Disturbances of purinergic system in affective disorders and schizophrenia. / Zaburzenia ukladu purynergicznego w chorobach afektywnych i schizofrenii.

Purinergic system plays a role in the regulation of many psychological processes, including mood and activity. It consists of P1 receptors, with adenosine as the agonist, and P2 receptors, activated by nucleotides (e.g., adenosine 5'-triphosphate - ATP). Propounded disturbances of uric acid in affective disorders were related to the introduction of lithium for the treatment of these disorders in the 19th and 20th century. At the beginning of the 21st century, new evidence was accumulated concerning a role of uric acid in the pathogenesis and treatment of bipolar disorder (BD). In patients with BD, higher prevalence of gout and increased concentration of uric acid have been found as well as the therapeutic activity of allopurinol, used as an adjunct to mood stabilizers, has been demonstrated in mania. In recent years, the research on the role of the purinergic system in the pathogenesis and treatment of affective disorders and schizophrenia focuses on the role of adenosine (P1) receptors and nucleotide (P2) receptors. Activation of adenosine receptors is related to an antidepressant activity. Alterations of P2 receptors are also significant for the pathogenesis of affective disorders. The role of purinergic system in schizophrenia is related to the effect of adenosine and nucleotide receptors on dopaminergic and glutamatergic neurotransmission. A lot of data indicate that schizophrenia is related to a deficit of adenosine system. Changes in the purinergic system are also significant for psychopathological symptoms of schizophrenia and for the action of antipsychotic drugs.

Electroconvulsive therapy and autobiographical memory in patients with treatment-resistant depression. / Terapia elektrowstrzasowa i pamiec autobiograficzna u pacjentów z depresja lekooporna.

OBJECTIVES: Electroconvulsive therapy (ECT) is the most effective treatment for drugresistant depression. In most studies, cognitive functions including working and semantic memory showed only transient impairment after ECT. However, the deficits of episodic (autobiographical) memory were demonstrated to be long-lasting. METHODS: We investigated autobiographical memory in 20 patients (8 male, 12 female), aged 21-64 years, with drug-resistant depression, treated with ECT, using the Polish adaptation of the Autobiographical Memory Interview-Short Form (AMI-SF). The assessments were performed before, immediately after 10-12 ECT sessions, and 3 months thereafter. RESULTS: Before the ECT, the mean severity of depression was 30 ± 6 points on the 17-item Hamilton Depression Rating Scale and the treatment produced a significant clinical improvement in all patients. The indices of autobiographical memory, as assessed by the AMI-SF, were significantly lower immediately after ECT and 3 months thereafter. The impairment in autobiographical memory did not show correlation with clinical improvement and with any other clinical factors. CONCLUSIONS: The results obtained in patients with drug-resistant depression confirm that ECT treatment produces a significant impairment of autobiographical memory persisting also three months after the procedure, suggesting that it may be the most important adverse cognitive effect of the ECT.

Ketamine augmentation rapidly improves depression scores in inpatients with treatment-resistant bipolar depression.

OBJECTIVE: To study the clinical effect of a single ketamine infusion, 0.5 mg/kg body weight, in bipolar depressive patients receiving mood-stabilising drugs, not improving on antidepressants. Previously, in such patients, we had found a correlation between clinical efficacy, serum brain-derived neurotrophic factor and vitamin B12 levels and a rapid improvement in neurocognitive performance. METHODS: The study included 53 patients (13 men, 40 women), aged 22-81 years, receiving ≥1 mood-stabilising medications of the first and/or second generation. Pre-infusion depression intensity on the Hamilton Depression Rating Scale (HDRS) was 23.4 ± 4.6 points and the assumed criterion for response was a reduction of ≥50% in the HDRS score after 7 days. RESULTS: Twenty-seven subjects (51%) met a criterion for response, more frequently males (77%) than females (43%). Responders did not differ from non-responders as to age, illness onset, duration of depressive episode, type of bipolar illness, family history of psychiatric illness, personal/family history of alcoholism or using lithium, quetiapine or a combination of these mood stabilisers. CONCLUSIONS: The results confirm a rapid antidepressant effect of ketamine infusion in a considerable proportion of those patients with bipolar depression receiving mood-stabilising drugs. Apart from male gender, no other clinical factors were predictors of response.

Kidney, thyroid and other organ functions after 40 years or more of lithium therapy: a case series of five patients.

We present the cases of five patients (two men aged 64 years and 79 years) and three women (aged 64 years, 65 years and 75 years) who have received lithium treatment for 40-45 years, with particular regard to kidney and thyroid functions, hypercalcaemia and cognition, in the context of disease course and overall functioning. Lithium was initiated in the early phase of the illness (in three patients within the first 2 years). In four patients, lithium concentration was between 0.60 and 0.65 mmol/l and in one patient, between 0.7 and 0.8 mmol/l. Four were very good lithium responders. One man had stage 3 chronic kidney disease, and the other stage 2/3 chronic kidney disease. All three women had asymptomatic stage 2 chronic kidney disease. One woman had severe thyroid dysfunction (Hashimoto's disease) with extremely high levels of antithyroid peroxidase antibodies and antithyroglobulin antibodies and was receiving thyroxine. Serum calcium levels were normal or borderline in all five patients, and most cognitive functions were comparable to healthy persons of similar gender, age and years of education. All the patients were professionally active until 55-65 years and their family and social functioning were satisfactory. It was concluded that, in good lithium responders, ultra-long-term treatment with lithium enables good professional and psychosocial functioning, and the possible somatic side effects are manageable.

Family-based association study of interleukin 6 (IL6) and its receptor (IL6R) functional polymorphisms in schizophrenia in the Polish population.

Schizophrenia is a heterogeneous disorder and its etiology remains incompletely elucidated. Among possible causes, immunological factors have been implicated in its pathogenesis and course. The inflammatory system may trigger or modulate the course of schizophrenia through complex mechanisms influencing neurodevelopment, neuroplasticity and neurotransmission. Recent studies indicate a role of excessive interleukin-6 (IL6) signaling in the pathogenesis of schizophrenia. Findings regarding changes in the circulating levels of soluble interleukin-6 receptor (sIL6R) in schizophrenia have been equivocal. The study was performed on a group of 147 trio (patients diagnosed with schizophrenia and their healthy parents). Polymorphisms of IL6 (rs1800795, rs1800797) and IL6R (rs4537545, rs4845617, rs2228145) genes were genotyped with the use of TaqMan SNP Genotyping Assays. No association of the polymorphisms from IL6 and IL6R genes with schizophrenia was found. We also investigated haplotypes in IL6 gene (consisting of rs1800795 and rs1800797) and in IL6R gene (consisting of rs4537545, rs2228145). We also found no preference in transmission of any haplotype. Our results do not support the theory that polymorphisms of IL6 and IL6R genes are involved in the pathogenesis of schizophrenia. It seems advisable to carry out further examinations of the role of these polymorphisms in schizophrenia by means of TDT method and classical (case-control) association method.

Analysis of PRKN Variants and Clinical Features in Polish Patients with Parkinson's Disease.

The etiology of Parkinson's disease (PD) is still unclear, but mutations in PRKN have provided some biological insights. The role of PRKN mutations and other genetic variation in determining the clinical features of PD remains unresolved. The aim of the study was to analyze PRKN mutations in PD and controls in the Polish population and to try to correlate between the presence of genetic variants and clinical features. We screened for PRKN mutations in 90 PD patients and 113 controls and evaluated clinical features in these patients. We showed that in the Polish population 4% of PD patients had PRKN mutations (single or with additional polymorphism) while single heterozygous polymorphisms (S167N, E310D, D394N) of PRKN were present in 21% of sporadic PD. Moreover, 5% PD patients had more than one PRKN change (polymorphisms and mutations). Detected PRKN variants moderately correlated with PD course and response to L-dopa. It also showed that other PARK genes (SNCA, HTRA2, SPR) mutations probably may additionally influence PD risk and clinical features. PRKN variants are relatively common in our Polish series of patients with PD. Analysis of the PRKN gene may be useful in determining clinical phenotype, and helping with diagnostic and prognostic procedures in the future.

Agomelatine-induced liver injury in a patient with choledocholithiasis.

OBJECTIVE: A case of agomelatine-induced hepatotoxicity is described in a 47-year female patient who has received the drug, 25 mg/day, for 4 months, for the treatment of depression. METHODS: The patient was admitted to the Department of Gastroenterology because of fatigue and nausea, with concomitant elevation of alanine aminotransferase (ALT), 550 U/L, and asparagine aminotransferase (AST), 300 U/L. RESULTS: Liver biopsy showed diffuse lymphocyte infiltration in the dilated portal spaces without lesion of hepatic lobules. Several weeks after stopping agomelatine, the liver enzymes returned to normal. Subsequently, small gallstones in common bile duct were detected and removed by the endoscopic sphincterotomy. CONCLUSIONS: It is hypothesized that choledocholithiasis could theoretically increase a risk of developing agomelatine-induced hepatotoxicity in this patient. Any pre-existing liver disease should be a contraindication for treatment with agomelatine.

[Factors connected with efficacy of single ketamine infusion in bipolar depression]. / Czynniki skutecznosci jednorazowego wlewu ketaminy w depresji w przebiegu choroby afektywnej dwubiegunowej.

AIM: The aim of this study was to evaluate the efficacy of single ketamine infusion and clinical and biochemical factors connected with such efficacy, in patients with bipolar depression, which had not improved on antidepressant treatment. METHODS: The study included 42 patients (32 women, 10 men), aged 22-67 years, with bipolar depression. They received > or = 1 mood-stabilizing medications of first and/or second generation. After discontinuation of antidepressants (> or = 7 days), intravenous infusion of ketamine (0.5 mg/kg body weight) was performed. The assessment of depression by the 17-item Hamilton Depression Rating Scale was made before, and after 1, 3, 7 and 14 days following administration of ketamine. The assumed criterion for clinical improvement was the reduction of > or = 50% score on the Hamilton scale after 7 days. In a subgroup of 20 patients, prior to administration of ketamine, serum concentrations of homocysteine, vitamin B12, folic acid, neurotrophins and inflammatory proteins were measured. RESULTS: In the whole group, the severity of depression on the Hamilton scale decreased significantly 24 hours after administration of ketamine from 22.6 +/- 5.1 to 15.6 +/- 7.4 points. After 7 days it was 13 +/- 7 and after 14 days - 11.8 +/- 7.8 points. Patients showing clinical improvement (n = 22) had significantly higher frequency of alcohol addiction and family history of alcoholism. Biochemical tests in the subset of 20 patients demonstrated that those with clinical improvement (n = 10) had higher serum concentrations of vitamin B12 and receptor-1 Vascular Endothelial Growth Factor before administration of ketamine. Ketamine infusion was well tolerated. CONCLUSIONS: The results confirm a rapid antidepressant effect of ketamine infusion maintaining for 2 weeks, in a considerable proportion of patients with bipolar depression, and good clinical tolerance of such procedure. Also, some clinical and biochemical factors associated with ketamine efficacy were shown.

Are genes connected with homocysteine metabolism associated with bipolar disorder?

BACKGROUND: Increased levels of homocysteine have been observed in various psychiatric disorders, among them in schizophrenia, depression and bipolar mood disorder. Of the genes connected with homocysteine metabolism, some studies have found an association between polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene and bipolar disorder. The aim of this study was to investigate a possible association between 5 polymorphisms of 4 genes coding enzymes of homocysteine metabolism and bipolar disorder. METHOD: A total of 120 patients with bipolar disorder (24 male, 96 female) and 167 subjects from the general population (81 male, 86 female) were included in the study. Genotyping was performed for the C677T (rs1801133) and A1298C (rs1801131) polymorphisms of the MTHFR gene, for the T833C polymorphism (rs5742905) of the cystathionine-ß-synthase (CBS) gene, for the A2756G polymorphism (rs1805087) of the homocysteine methyltransferase gene, and for the A66G polymorphism (rs1801394) of the methionine synthase reductase (MTRR) gene. RESULTS: An association with bipolar disorder was found for the T833C polymorphism (rs5742905) of the CBS gene. However, in the patient sample, the genotypes of this polymorphism were not in Hardy-Weinberg equilibrium. No relationship to bipolar disorder was obtained for the remaining polymorphisms studied. CONCLUSIONS: These results are the first suggesting a possible association between T833C polymorphism (rs5742905) of the CBS gene and bipolar disorder. We were unable to confirm an association between bipolar disorder and C677T polymorphism (rs1801133) of the MTHFR gene, as suggested in some previous studies.

[Homocysteine and cognitive functions in bipolar depression]. / Homocysteina a funkcje poznawcze w depresji w przebiegu choroby afektywnej dwubiegunowej.

AIM: The aim of the study was to evaluate a relationship between concentrations of hoocysteine (HCY), vitamin B12 and folic acid and disturbances of cognitive functions during acute episode of bipolar depression. METHODS: 116 patients were studied (93 women, 23 men), aged 20-78 (mean 51±13) years during acute episode of bipolar depression. Depression was evaluated by the 17-item Hamilton's Depression Rating Scale (HDRS). The following tests measuring cognitive functions were applied: Trail Making Test, Wisconsin Card Sorting Test, Stroop Test and Wechsler Adult Intelligence Scale-Revised. In all patients, the measurements of serum homocysteine, vitamin B12 and folic acid were carried out. RESULTS: Hyperhomocystemia (HCY>15µM/l) was detected in 41 patients (35%), more frequently in men (52%) than in women (31%). Patients with hyperhomocysteinemia achieved worse results in sub-tests of WAIS-R (verbal understanding and perceptional organization). In men, negative correlation was found between HCY concentration and number of errors in Stroop Test, and WCST (total errors and non-perseverative errors). In women with bipolar disorder, type II, negative correlation between HCY concentration and time of Stroop Test, and between vitamin B12 concentration and number of errors in Stroop Test, were demonstrated. In the whole group and in men, there was positive correlation between higher folic acid concentration and the number of errors in Stroop Test. CONCLUSIONS: The results obtained show higher HCY concentration in considerable proportion of patients with bipolar depression, especially in men. They also confirm a connect between high homocysteine concentration and worse performance in some neuropsychological tests. Such relationship was more marked in men.

Hyperhomocysteinemia in bipolar depression: clinical and biochemical correlates.

BACKGROUND: Depression may be associated with elevated homocysteine (HCY) levels. Procedures aiming at its decrease, i.e. supplementation with folic acid or vitamin B12, have antidepressant effect. Both depression and elevated HCY can increase cardiovascular risk. In this study, clinical and biochemical factors, including markers of endothelial function, in relation to hyperhomocysteinemia, in patients with bipolar depression during acute episode were studied. METHOD: One hundred and twelve patients (24 male, 88 female), aged 20-78 (mean 51 ± 14 years), with depressive episode in the course of bipolar mood disorder have been included. The assays were made of serum concentrations of HCY, vitamin B12, folic acid as well as markers of endothelial function such as E-selectin and intracellular adhesion molecule-1 (ICAM-1). RESULTS: Hyperhomocysteinemia (>15 mM) was found in 50 patients (45%), significantly more frequently in male (67%) than in female subjects (39%). Female patients with hyperhomocysteinemia were significantly older than the remaining ones. A significant inverse correlation between HCY level and concentration of folic acid and vitamin B12 as well as with E-selectin and ICAM-1 was observed. CONCLUSION: The results point to a significant prevalence of hyperhomocysteinemia in bipolar depressed patients during an acute episode. They also corroborate the correlation between increased concentration of HCY and lower level of vitamin B12 and folic acid. An unexpected finding of negative correlation of HCY level with markers of endothelial functions in such patients is discussed in view of current concepts of the role of HCY in various conditions.

Single ketamine infusion in bipolar depression resistant to antidepressants: are neurotrophins involved?

OBJECTIVES: We investigated serum brain-derived neurotrophin factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NTF3), neurotrophin-4 (NTF4) and the glial-derived neurotrophic factor (GDNF), in relation to ketamine efficacy, in bipolar depressed patients resistant to treatment with antidepressants. METHODS: Twenty-five patients (4 male, 21 female), aged 27-67 years, with bipolar depression, receiving mood-stabilizing medications, were studied. Antidepressants were discontinued for at least 7 days before single intravenous ketamine infusion (0.5 mg/kg body weight). Response to ketamine was defined as ≥ 50% reduction on 17-item Hamilton Depression Rating Scale (HDRS) after 1 week, and remission as HDRS score ≤ 7. Serum BDNF, NGF, NTF3, NTF4 and GDNF levels were estimated by enzyme-linked immunosorbent assay. RESULTS: There were 13 ketamine responders and 12 non-responders. The remission was obtained in eight and 12 patients after seven and 14 days, respectively. At baseline, there were no differences between responders and non-responders in any of the neurotrophins. Serum BDNF was significantly reduced after 7 days in non-responders. Serum NGF, NT3, NT4 and GDNF did not significantly change. CONCLUSIONS: The results confirm an antidepressant effect of ketamine infusion as an add-on to mood-stabilizing drugs in bipolar depression resistant to antidepressant treatment. They may also suggest a possible involvement of BDNF in this effect.

Clinical and pathogenic aspects of candidate genes for lithium prophylactic efficacy.

A number of candidate genes for lithium prophylactic efficacy have been proposed, some of them being also associated with a predisposition to bipolar illness. The aim of the present study was to investigate a possible association between polymorphisms of 14 common genes with the quality of prophylactic lithium response in patients with bipolar mood disorder, in relation to the putative role of these genes in the pathogenesis of this disorder. Some association with lithium prophylactic efficacy was found for the polymorphisms of 5HTT, DRD1, COMT, BDNF and FYN genes, but not for 5HT2A, 5HT2C, DRD2, DRD3, DRD4, GSK-3, NTRK2, GRIN2B and MMP-9. Possible aspects of these genes with regard to the mechanism of lithium activity and pathogenesis of bipolar mood disorder are discussed.

[Glutamatergic conception of mood disorders]. / Koncepcja glutaminergiczna chorób afektywnych.

The neurotransmitter theories of the pathogenesis and treatment of mood disorders presented so far focused mainly on serotonergic and catecholaminergic (noradrenergic and dopaminergic) transmission. In recent decades the attention has been also directed towards a role in the pathogenesis of mood disorders of stress axis dysregulation and of neuroplasticity disturbances, which involve the glutamatergic system. In this paper, a role of glutamatergic neurotransmission in the pathogenesis and treatment of unipolar and bipolar affective illness is presented. In the first part, a role of glutamatergic neurotransmission in the central nervous system is presented, with special focus on glutamatergic receptors. The results of molecular-genetic studies pointing to an association between glutamatergic system genes and a predisposition to unipolar and bipolar affective illness are discussed. In the next part, a summary of neurobiological, including neuroimaging findings as to changes in glutamatergic system in mood disorders is done. Following this, a role of glutamatergic system in the mechanism of action of antidepressant and mood-stabilizing drugs as well as therapeutic activity of drugs modifying glutamatergic system is reviewed. Glutamatergic conception of mood disorders allows for a new look on the pathogenesis and treatment of unipolar and bipolar affective illness.

Response to prophylactic lithium in bipolar disorder may be associated with a preservation of executive cognitive functions.

We assessed performance on the Wisconsin Card Sorting Test (WCST), measuring executive functions, in 30 patients showing different prophylactic effect of lithium (excellent lithium responders-ER, partial responders-PR and non-responders-NR), and in fifty persons of their offspring (12 of ER, 26 of PR, and 12 of NR). Age- and gender head-to-head matched population consisted of 30 subjects for lithium group and 50 subjects for the offspring of lithium patients. In lithium patients, NR had significantly worse results compared to the remaining groups and to control subjects on perseverative errors (WCST-P) and conceptual responses (WCST-%conc). No differences were observed in the offspring of patients with different effect of lithium, however, they showed an impairment on WCST-P and WCST-%conc compared to matched healthy controls. Therefore, the favorable effect of lithium prophylaxis may be associated with a preservation of executive cognitive functions and the offspring of bipolar patients shows an impairment of such functions.