2011, volume 27, issue 2

Review article

The role of glutamatergic system in the mechanism of antidepressant and mood-stabilizing action in mood disorders

Agnieszka Permoda-Osip, Janusz Rybakowski
Farmakoterapia w Psychiatrii i Neurologii, 2011, 2, 57-65

In recent years, an increasing evidence has been accumulated pointing on a role of glutamatergic system in the  pathogenesis of mood disorders and in the mechanism of action of antidepressants and mood-stabilizing drugs. In the beginning of this paper, the elements of glutamatergic system were described and the results of molecular-genetic studies on the association of glutamatergic system genes with a predisposition to affective illness, unipolar and bipolar. Next, a role of glutaminergic receptors, mainly NMDA and AMPA, as well as the processes of glutamate release and transport in the mechanisms of antidepressants and mood-stabilizing drugs was presented. The one of the most important mechanism of antidepressant action is reduction of the expression and function of glutamatergic receptor NMDA. In recent decade an evidence has been obtained for a rapid antidepressant effect connected with the influencing glutamatergic system by single infusion of NMDA antagonist receptor, ketamine. Besides of ketamine, data are provided concerning a possibility of antidepressant action for other substances influencing glutamatergic system such as D-cycloserine, amantadine, memantine, traxoprodil, riluzole as well as zinc and magnesium ions. Further elucidation of a role of glutamatergic system in the mechanisms of antidepressants and mood-stabilizing drugs may provide new therapeutic perspectives in mood disorders.

Review article

Topiramate, antiepileptic drug of second generation – new applications

Adrianna Grzesiak, Jadwiga Zalewska-Kaszubska
Farmakoterapia w Psychiatrii i Neurologii, 2011, 2, 67-74

Topiramate is a second generation antiepileptic drug, with a wide range of anticonvulsive activity, both in experimental models and clinical trials. Topiramate has multiple mechanism of action including enhancement of GABA-A transmission and blocking the excitatory glutamate neurotransmission by AMPA and kainate receptors but not by NMDA receptors. Moreover, topiramate blocks sodium voltage channels as also calcium channels type L and decrease some of neurotransmitters
release, enhances the potassium ion channels as well as inhibits carbonic anhydrase. Topiramate is present approved for the treatment of epilepsy and migraine prevention in adults. Multifaceted mechanism of action of topiramate may explain its therapeutic activity also in other diseases. Numerous clinical trials confirm its efficacy in drug and alcohol dependence, eating disorder, neuropathic pains, mental diseases, the posttraumatic stress disorders, essential tremor or Gilles de la Tourette syndrome. 

Review article

Memantine and cholinesterase inhibitors: combination therapy in Alzheimer’s disease

Marcin Flirski, Tomasz Sobów
Farmakoterapia w Psychiatrii i Neurologii, 2011, 2, 75-83

In spite of ongoing research, Alzheimer’s disease (AD) remains an incurable disorder with a progressive course. Currently available treatment methods are mainly symptomatic, aimed at counteracting AD-related neurotransmitter changes. Among the potential combination therapies for AD, the largest body of evidence points to the concomitant use of a cholinesterase inhibitor (ChEI) and memantine. In short-term trials adding memantine to a previously administered ChEI (donepezil or rivastigmine) resulted in a significant improvement in cognitive functions, language, behavior and activities of daily living of moderate-to-severe AD patients, compared to ChEI monotherapy. The symptomatic benefits of combination therapy in earlier disease stages are dubious, administering it is nevertheless a common practice. The putative neuroprotective effects of memantine, potentially modifying the natural course of AD, particularly with early enough treatment initiation, might encourage physicians to use the combined treatment strategy even in mild AD. The results of long-term open-label studies prove that memantine-ChEI therapy can slow down the symptomatic progression of AD (both in terms of cognition and functional skills), delay nursing home placement, and significantly alleviate caregiver burden. However, one has to bear in mind that in Poland memantine use is approved only in moderate and severe AD. Combination therapy is perfectly safe, often even minimizing the risk of adverse effects associated with ChEI use. It’s cost-effectiveness has also been consequently demonstrated. 

Review article

Almorexant, an antagonist of the brain orexinergic receptors in the therapy of sleep disorders

Artur Pałasz, Rafał Skowronek, Marek Krzystanek, Katarzyna Bogus, Aleksandra Bryzek, Ryszard Wiaderkiewicz, Alicja Kost
Farmakoterapia w Psychiatrii i Neurologii, 2011, 2, 85-94

The sleep disturbances are at present a serious medical and social problems. The inappropriate pharmacotherapy of insomnia may be dangerous to health and apart from that usually cause a drug dependance. Orexines and their receptors OX1R, OX2R identified in many structures of the central nervous system play a crucial role in the control of sleep/wake states in humans. Synthesis of almorexant, the double antagonist of orexinergic receptors (DORAs), seemed to be a great progress in the treatment of sleep disorders. It is uniquely important that this experimental drug as opposed to GABA agonists do not disturb the sleep architecture. In spite of its many advantages, pharmaceutical companies abandoned further research, because of its unfavourable tolerability profile. It should be also taken into consideration that the deficit of the brain orexinergic transmission playing an essential role in the pathogenesis of narcolepsy would be corrected by the selective agonists of orexinergic receptors. 

Original article

The effect of lithium on oxidant-antioxidant balance in vitro

Oliwia Gawlik, Wojciech Mielicki, Jolanta Rabe-Jabłońska
Farmakoterapia w Psychiatrii i Neurologii, 2011, 2, 95-104

Introduction: Mechanism of therapeutic action of lithium has not been fully understood. Proposed hypotheses include: neurotransmitters transport and signalling modulation, interference with the secondary and other intracellular messenger systems, regulation of gene expression and finally many neuroprotection and antioxidant effects.
Oxidative stress is a state of imbalance between oxidant processes and antioxidant defence. It probably plays important role in the patophysiology and the course of bipolar disorder.
Aim: The aim of this research was to estimate the lithium’s influence on oxidative stress parameters in human plasma (in vitro).
Material and methods: Evaluated oxidative stress parameters were: lipid peroxidation and total antioxidant capacity. Lipids peroxidation was measured by the concentration of thiobarbituric acid reactive substances (TBARs) (the method of Rice-Evans). Measurement of total antioxidant capacity was done as a decolorization assay with the pre-formed radical monocation ABTS•+ (the method of Re).
Plasma samples from healthy volunteers were incubated with lithium concentrations corresponding to concentrations used in the prophylaxis and treatment of bipolar disorder. The control plasma samples were prepared without the drug.
Results: It was shown that incubation of plasma with lithium did not cause statistically significant changes of TBARS levels nor total antioxidant status.
Conclusions: The study showed that lithium did not induce any significant changes of oxidative stress parameters in human plasma in vitro. The results indicate the necessity for further researches in the field in vivo in patients. 

Case report

Simple schizophrenia – problems in differential diagnostic with frontotemporal dementia and favorable effect of treatment with aripiprazole

Piotr Joachimiak, Jan Jaracz, Lucyna Raczkowiak, Janusz Rybakowski
Farmakoterapia w Psychiatrii i Neurologii, 2011, 2, 105-110

In this case report we present a 27 year old male patient diagnosed finally as simple schizophrenia who had an earlier diagnosis of frontotemporal dementia and frontotemporal syndrome. This case ilustrates difficulties in differential diagnosis of a group of diseases like schizophrenia, frontotemporal dementia and autism, in which dysfunction of prefrontal cortex is a common feature. These disorders usually manifest with apathy, anhedonia, social withdrawal, lack of insight, mental rigidity and inflexibility insidious onset and gradual progression. Treatment with aripiprazole led to significant amelioration of negative symptoms and improvement of social functioning.