or supplements rich in DHA and EPA may be a reasonable prophylactic-therapeutic strategy useful in combating various ailments of our organism, including disorders of the central nervous system.

Original article

Depressive symptoms in the first episode of schizophrenia – analysis of Polish results of the EUFEST Study

Tomasz Szafrański, Jerzy Samochowiec, Marcin Olajossy, Jolanta Rabe-Jabłońska, Janusz Rybakowski
Farmakoterapia w Psychiatrii i Neurologii, 2009, 3-4, 147–154

Objective. The aim of the study was an analysis of the frequency and course of depressive symptoms in Polish patients with the first episode of schizophrenia and an assessment of treatment results.
Methods. The study included 94 patients with the first episode of schizophrenia allocated in a randomized fashion to the treatment with low dose haloperidol (n=26), amisulpride (n=27), olanzapine (n=26), quetiapine (n=12) or ziprasidone (n=3), for the period of 12 months. Depressive symptoms were assessed using the Calgary Depression Scale for Schizophrenia (CDSS) at baseline, and then after 1, 3, 6 and 12 months.
Results. At baseline, depressive symptoms with the score of >6 on CDSS were found in 44.7% of cases. The mean intensity of these symptoms was slightly lower than in other Polish studies on patients with the first episode of schizophrenia but similar as in the whole EUFEST group. Patients with depressive symptoms were younger and had lower quality of life as assessed by MANSA. Otherwise, no relationship was found between the intensity of depressive symptoms and selected demographic parameters, intensity of psychopathology measured by PANSS and improvement after treatment. Antidepressant drugs were added to antipsychotic treatment three times more frequently in Polish group compared with the whole EUFEST group, SSRIs being used in >90% of the cases. The reduction of depressive symptoms was similar in the group receiving antidepressant treatment as in the group without such treatment.
Conclusion. Depressive symptoms are frequent among patients with the first episode of schizophrenia and usually improve with antipsychotic treatment. No significant differences were found between antipsychotic drugs studied in their efficacy against depressive symptoms. In Polish patients, antidepressant drugs were used very frequently (mainly SSRIs) as an addition to antipsychotic treatment. A favorable prognostic value of depressive symptoms occurring in the early
stages of schizophrenia was not confirmed.

Original article

Prolactin concentration in Polish patients with the first episode of schizophrenia participating in the EUFEST

Janusz Rybakowski, Jolanta Formanowicz, Marcin Olajossy, Jerzy Samochowiec
Farmakoterapia w Psychiatrii i Neurologii, 2009, 3-4, 155–159

Objective. The aim of the study was an analysis of prolactin concentration before, and in the course of one-year antipsychotic treatment in Polish patients participating in EUFEST study.
Methods. The study included 78 patients (41 mqle, 37 female) with the first episode of schizophrenia allocated in a randomized fashion to the treatment with low dose haloperidol (n=23), amisulpride (n=21), olanzapine (n=22), quetiapine (n=11) or ziprasidone (n=1), for the period of 12 months. Prolactin concentration was assessed at baseline and after 6 and 12 months of treatment.
Results. At baseline, the mean prolactin concentration in the whole group was 56,5 ng/ml and hyperprolactinemia (hPRL) was observed in 86% of patients studied, slightly more than in the whole EUFEST group (71%). Prolactin concentration was similar in drug-naïve patients as in those who had previously received short-term antipsychotic treatment. There was no correlation between prolactin concentration and PANSS and CDSS scores. After 6 month of treatment, the percentage of hyperprolactinemia was 67%, lowest in haloperidol (29%) and highest in amisulpride group (93%). After 12 months of treatment the percentage of hyperprolactinemia was 56%, lowest in quetiapine (36%) and highest in amisulpride group (80%). In female patients there was a significant correlation between prolactin concentration and side-effect measured with UKU scale after 6 and 12 months of treatment.
Conclusions: The finding of hPRL in the majority of patients with the first episode of schizophrenia at the baseline, including patients which were drug-naïve may suggest that hPRL is not due to neuroleptic drugs and may be connected with a pathogenesis of the illness. In the course of one-year antipsychotic treatment, only in patients receiving amisulpride the hyperporlactinemia has been maintained at the initial high level while in remaining groups, there was a reduction by
about 50% of the number of patients having hypeprolactinemia at baseline.

Original article

Comparison of therapeutical results: pharmacotherapy and ECT in patients with drug-resistant depression

Robert T. Hese, Jarosław Sobiś, Tomasz Zyss, Piotr Gorczyca, Jerzy Matysiakiewicz, Robert Pudlo, Magdalena Jarząb
Farmakoterapia w Psychiatrii i Neurologii, 2009, 3-4, 161–165

Aim. The aim of the study was the comparison of therapeutical efficacy of mirtazapine and mirtazapine/olanzapine combination with efficacy of ECT in patients with drug-resistant, recur rent, major depression.
Methods. 32 inpatients with treatment-resistant, recurrent, major depression were subjected; 30 patients among them suffered from severe depression (with median 30,5 pt of HDRS). Patients were divided into two groups. In the group I (non-psychotic, drug –resistant depression), 12 patients obtained mirtazapine and 4 were treated with ECT. In the group II (psychotic, drug – resistant depression) 8 patients were treated with mirtazapine/olanzapine combination and 8 with ECT. Referrals for ECT were based on informed (written),.voluntary consent.
Results. Severity of psychotic depression, estimated with HDRS was 32,5 and appeared significantly larger (p = 0,04), in patients treated with ECT than in patients treated with mirtazapine/olanzapine combination (24,0). In patients with non-psychotic depression treated with mirtazepine the decrease of depressive symptoms estimated with HDRS was 66,7% and in ECT group was 70,3% (not statistical significant). Patients with psychotic depression treated with mirtazapine/olanzapine combination the reduction of symptoms in HDRS was 70,8% in comparison to the result of 64,6% in patients treated with ECT (not significant).
Conclusions: There were no differences between therapeutical efficacy of ECT and mirtazapine in patients with non-psychotic depression. In patients with psychotic depression there was also no statistical significant difference in the degree of the improvement after treatment with mirtazapine/olanzapine or ECT.

Review article

Fourty six years of lithium in prevention of recurrences of bipolar affective illness

Sebastian Kliwicki, Janusz Rybakowski
Farmakoterapia w Psychiatrii i Neurologii, 2009, 3-4, 167–172

Lithium was introduced into contemporary psychiatric therapy in 1949, whereas in 1963 the first article appeared pointing to a prophylactic effect of this ion, preventing the recurrences of affective episodes. In 46 years which have passed, this effect has been confirmed in numerous controlled studies and meta-analyses, and lithium has became a prototype of mood-stabilizing drugs. As for lithium, the property of prevention of suicidal behaviors has been best documented among mood-stabilizing drugs. Neurobiological mechanisms of lithium mood-stabilizing action include, among others, the effect on transmembrane transport, on brain neurotransmitters and intracellular signaling as well as neuroprotective effect. About 1/3 of patients with bipolar affective illness receiving lithium monotherapy experience excellent prophylactic effect (excellent lithium responders). These patients are characterized by the most classical picture and course of the illness. The quality of lithium prophylactic effect has been used as a phenotype for molecular-genetic studies. In 2007, the International Consortium on Lithium Genetics (ConLiGen) has been founded for performing the GWAS (genome-wide association study) in about 2000 of patients receiving lithium prophylaxis. Lithium salts, valproates and carbamazepine were introduced for the treatment and prophylaxis of bipolar affective illness in 1960-1980s and may be regarded as mood-stabilizing drugs of first generation. Since mid-1990s mood-stabilizing properties have been documented for atypical neuroleptic drugs (clozapine, olanzapine, quetiapine, aripiprazole) and for new antiepileptic drug, lamotrigine. These drugs can be classified as mood-stabilizing drugs of second generation.

Review article

Two faces of GABA: inhibition and excitation

Wojciech Kostowski, Anna Witanowska
Farmakoterapia w Psychiatrii i Neurologii, 2009, 3-4, 173–178

GABA (γ-aminoburytic acid) is the primary inhibitory neurotransmitter in the adult brain. It regulated neuronal activity through hyperpolarization of the membrane potential . However, during early postnatal period, GABAergic transmission is excitatory. The nature of GABAergic neurotransmission is determined by the electrochemical gradient for Cl- , which depends on extra- and intracellular concentrations of chloride. During the postnatal period GABAergic transmission undergo from being excitatory to inhibitory. The switch of GABAergic responses is due to changes in expression of K+ -coupled Cl- transporter (KCC2 cotransporter).
Excitatory GABA action (i.e. membrane depolarization) is essential for morphological maturation of neurons in immature animals. GABA regulates also synaptic integration of newly generated neurons in the adult brain.
GABA-induced excitation plays also a role in mechanism of epilepsy. Interneurons producing GABA together with aberrantly behaving population of pyramidal neurons in the hippocampus can precipitate epileptic seizures. The findings showing that GABA in some instances can be ictogenic may explain why some antiepileptic GABA-promoting drugs, have occasionally been reported to be proconvulsant in clinical cases.
Further, GABA is able to induce depolarization in injured neurons thus leading to neuronal Ca2+ - dependent excitotoxicity.
GABA has also been found to evoke hormone release from neuroendocrine cells.
GABA-A receptor are expressed upon neuroendocrine cells such as insulin-secreting pancreatic β-cells and catecholamine-releasing adrenal chromaffin cells.
Thus, GABA can no longer be simply viewed as and inhibitory neurotransmitter which causes hyperpolarization of neuronal cells. The pharmacological and clinical consequences of excitatory properties of GABA seem to be of great importance.

Review article

NMDA receptor insufficiency in pathogenesis of schizophrenia

Marek Krzystanek, Artur Pałasz, Ewa Krzystanek, Irena Krupka-Matuszczyk
Farmakoterapia w Psychiatrii i Neurologii, 2009, 3-4, 179–190

In last years, many experimental and clinical studies helped to create the hypothesis of disturbed glutamatergic transmission in schizophrenia. The hypothesis is based on clinical finding that agonists of NMDA receptors may produce schizophrenia-like symptoms.
Contemporary data confirm that hypofunction of NMDA receptors plays a significant role in pathogenesis of schizophrenia. It seems that the systems: glutamatergic, dopaminergic and serotoninergic are functionally connected in schizophrenia. Classical and atypical neuroleptics may modulate activity of NMDA receptors. The known agonists of NMDA receptors and glycine re-uptake inhibitors seem to be more effective in the treatment of negative than positive schizophrenia symptoms. Their influence on cognitive dysfunctions is also possible. Results of clinical studies suggest that drugs enhancing NMDA receptor activity are more effective in combination with classical or atypical neuroleptic than in monotherapy of schizophrenia.
More clinical trials are necessary to establish the clinical position of drugs producing activation of NMDA receptor.

Review article

Copper – involving in neurodegeneration: from molecular mechanisms to therapeutic strategy

Magdalena Rudnicka
Farmakoterapia w Psychiatrii i Neurologii, 2009, 3-4, 191–197

Human organism for normal grows and functioning needs many various molecules, including metal ions like copper. This transition metal is participating in many chemical reactions in cells. Imbalance in amount of this metal abolished cell’s homeostasis and leads to malfunction whole human organism. Inherited disorder, Wilson disease, comes from increased accumulation of copper ions in cells and organism is exposed to copper toxicity. Thus, neurodegenerative process depends on increase of amount of this transition metal ion. This review is focused on copper influence on progression and manifestation of neurodegenerative disorders, discuss molecular mechanisms underlay of copper toxicity and indicate therapeutic strategy that could be used in therapy of neurodegenerative diseases in future.

Scientific conference report

The First ECNP School of Neuropsychopharmacology (Oxford, UK, July 5-10 th 2009)

Tomasz Pawełczyk, Wiesław Jerzy Cubała
Farmakoterapia w Psychiatrii i Neurologii, 2009, 3-4, 199–206

The first ECNP School of Neuropsychopharmacology was held in Oxford, United Kingdom from 5-10 July 2009. The idea of organizing that meeting was born trying to answer the following question: how to ensure high standard neuropsychopharmacologists in 20 years time? The ECNP executives decided that one of the main targets of that organization should be training in psychopharmacology, encouraging excellence in qualified, but still junior clinicians by teaching them high standard practice in neuropsychopharmacology and involving them in the development of local good practice in teaching and training. 42 representatives of the ECNP Advisory Board of National Societies – young clinicians (psychiatrists) were invited to Oxford to acquire up-to-date knowledge in order to make practice of psychopharmacology more uniform across Europe. Panel of speakers was composed of well-known clinical researchers and clinicians from all-over the world. The aim of the School was to provide high quality learning experience for young qualified clinicians and to inspire them to be the leaders of psychopharmacology practice in their own countries. The first part of that aim was undoubtedly achieved in Oxford. The knowledge and skills acquired during the meeting motivated the vast majority of participants to intensive work and promote EBM in their local clinical setting. After 2009 School success ECNP plans to organize further edition of that exciting, useful and inspiring meeting in the following years.