Aleksandra Suwalska

Excellent lithium responders have normal cognitive functions and plasma BDNF levels.

In bipolar patients, neuropsychological and biochemical disturbances persist into the remission period. Excellent lithium responders (ELRs) comprise around one third of lithium-treated patients and have total remission of recurrences on lithium monotherapy. The objective of the study was to assess the performance on neuropsychological tests and to measure brain-derived neurotrophic factor (BDNF) plasma levels in ELRs compared to patients where the effect of lithium was not optimal, and with matched healthy control subjects. The study was performed with 60 patients on prophylactic lithium treatment, 13 of whom were ELRs, and with 60 matched healthy controls. Neuropsychological tests from the CANTAB battery measuring spatial working memory and sustained attention were used. ELRs performed better on all neuropsychological tests, and had higher plasma BDNF levels than the remaining lithium patients but not different from those of healthy controls. ELRs may constitute a specific subgroup of bipolar patients in which long-term lithium administration can produce complete normality.

Response to lithium prophylaxis: interaction between serotonin transporter and BDNF genes.

Both serotonin transporter and brain‐derived neurotrophic factor (BDNF) genes have been previously implicated in the efficacy of lithium prophylaxis. The aim of the present study was to assess a possible interaction between serotonin transporter genotype (5HTTLPR) and BDNF Val66Met polymorphism, and the prophylactic response to lithium. The study was performed on 111 patients with bipolar mood disorders (43 male, 68 female), aged 30–77 (mean 54 years) who have been treated with lithium carbonate for at least 5 years (5–27 years, mean 15 years). In the group studied, 31 patients (28%) were classified as excellent responders (ER), 54 (49%) as partial responders (PR), and 26 (23%) as non‐responders (NR) to lithium prophylaxis. Age at onset of the illness, duration of illness before treatment introduction and on lithium as well as number of affective episodes before lithium treatment did not differ between these three subgroups of patients. A significant interaction between BDNF and 5HTTLPR polymorphism and lithium response was found. S individuals (patients with s/s or s/l genotype) having Val/Val genotype were significantly more frequent in NR compared with ER or/and PR. Also, S individuals showed extreme differences in response to lithium prophylaxis depending on having either Val/Val or (Val/Met + Met/Met) genotypes of BDNF polymorphism: 9/48 (19%) of ER and 18/48 (37%) of NR in the first group, and 12/30 (40%) and 1/30 (3%) in the second group, respectively. The results obtained may show a significant epistatic interaction between 5‐HTTLPR and BDNF polymorphism, and response to lithium prophylaxis.

Association studies of the BDNF and the NTRK2 gene polymorphisms with prophylactic lithium response in bipolar patients.

The neuroplasticity hypothesis of bipolar disorder indicates that the BDNF/Trk signaling pathway is associated with the pathogenesis of this illness and treatment with mood stabilizers, such as lithium. This paper describes a relationship between response to lithium prophylaxis and polymorphisms of two functionally connected genes: BDNF and NTRK2, in bipolar illness. Analyses of four SNPs of the BDNF gene (rs2030324, rs988748, rs6265 [Val66Met]and rs2203877) and three of the NTRK2 gene (rs1187326, rs2289656, rs1187327) were performed in the 108 bipolar patients, classified as excellent responders (23%), partial responders (51%) and nonresponders (26%) to lithium. An association of C/G (rs988748) and G/A (rs6265) polymorphisms of the BDNF gene with a degree of prophylactic lithium response were found. No association with lithium response was revealed with the polymorphism of NTRK2 gene, neither with interaction of BDNF and NTRK2 genes.

Association study of the glycogen synthase kinase-3β gene polymorphism with prophylactic lithium response in bipolar patients

A relationship between response to lithium prophylaxis and T-50C polymorphism of glycogen synthase kinase-3β (GSK-3β) gene was investigated in 89 bipolar patients (41 male and 48 female) who have been taking lithium for at least 5 years. The patients were delineated as excellent responders, partial responders and non-responders to lithium. The results obtained suggest that this polymorphism may not be related to the degree of prophylactic lithium response.

Neuroprotective effect of lithium on hippocampal volumes in bipolar disorder independent of long-term treatment response.

BACKGROUND Neuroimaging studies have demonstrated an association between lithium (Li) treatment and brain structure in human subjects. A crucial unresolved question is whether this association reflects direct neurochemical effects of Li or indirect effects secondary to treatment or prevention of episodes of bipolar disorder (BD). METHOD To address this knowledge gap, we compared manually traced hippocampal volumes in 37 BD patients with at least 2 years of Li treatment (Li group), 19 BD patients with <3 months of lifetime Li exposure over 2 years ago (non-Li group) and 50 healthy controls. All BD participants were followed prospectively and had at least 10 years of illness and a minimum of five episodes. We established illness course and long-term treatment response to Li using National Institute of Mental Health (NIMH) life charts. RESULTS The non-Li group had smaller hippocampal volumes than the controls or the Li group (F 2,102 = 4.97, p = 0.009). However, the time spent in a mood episode on the current mood stabilizer was more than three times longer in the Li than in the non-Li group (t(51) = 2.00, p = 0.05). Even Li-treated patients with BD episodes while on Li had hippocampal volumes comparable to healthy controls and significantly larger than non-Li patients (t(43) = 2.62, corrected p = 0.02). CONCLUSIONS Our findings support the neuroprotective effects of Li. The association between Li treatment and hippocampal volume seems to be independent of long-term treatment response and occurred even in subjects with episodes of BD while on Li. Consequently, these effects of Li on brain structure may generalize to patients with neuropsychiatric illnesses other than BD.

Potentiation of Antidepressants with Lithium or Carbamazepine in Treatment-Resistant Depression

Fifty-nine patients with treatment-resistant depression were randomly allocated an addition of either lithium (Li; 31 patients) or carbamazepine (CBZ; 28 patients) to ongoing antidepressant treatment. The therapeutic efficacy of both strategies, assessed after 28 days, was not significantly different. In the Li group, clinical improvement significantly correlated with decrease in thyroxine concentration. Also, a decrease in cortisol level in Li responders and an increase in nonresponders was observed, suggesting a regulatory effect of Li on the hypothalamic-pituitary-adrenal axis activity. CBZ responders had lower baseline severity of depression than CBZ nonresponders and clinical improvement significantly correlated with increase in erythrocyte ATPase activity in the CBZ group.

Types of depression more frequent in bipolar than in unipolar affective illness: results of the Polish DEP-BI study.

Background: The aim of the study was to assess the relative frequency of various kinds of depression in patients with bipolar and unipolar affective illness. The study was performed in the framework of the DEP-BI project aimed at assessing the prevalence of bipolar disorders among depressive outpatients treated by psychiatrists in Poland. Methods: Eight-hundred and eighty patients (237 male, 643 female) participated in the study. The patients were classified into the following diagnostic categories: bipolar affective illness type I, type II, bipolar spectrum disorder and unipolar affective illness. The various kinds of depression in each group were assessed by means of a semistructured questionnaire added to the diagnostic interview. Results: In the group of bipolar patients, a significantly higher frequency of psychotic depression in male compared to female patients was observed. Male bipolar patients compared with unipolar depressed ones had significantly more episodes of psychotic depression (odds ratio, OR, 4.29) and atypical depression (hypersomnia and hyperphagia; OR 2.82), and those with bipolar spectrum had more episodes of treatment-resistant depression (OR 2.56). Female bipolar patients compared with unipolar depressed ones had significantly more frequently an early onset of depression (before 25 years; OR 2.95) and postpartum depression (OR 2.48). On the other hand, the percentage of agitation, irritability, distractibility, thought racing and panic attacks during depression was not different in patients with bipolar and unipolar affective illness either in males or females. Conclusions: Some kinds of depression occur with a higher frequency in patients with bipolar compared to unipolar affective illness. The occurrence of a given type of depression may constitute an aid for the diagnosis of bipolar illness. The results of this study did not confirm the concept of bipolar mixed depression based on the presence of anxiety symptoms occurring during the depressive episode. The limitation of our study may be the lack of formal criteria or a structured interview to assess the symptoms occurring during depressive episodes.

Dopamine D1 Receptor Gene Polymorphism is Associated with Prophylactic Lithium Response in Bipolar Disorder

BACKGROUND Previously, we have found an association between the -48 A/G polymorphism of the dopamine receptor D1 (DRD1) gene and bipolar disorder. The aim of the present study was to investigate a possible association of this polymorphism with the quality of the prophylactic lithium response in bipolar patients. METHODS Ninety-two patients (39 male, 53 female), aged 30-77 (mean: 54 years) were studied. They have received lithium for prophylactic purposes for 5-27 years (mean: 15 years). Twenty-four patients were identified as excellent lithium responders (ER), 48 patients as partial responders (PR), and 20 patients were non-responders (NR). They all were genotyped for -48 A/G polymorphism of the DRD1 gene. RESULTS The frequency of G/G genotype in ER, PR, and NR patients was 21%, 48%, and 60%, respectively, and the frequency of G allele was 58%, 76%, and 80%, respectively. DISCUSSION The results obtained suggest that the higher frequency of G allele, and G/G genotype, which has been associated with a predisposition to bipolar illness, is also connected with a poorer prophylactic effect of lithium.

Influence of atypical features on the quality of prophylactic effectiveness of long-term lithium treatment in bipolar disorders

OBJECTIVES There is still debate about whether the quality of long-term efficacy of lithium in patients with bipolar disorders is influenced by atypical features. Extended Cox regression models allow for the use of all follow-up data on diseases with multiple episodes. The aim of the present analysis was to apply the best suited of these models to analyze the influence of atypical features on the widely used outcome measure of time to recurrence in a large multicenter cohort of lithium responders established by the International Group for the Study of Lithium Treated Patients. METHODS A conditional extended Cox model with a random frailty term was applied to the data of 336 bipolar I and II disorder patients, all of whom were responders to lithium with treatment for up to 30 years. RESULTS Differences were found in the long-term outcome, even in patients who have demonstrated a relatively good response to lithium treatment. The hazard for recurrence was negatively influenced by the presence of atypical features, mainly mood-incongruent psychotic symptoms, interepisodic residual symptomatology, and rapid cycling. CONCLUSIONS As a result of the findings, physicians should regularly reassess the quality of response in bipolar disorder patients with atypical features and, if necessary, modify treatment. Extended Cox regression models are well suited for evaluating long-term outcome and should be used more extensively to analyze treatment outcome in psychiatric and somatic disorders.

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.