Search

Background: Tricyclic antidepressants (TCA) continue to be an important group of drugs, but it is unclear whether a dose-response relationship is supported by high-level evidence., Methods: Systematic review in the Cochrane Collaboration's Central Register of Controlled Trials (CENTRAL) of studies randomizing patients to at least two doses of one TCA, complemented by searches in Medline, Embase, and PsycInfo. In multilevel regression, we calculated the standardized mean difference (SMD) in antidepressant efficacy per mg TCA dose increase, and we analyzed drop-outs due to adverse events. Finally, we computed random effects meta-analyses of all dose comparisons investigated in a minimum of two studies., Results: Out of 5365 studies screened, we included 15 randomized trials on 24 comparisons of 14 different dose contrasts. We found a statistically non-significant positive effect of increasing the dose: 0.34 SMD with 100 mg/d dose increase ([-0.03; 0.70] p = 0.073). While several comparisons showed no clear signal of a dose gradient, 300 mg of imipramine/desipramine is statistically significantly superior to 150 mg (SMD: 0.80 [0.28; 1.33], p = 0.003, I 2 : 0%). Drop-outs increased with higher doses, albeit not statistically significantly: Odds ratio (OR) of 1.44 with 100 mg dose increase [0.54; 3.86]. Overall, risk of bias was high., Limitations: Limited number of studies with mainly high risk of bias., Conclusions: So far, data on a dose-response relationship in TCAs from direct dose comparisons are inconclusive. Clinically, escalation to high doses may be justified if side effects are bearable., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: A recent study by Hengartner and Plöderl describes a strong increase for suicides (odds ratio (OR) of 2.83, 95% CI=1.13-9.67) and suicide attempts (OR=2.38 95%, CI=1.63-3.61) in antidepressant treated patients as compared to placebo. The authors re-analyzed data presented by Khan et al. who found no drug-placebo differences in suicide and suicide attempt rates. Hengartner and Plöderl base their findings on calculating the OR from a 2×2 table of the sum of the events and the totals of the sample sizes across studies. We here argue that pooling data from all drugs may not be the adequate approach., Methods: We applied a meta-analytical approach to account for between-drug variance and conducted several statistical analyses as a sensitivity analysis. We argue that a more suitable approach for finding an overall effect from several observations is a meta-analytical approach namely the Mantel-Haenszel method without continuity correction., Results: Our analysis leads to different conclusions as opposed to Hengartner and Plöderl. With the recommended method we estimate an OR of 1.98, 95% CI 0.71-5.50 for suicides and 1.63 (95%CI=1.09-2.43) for suicide attempts., Limitations: The conducted analysis was restricted to the data available from the previous studies. Possibly, a more extensive search of the literature would lead to different results. However, we showed that re-analysing the re-analysis with several different approaches underlines the necessity of sensitivity analysis., Conclusion: We could show that, in the case of rare events, the data is very sensitive to different analytical approaches underlining the importance of further investigations., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2020. Published by Elsevier B.V.)

Background: Lithium augmentation (LA) of antidepressants is an effective strategy for treatment-resistant depression (TRD). Nevertheless, it is rarely used in geriatric patients. The purpose of this study was to investigate treatment response of LA in geriatric compared to non-geriatric patients., Method: In a prospective multicenter cohort study, severity of depression was measured weekly in 167 patients with unipolar depression (n age≥65years  = 22; n age<65years  = 145) at baseline and over at least four weeks of LA., Results: Geriatric patients showed a significantly better response to LA compared to non-geriatric patients (Hazard Ratio = 1.91; p = 0.04)., Limitations: An important limitation of our study is the lack of a control group of LA and the missing evaluation of side effects in both groups., Conclusions: This is the first study investigating the efficacy of LA for TRD in geriatric compared to non-geriatric patients. Our data suggest that LA is an effective treatment option in geriatric patients that clinicians might consider more frequently and earlier on in the course of treatment., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Recent reports indicate that the prevalence of bipolar disorder (BD) in patients with an acute major depressive episode might be higher than previously thought. We aimed to study systematically all patients who sought therapy for major depressive episode (MDE) within the BRIDGE study in Germany, reporting on an increased number (increased from 2 in the international BRIDGE report to 5) of different diagnostic algorithms., Methods: A total of 252 patients with acute MDE (DSM-IV confirmed) were examined for the existence of BD (a) according to DSM-IV criteria, (b) according to modified DSM-IV criteria (without the exclusion criterion of 'mania not induced by substances/antidepressants'), (c) according to a Bipolarity Specifier Algorithm which expands the DSM-IV criteria, (d) according to HCL-32R (Hypomania-Checklist-32R), and (e) according to a criteria-free physician's diagnosis., Results: The five different diagnostic approaches yielded immensely variable prevalences for BD: (a) 11.6; (b) 24.8%; (c) 40.6%; (d) 58.7; e) 18.4% with only partial overlap between diagnoses according to the physician's diagnosis or HCL-32R with diagnoses according to the three DSM-based algorithms., Conclusions: The diagnosis of BD in patients with MDE depends strongly on the method and criteria employed. The considerable difference between criteria-free physician's diagnosis and the remaining algorithms indicate the usefulness of criteria lists within the everyday clinical setting., Limitations: Diagnoses based on DSM were only made with checklists. The diagnoses of (hypo-) manic episodes in the patient history were not systematically verifiable by indirect anamnesis., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: To investigate the long-term effects of supraphysiological, TSH suppressive doses of levothyroxine (TSDL) on bone mineral density (BMD) in patients with affective disorders during an average treatment duration of 69 months., Methods: In 22 patients, BMD of the spine (lumbar vertebrae L1-4) and femur (femoral neck) was measured by dual energy X-ray absorptiometry (DXA). Forty (40) measurements from the prior study and 48 new follow-up measurements were included. BMD was expressed as Z-scores as a population standard reference. We used a linear mixed model to investigate the duration of TSDL as an explanatory factor for change in BMD compared to an age and gender matched reference population., Results: We found no significant differences in bone loss between the study and the reference population. The estimated non-significant decrease in Z-score compared to the reference population found was: a) lumbar spine (L1-4): -0.00069/month (p=0.9759) b) neck region of femur: -0.01405/month (p=0.4436). We did not find the factors age, thyroxine-dose or postmenopausal state as predictors for a decline in BMD., Limitations: Small sample size, no bone density assessment prior to treatment with TSDL, no patient control group with mood disorders who did not receive TSDL, variable bone density follow-up intervals., Conclusion: This study did not demonstrate evidence that long-term treatment of affectively ill patients with TSDL accelerates loss of BMD compared to an age- and gender-matched reference population., (Copyright © 2011 Elsevier B.V. All rights reserved.)

With the widespread recognition of the value of active patient participation in their care, ChronoRecord software was developed to automate daily self-reporting by patients with bipolar disorder. A prior study demonstrated concurrent validity between self-ratings on ChronoRecord and clinician ratings on the Hamilton Depression Rating Scale (HAMD), but validity with the Young Mania Rating Scale (YMRS) could not be shown due to a lack of data when the outpatients were manic (Bauer et al., Bipolar Disorders 6, 67-74, 2004). This study expanded upon the prior validation study to include inpatients with mania. Self-reported mood ratings on ChronoRecord and clinician ratings on the YMRS were obtained on the same day from 27 inpatients (57 ratings); these data were also combined with the ratings from the 80 outpatients (total 107 patients, 340 ratings). Using Pearson correlation, the self-reported ratings on ChronoRecord were significantly correlated with the YMRS. The accuracy of ChronoRecord to discriminate hypomania and mania was high, as described by the area under the receiver operating characteristic curve. Post-hoc analysis of the level of agreement between ChronoRecord and YMRS ratings was excellent or good in all cases using the kappa statistic. These data demonstrate concurrent validity between ChronoRecord and YMRS.

Background: To determine thyroid gland volume and the prevalence of goiter in patients receiving long-term lithium treatment for affective disorders., Methods: In this cross-sectional study, we performed ultrasonographic examinations in 96 patients on long-term lithium treatment, including those with bipolar, major depressive, and schizoaffective disease. Patients with documented continuous and adequate serum lithium levels for more than or equal to 6 months were recruited consecutively from the Berlin Lithium Clinic. Ultrasonographic examinations were also performed in 96 gender- and age-matched control subjects. Patients and controls were 18 years of age or older and were residents of Berlin, Germany and surrounding areas., Results: Total thyroid volume was significantly greater in the lithium-treated group than among controls (23.7 ml vs. 13.6 ml). Ultrasonography detected that significantly more lithium-treated subjects had goiter than did control subjects (N=53 vs. N=19). Clinical inspection and palpation only detected goiter in 24 of the lithium-treated patients and in 12 control subjects. In a patient subgroup taking levothyroxine, the prevalence of goiter was still 37%. Patients who were not taking levothyroxine had significantly higher TSH basal levels than normal controls (2.1 mU/L vs. 1.3 mU/L)., Limitations: Cross-sectional study; no control for other factors related to thyroid enlargement and goiter such as dietary issues, smoking, or iodine intake; affectively ill subjects were treated with additional psychotropic medications., Conclusions: Thyroid enlargement was found in a significant number of lithium-treated patients. Ultrasonography proved superior to palpatory inspection in detecting goiter. Regular use of ultrasonography for early detection of thyroid enlargement in patients on long-term lithium treatment is therefore recommended.

Background: This prospective study was designed to determine whether patients with prophylaxis-resistant affective disorders, receiving adjunctive maintenance therapy with supraphysiological doses of levothyroxine (L-T4), show evidence of accelerated bone loss compared to the reference population database., Methods: In 21 patients, bone mineral density (BMD) of the spine (lumbar vertebrae L1-L4) and femur (femoral neck, trochanter, and Ward's triangle) was measured by dual energy X-ray absorptiometry (DXA). BMD measurement was performed first after patients had been on thyroid-stimulating hormone (TSH)-suppressive therapy with L-T4 (mean dose=411 mcg/d) for an average of 16.4 months and again after 33.6 months of L-T4 (mean dose=416 mcg/d) therapy., Results: There was no statistically significant difference between the actual percentage decline in bone mineral density and the expected percentage decline in any of the measured bone regions. In a stepwise linear regression analysis, age was identified as a predictor of percentage change in BMD. After controlling for age, the only other variable that showed a consistent trend was the dose of L-T4, with higher doses being positively correlated with the percentage decline of BMD., Limitations: Relatively small sample size, no bone density assessment prior to treatment with L-T4, no patient control group with mood disorders who did not receive L-T4 treatment, and bone density follow-up intervals were variable., Conclusions: This study did not demonstrate evidence that long-term treatment of affectively ill patients with supraphysiological doses of L-T4 significantly accelerates loss of bone mineral density compared to the age-matched reference population. However, the decline of BMD in one individual patient underscores that caution is indicated and that regular assessment of BMD during longer-term supraphysiological thyroid hormone treatment is needed.

Objectives: This study was conducted (1) to assess the prophylactic efficacy of lithium and carbamazepine in the maintenance treatment of schizoaffective disorder (SAD) with long-term follow-up, (2) to find predictors of the success or failure of prophylaxis, and (3) to search for differences in outcome between schizoaffective patients diagnosed according to either ICD-10 or DSM-IV., Methods: Participating patients met the ICD-10 and/or DSM-IV criteria for schizoaffective disorder. Outcome was assessed using the Morbidity Index and time elapsed until the first recurrence during prophylaxis. Predictor variables were age at onset of illness, gender, and family history, as well as the following parameters prior to prophylaxis: time between onset of illness and start of prophylactic treatment (latency), severity of illness (hospitalization rate), number of hospital admissions and polarity of schizoaffective disorder (schizobipolar vs. schizounipolar). The time spent in the hospital per year was used to compare the course of illness before maintenance therapy to the time during maintenance therapy. Co-medication was taken into account. The clinical data during prophylaxis were ascertained prospectively., Results: Forty-nine patients met the ICD-10 criteria for schizoaffective disorder, 34 of whom also met the DSM-IV criteria. All 49 patients underwent prophylactic therapy with either lithium (n=41) or carbamazepine (n=8) for an average of 6.8 years. After initiating prophylaxis, the number of days spent in the hospital declined dramatically from an average of 71 days to 11 days per year. No independent variable proved to be a consistent predictor of the course of treatment. In regard to the subgroup of patients diagnosed according to DSM-IV, no significant differences were observed when this subgroup was compared to the whole sample., Limitations: As this is a naturalistic study it does not allow for exact quantitative measures of effectiveness., Conclusions: This study is the first of its kind to investigate the efficacy of maintenance therapy in SAD over such an extended period of time. The results of the study show that lithium and carbamazepine appear to be highly effective in treating patients with schizoaffective disorder. However, it remains unclear how many schizoaffective patients will respond to mood stabilizer treatment and whether predictors of clinical relevance exist. In our sample, differences in the ICD-10 and DSM-IV diagnostic criteria for schizoaffective disorder were not related to significant differences in clinical outcome.

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.

Background: Although supplementation with supraphysiological doses of levothyroxine (T4) has been an effective treatment for refractory affective disorders in open studies, questions remain as to the tolerability of this treatment. This is the first study to investigate subjective patient response and tolerability to long-term treatment with adjunctive T4., Methods: Of 24 patients with refractory affective disorders or schizoaffective disorder who were consecutively included into an open trial with supraphysiological T4, 16 were eligible for this study. Four measures were used to rate tolerability to T4 treatment. Subjective response was graded on a scale ranging from -33 (maximal negative response) to +33 (maximal positive response). Positive and negative effects were assessed on a structured questionnaire. Clinical tolerance was assessed with the clinician-rated Thyroid Symptom List and the self-rated Von Zerssen Complaint Lists. Outcome was assessed with the CGI for prophylactic ratings (CGI-BP)., Results: At the time of assessment, patients had been treated with supraphysiological T4 (mean dose 368 microg/d) for a mean of 54 months. The total subjective response score was +25.2. Positive subjective response and observer-rated treatment success were moderately correlated. Ratings on the Thyroid Symptom List indicated an overall favorable side effect profile. General physical and mental symptoms were only slightly higher than in the general population., Limitations: This was an open, cross-sectional study that only included responders and partial responders to T4 treatment., Conclusions: Subjective response and side-effect tolerability of long-term supraphysiological doses of T4 is favorable in patients with refractory mood and schizoaffective disorders who respond to the intervention.