Tom Bschor

World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Unipolar Depressive Disorders in Primary Care

These practical guidelines for the biological treatment of unipolar depressive disorders in primary care settings were developed by an international Task Force of the World Federation of Societies of Biological Psychiatry (WFSBP). They embody the results of a systematic review of all available clinical and scientific evidence pertaining to the treatment of unipolar depressive disorders and offer practical recommendations for general practitioners encountering patients with these conditions. The guidelines cover disease definition, classification, epidemiology and course of unipolar depressive disorders, and the principles of management in the acute, continuation and maintenance phase. They deal primarily with biological treatment (including antidepressants, other psychopharmacological and hormonal medications, electroconvulsive therapy, light therapy).

Time experience and time judgment in major depression, mania and healthy subjects. A controlled study of 93 subjects

Objective:  Studies on the time sense of depressed patients have revealed inconsistent results. Manic patients have been almost neglected.

Lithium augmentation therapy in refractory depression-update 2002.

Abstract.Lithium has been used to augment the efficacy of antidepressant medications for more than 20 years. The present study examines whether evidence exists to support the clinical efficacy of lithium augmentation in refractory, treatment resistant depression. Studies were identified by searching Medline (1980 to August 2002) and by scanning the references of published reviews and standard textbooks. Studies were selected if they were open-labeled or double-blind, placebo-controlled or comparator trials that involved patients who had not responded to conventional antidepressants. 27 prospective studies were identified that included a total of 803 depressed patients displaying the following designs: 10 double-blind, placebo-controlled trials, 2 randomized, double-blind comparator trials, 2 randomized, open comparator trials, and 13 open-label trials. The majority of randomized controlled trials has demonstrated substantial efficacy of lithium augmentation in partial and non responders to antidepressant treatment. In the placebo-controlled trials, the response rate in the lithium group was 45% and in the placebo group 18% (p<0.001). Summarizing all open and controlled studies, approximately 50% of patients responded to lithium augmentation within 4 weeks. In conclusion, lithium is the foremost and most well-documented augmentation strategy in refractory depression.Therefore, it should be considered a first-line treatment strategy in patients with major depression who do not adequately respond to standard antidepressants.

Lithium’s Emerging Role in the Treatment of Refractory Major Depressive Episodes: Augmentation of Antidepressants

Background: The late onset of therapeutic response and a relatively large proportion of nonresponders to antidepressants remain major concerns in clinical practice. Therefore, there is a critical need for effective medication strategies that augment treatment with antidepressants. Methods: To review the available evidence on the use of lithium as an augmentation strategy to treat depressive episodes. Results: More than 30 open-label studies and 10 placebo-controlled double-blind trials have demonstrated substantial efficacy of lithium augmentation in the acute treatment of depressive episodes. Most of these studies were performed in unipolar depression and included all major classes of antidepressants, however mostly tricyclics. A meta-analysis including 10 randomized placebo-controlled trials has provided evidence that lithium augmentation has a statistically significant effect on the response rate compared to placebo with an odds ratio of 3.11, which corresponds to a number-needed-to-treat of 5. The meta-analysis revealed a mean response rate of 41.2% in the lithium group and 14.4% in the placebo group. One placebo-controlled trial in the continuation treatment phase showed that responders to acute-phase lithium augmentation should be maintained on the lithium-antidepressant combination for at least 12 months to prevent early relapses. Preliminary studies to assess genetic influences on response probability to lithium augmentation have suggested a predictive role of the –50T/C single nucleotide polymorphism of the GSK3β gene. Conclusion: Augmentation of antidepressants with lithium is currently the best-evidenced augmentation therapy in the treatment of depressed patients who do not respond to antidepressants.

Lithium Augmentation Therapy in Refractory Depression: Clinical Evidence and Neurobiological Mechanisms

Objective: This systematic review examines the evidence and discusses the clinical relevance of lithium augmentation as a treatment strategy for refractory major depressive episodes. It also examines hypotheses on the mode of action of lithium augmentation, with a focus on serotonin (5-HT) and neuroendocrine systems, and proposes recommendations for future research. Method: We searched the Medline computer database and the Cochrane Library for relevant original studies published in English from January 1966 to February 2003. The key words were as follows: lithium, augmentation strategies, lithium augmentation, major depression, refractory depression, treatment-resistant depression, neuroendocrinology, and serotonin. Results: Of 27 prospective clinical studies published since 1981, 10 were double-blind, placebo-controlled trials, 4 were randomized comparator trials, and 13 were open-label trials. Five of 9 acute-phase placebo-controlled trials demonstrated that lithium augmentation had substantial efficacy. In the acute-treatment trials, the average response rate in the lithium group was 45%, and in the placebo group, 18% (P < 0.001). One placebo-controlled trial showed the efficacy of lithium augmentation in the continuation-phase treatment. Summarizing the open and controlled data, approximately 50% of patients responded to lithium augmentation within 2 to 6 weeks. Animal studies offer robust evidence that lithium augmentation increases 5-HT neurotransmission, possibly by a synergistic action of lithium and the antidepressant on brain 5-HT pathways. Conclusions: Augmentation of antidepressants with lithium is the best-documented augmentation therapy in the treatment of refractory depression. Emerging data from animal studies suggest that the 5-HTergic system is involved in the augmentatory effect of lithium.

PREDICTORS OF RESPONSE TO LITHIUM AUGMENTATION IN TRICYCLIC ANTIDEPRESSANT-RESISTANT DEPRESSION

BACKGROUND The efficacy of lithium augmentation in therapy-resistant depression has been shown in a series of well-designed, placebo-controlled studies. However, little is known about the predictors of a good response to this treatment strategy. METHODS We retrospectively examined the predictive value of 20 demographic, clinical, biochemical and endocrinological variables using a two-step logistic regression. Seventy-one in-patients with depression refractory to tricyclic antidepressants had received lithium augmentation as part of a standardised treatment protocol. RESULTS Within 4 weeks 37 patients (52%) responded to lithium augmentation. Five variables with predictive value were found. Responders were more severely depressed according to the Bech-Rafaelsen Melancholia Scale. The duration of their index episode was shorter. Triiodothyronine serum levels were lower and neuroleptic co-medication and co-diagnosis of personality disorder were less frequent. LIMITATIONS This was an open, retrospective study. CONCLUSIONS Severity of depression is a predictor of response to lithium augmentation. This result conflicts with recent studies but is similar to results found in studies of other pharmacological antidepressant strategies.

Prophylaxis Latency and Outcome in Bipolar Disorders

Objective: To analyze new and reviewed findings to evaluate relations between treatment response and latency from onset of bipolar disorder (BD) to the start of mood-stabilizer prophylaxis. Method: We analyzed our own new data and added findings from research reports identified by computerized searching. Results: We found 11 relevant studies, involving 1485 adult patients diagnosed primarily with BD. Reported latency to prophylaxis averaged 9.6 years (SD 1.3), and follow-up in treatment averaged 5.4 years (SD 3.1). Greater illness intensity and shorter treatment latency were closely associated, resulting in a greater apparent reduction in morbidity with earlier treatment. However, this finding was not sustained after correction for pretreatment morbidity, and treatment latency did not predict morbidity during treatment. Therefore, assessments based on improvement with treatment, or without correction for pretreatment morbidity, can be misleading. Conclusions: Available evidence does not support the proposal that delayed prophylaxis may limit response to prophylactic treatment in BD and related disorders.

Supraphysiological Doses of L-Thyroxine in the Maintenance Treatment of Prophylaxis-Resistant Affective Disorders

This prospective open-label study examined the efficacy of adjunctive supraphysiological doses of L-thyroxine (T4) in the maintenance treatment of prophylaxis-resistant affective disorder. Twenty-one (16 women, 5 men) of 25 patients enrolled consecutively over an 8-year period on the basis of their status of prophylaxis resistance (defined as two or more failures to standard prophylactic trials) participated for more than four months in the study and were eligible for the intention-to-treat analysis. The mean length of adjunctive treatment with T4 was 51.4 ± 21.7 months. The mean T4 dose at study end was 378.6 ± 90.2 μg/d. The number of episodes and hospitalizations, and the morbidity indices during the time of prophylactic T4 treatment, were compared with those measured for the same length of time before the start of T4 treatment (mirror-image method). On the Clinical Global Impression for Bipolar Disorder scale (CGI-BP, Change from Worst Phase of Illness), eleven subjects (52.4%) were rated as “very much improved”, four (19%) as “much improved”, two (9.5%) as “minimally improved” and four (19%) as “no change.” The mean total number of recurrences (8.6 before T4 treatment vs. 2.8 during T4 treatment; p = .004), the number of hospitalizations (3.1 vs. 1.9; p = .026) and the Morbidity Index (MITotal = 0.71 vs. MITotal = 0.28; p < .001) significantly declined during T4 treatment. Subjects with bipolar disorder (n = 13) benefited more from the T4 treatment intervention than did subjects with unipolar major depressive disorder (n = 4) and schizoaffective disorder (n = 4). In conclusion, adjunctive treatment with L-thyroxine in supraphysiological doses may be an effective strategy in the maintenance treatment of patients with prophylaxis-resistant affective disorders.

Spontaneous speech of patients with dementia of the Alzheimer type and mild cognitive impairment.

This article discusses the potential of three assessments of language function in the diagnosis of Alzheimer-type dementia (DAT). A total of 115 patients (mean age 65.9 years) attending a memory clinic were assessed using three language tests: a picture description task (Boston Cookie-Theft picture), the Boston Naming Test, and a semantic and phonemic word fluency measure. Results of these assessments were compared with those of clinical diagnosis including the Global Deterioration Scale (GDS). The patients were classified by ICD-10 diagnosis and GDS stage as without cognitive impairment (n = 40), mild cognitive impairment (n = 34), mild DAT (n = 21), and moderate to severe DAT (n = 20). Hypotheses were (a) that the complex task of a picture description could more readily identify language disturbances than specific language tests and that (b) examination of spontaneous speech could help to identify patients with even mild forms of DAT. In the picture description task, all diagnostic groups produced an equal number of words. However, patients with mild or moderate to severe DAT described significantly fewer objects and persons, actions, features, and localizations than patients without or with mild cognitive impairment. Persons with mild cognitive impairment had results similar to those without cognitive impairment. The Boston Naming Test and both fluency measures were superior to the picture description task in differentiating the diagnostic groups. In sum, both hypotheses had to be rejected. Our results confirm that DAT patients have distinct semantic speech disturbances whereas they are not impaired in the amount of produced speech.

Efficacy and mechanisms of action of lithium augmentation in refractory major depression.

Lithium augmentation refers to the addition of lithium to an antidepressant in the acute treatment phase of patients with depressive episodes who have failed to respond satisfactorily to treatment with antidepressant monotherapy. This article reviews the clinical evidence and hypotheses on the mode of action of lithium augmentation. For this purpose, studies were identified by searching Medline and by scanning the references of published reviews and standard textbooks. With regard to efficacy, 28 prospective studies (with a total of 838 depressed patients) were identified. The majority of randomized controlled trials has demonstrated substantial efficacy of lithium augmentation. A recent meta-analysis including only double-blind, placebo-controlled trials (N = 9) provided firm evidence that lithium augmentation has a statistically significant effect on response rate compared to placebo, and showed that lithium augmentation should be administered for at least 2 weeks to allow assessment of the patients response. A recent double-blind, placebo-controlled trial revealed that responders to lithium augmentation should be maintained on the lithium-antidepressant combination for a minimum of 12 months. From animal studies there is robust evidence that lithium augmentation increases serotonin (5-HT) neurotransmission, possibly through a synergistic action of lithium and the antidepressant on brain 5-HT pathways. Neuroendocrine studies in humans on the effects of lithium augmentation on the HPA system showed an unexpected and marked increase in the ACTH and cortisol response in the combined dexamethasone/CRH test. These results are in contrast to the established decline of HPA system activity during treatment with antidepressants. In conclusion, lithium is the foremost and most well-documented augmentation strategy in refractory depression. In international treatment guidelines and algorithms, lithium augmentation is considered a first-line treatment strategy for patients with a major depressive episode who do not adequately respond to standard antidepressant treatment.