2009, volume 25, issue 1

Only for Pharmacotherapy in Psychiatry and Neurology

Biological mechanisms of lithium action in the context of mood-stabilizing effect

Agnieszka Permoda-Osip, Janusz Rybakowski
Farmakoterapia w Psychiatrii i Neurologii, 2009, 1, 7–15

In this paper, the attempt was made of summing up the knowledge on the mechanisms of action of lithium – the oldest normothymic drug used for the treatment and prophylaxis of bipolar affective illness. Current neurobiological and molecular genetic studies enable better understanding of the mechanism of prophylactic effect of lithium in bipolar patients. Lithium infl uences cell membrane transport, among others by stimulating the activity of sodium-potassium adenosinotriphosphate (ATPase) and by stabilizing intracellular sodium level. As to its effect on neurotransmission, lithium exerts a signifi cant effect on serotoninergic system (an increase of serotonin synthesis, 5HT2A receptor inhibition, selective modifi cation of 5HT2A/2C and 5HT1B receptors), on dopaminergic transmission (blocking dopaminergic receptor hypersensitivity, conformational alterations of dopamine D2 receptors), on noradrenergic transmission (increasing noradrenaline inactivation and reducing an availability of this neurotransmitter on synapses), and on glutaminergic and GABA-ergic transmission (lithium-induced reduction of glutaminic acid in basal ganglia, and an increase of GABA levels in prefrontal cortex). Especially important role has been assumed for lithium effect on second messenger systems, particularly on phosphatidylinositol and cyclic adenosinomonophosphate (cAMP). This effect may be intimately linked to pathogenic mechanisms of bipolar illness as well as to mechanisms of other fi rst generation mood stabilizing drugs (carbamazepine, valproates). In the paper, the processes connected with neuroprotective action of lithium such as activation of the brain derived neurotrophic factor (BDNF), an increase of bcl-2 protein concentration and inhibition of glycogen synthase kinase (GSK-3) have been also described. The evidence has been presented for the role of some processes in the mechanism of lithium prophylactic effect, obtained on the basis of own molecular-genetic studies in patients with different prophylactic effect of lithium. In the fi nal chapter, some aspect of immunomodulatory and anti-viral effects of lithium have been discussed which may be of signifi cance for normothymic effect of this ion in bipolar illness.

Original article

Augmentation of antidepressant drugs in treatment-resistant depression with lithium or lamotrigine (preliminary study)

Janusz Rybakowski, Maryla Tuszewska, Maria Chłopocka-Woźniak
Farmakoterapia w Psychiatrii i Neurologii, 2009, 1, 17–21

Aim: The addition of lithium to antidepressant drugs is recognized strategy in case of suboptimal therapeutics results. Lamotrigine is a new generation mood stabilizer exerting distinct antidepressant effect and possible augmentation of antidepressant drugs. The aim of this study was an assessment of augmentation by lithium or lamotrigine of two antidepressant drugs: paroxetine and venlafaxine, in treatment-resistant depression.
Methods: The study was performed on 42 patients (11 men, 32 women), aged 20-67 (mean 47) years with treatmentresistant depression in the course of unipolar or bipolar affective illness. All patients had at least two ineffective courses of antidepressant treatment. The drug immediately preceding lithium or lamotrigine addition was either paroxetine, in the dose up to 60 mg/day, or venlafaxine, in the dose up to 300 mg/day, given for 4 weeks. The addition of lithium (concentration 0.6-0.8 mmol/l) or lamotrigine, 200 mg/day, was randomized.
Results: The intensity of depression before lithium or lamotrigine addition was on Hamilton Depression Scale 18-42 (mean 25) points. The addition of lithium or lamotrigine for 4 weeks resulted in a signifi cant reduction of depressive symptoms (on the average by 19 points). No differences in therapeutic effectiveness were observed between patients added lithium or lamotrigine, however, in the whole group, better effi cacy was obtained in venlafaxine than in paroxetine-treated patients. No correlation was found between the effectiveness of potantiation and type of depression (unipolar or bipolar), duration of illness and duration of depressive episode.
Conclusions: The results of this study point to similar augmentation effi cacy of lithium and lamotrigine. Such augmentation is more effective if added to venlafaxine than to paroxetine.

Original article

A study of brain derived neurotrophic factor (BDNF) serum level in depressed patients

Jakub Filuś, Janusz Rybakowski
Farmakoterapia w Psychiatrii i Neurologii, 2009, 1, 23–29

Aim of the study: Was serum BDNF levels measurement in depressed patients, in severe depression and in time of remission after antidepressant treatment and studying of connection between serum BDNF level and severity of depression.
Methods: In studies took part 60 patients hospitalized with the diagnosis of depressive episode in course of unipolar (28 patients) or bipolar disorder (32 patients). Severity of depression was assessed with HAM-D and Beck Scales. Serum BDNF was assayed with sandwich ELISA method using Quantikine Human BDNF Immunoassay (R&D Systems).
Results: The average serum BDNF levels in severe depressed patients were signifi cantly lower than those in remission. Difference was statistically signifi cant in whole patients group, as well as in men and women or bipolar and unipolar. We also found statistically signifi cant negative correlation between severity of depression ( measured with HAM-D) and serum BDNF levels in severe depression and remission.
Conclusions: Our results confi rm increase in serum BDNF level after antidepressant treatment in unipolar and bipolar patients and correlation between BDNF serum level and severity of depression

Review article

Ampakines. CX516 in treatment of schizophrenia

Dominik Strzelecki
Farmakoterapia w Psychiatrii i Neurologii, 2009, 1, 31–35

Ampakines are a new group of glutamatergic system modulators with potential benefi cial infl uence on schizophrenic symptomatology what is suggested by outcome of a few published preclinical and clinical studies. Ampakines are agonists of ionotropic AMPA receptor secondarily induce NMDA receptor excitation. Intensifi cation of glutamatergic transmission and normalization of hypoNMDA state is accountable for negative and cognitive symptom improvement. Article describes important properties of AMPA receptor, ampakines and presents results of clinical trials with AMPA agents, mostly concerning CX516.

Review article

Treatment of psychosis and behavioural disturbances in older patients: efficacy and safety of antipsychotic drugs and mood stabilisers

Małgorzata Rzewuska
Farmakoterapia w Psychiatrii i Neurologii, 2009, 1, 37–46

For many years typical antipsychotic drugs were the most common treatment in management of the behavioural symptoms of dementia, in psychosis and mania in older people. Although there has been extensive experience with their use, this drugs are only modestly effective and have potentially serious adverse effects that, limit their usefulness in older adults. Atypical antipsychotics and mood stabilizers are efficacious treatment in mania and are increasingly used also to treat aggressiveness and agitation in older patients without psychosis.
Although some placebo-controlled trials and meta-analysis of antipsychotic drugs, mood stabilizers and cholinesterase inhibitors have show statistically signifi cant differences favoring their use, the magnitude of effect is small.
If pharmacotherapy is considered necessary, it should be tailored to the individual and balanced against the serious potential risk associated with therapy, including cerebrovascular adverse events, increased mortality and trombocythopenia, and drug interactions.

Review article

Regulation of a circadian rhythms by sustained-release melatonin

Małgorzata Lehner, Adam Hamed, Adam Płaźnik
Farmakoterapia w Psychiatrii i Neurologii, 2009, 1, 47–66

The aim of his study is to review the basic features of biological rhythms and the involvement of the pineal hormone melatonin in the regulation of biological clock, role of melatonin receptors, melatonin is endocrine functions and its use in insomnia therapy. Melatonin is an important component of the internal time-keeping system, its production is regulated by the lightening conditions, light suppresses melatonin synthesis, and darkness enhances it. It regulates physiological processes including the sleep wake cycle, pubertal development and seasonal adaptation. Melatonin possesses also antioxidant activity, modifi es immunological processes and the stress response. Many of its proposed therapeutic or preventive indications are based on these properties. The multiplicity of actions and variety of biological effects of melatonin suggest the potential for a range of clinical and wellness-enhancing uses. Special emphasis, is given to the effectiveness of melatonin prolonged release supplementation therapy in the treatment of the biological rhythm-related disorders. Synthetic melatonin supplementation has been used for chronobiotic therapy and assists with tapering or cessation of benzodiazepine depending. Exogenous melatonin reduces such disturbances related to sleep as adverse effects induced by beta-blockers which depress melatonin secretion. Melatonin administration does not cause toleration and serious adverse effects. Preclinical and clinical data indicate that melatonin can be helpful in many disorders. Synthetic melatonin supplements have been used for a variety of medical conditions, most notably for disorders related to sleep but a survey of the medical data should be done to determine its effi cacy and side effects in a number of conditions, the main attention focused on: sleep disturbances, seasonal affective disorder, neuroendocrine disorder and cancer therapy. This review summarizes the physiology of melatoninergic system and discusses the potential therapeutic uses of melatonin.