Recent investigations have indicated that adequate lithium treatment lowers the suicide mortality associated with affective illness. One important question is whether the mechanism by which lithium ...prophylaxis may be effective in prolonging survival can be explained exclusively in terms of successful protection against the recurrence of depressive episodes, or whether one should consider an independent anti-suicidal factor.
We investigated a group of high-risk patients with recurrent affective disorders (n = 167) who had committed one or more suicide attempts before the start of lithium prophylaxis within a collaborative project by the International Group for the Study of Lithium Treated Patients (IGSLI). According to their recurrence-related response to long-term lithium prophylaxis, patients were classified into three groups: excellent (n = 45), moderate (n = 81) and poor responders (n = 41). Only depressive episodes resulting into hospitalisation were considered. A marked reduction in the number of suicide attempts was observed in the excellent lithium responders. However, we also found that over 80% of moderate responders and nearly 50% of poor responders did not exhibit any further suicidal behaviour during lithium treatment. Furthermore, we could demonstrate a significant reduction of suicide attempts per year as compared to a corresponding pre-lithium period in all three groups (0.10 vs. 0.33, 0.06 vs. 0.27, 0.02 vs. 0.26). There were four suicides in this high-risk group, corresponding to a suicide-related standardised mortality ratio (SMR) of 13.7. This contrasts sharply with an expected suicide SMR of approx. 100 in this population. Suicide risk was not related to the recurrence-preventing effect.
The reduction in suicide attempts, in both responders and non-responders, indicates that lithium possesses a specific anti-suicidal effect besides its mood-stabilising property.
A robust association between "suicidality" and deficits of the serotoninergic neurotransmission has been claimed in the past. However, many studies having investigated the relationship between ...suicidality and peripheral indicators of serotoninergic neurotransmission suffer from considering only one or a very small number of potentially useful serotoninergic parameters, whereas a synoptic multidimensional approach appears to be more appropriate. Furthermore, the psychiatric context within which suicidal behaviour occurs should be considered when interpreting biochemical findings of patients with suicidal ideation and suicide attempts.
In the present study 5 peripheral serotonergic markers, (platelet 5HT concentration, 5HT uptake activity, 5HT(2A) receptor binding characteristics, MAO-B activity and tryptophan concentration in plasma) were assessed simultaneously. Of the 60 acutely suicidal inpatients (ICD-10: F43.xx, n = 52; F31/32/33, n = 8), 45 were suicide attempters. Data of 28 nonsuicidal patients with major depression (F31, n = 4; F32, n = 14; F33, n = 10) and 123 healthy volunteers represented the control groups.
Mean platelet 5HT concentration was significantly lower in suicidal inpatients when compared to nonsuicidal depressed patients, but did not differ from the figure in healthy subjects. Nonsuicidal depressed patients showed significantly higher mean platelet-5HT concentration than healthy controls. Mean V(max) of 5HT uptake in washed platelets, but not in platelet-rich plasma, was significantly higher in suicidal patients than in healthy controls, not, however, when compared to nonsuicidal depressed patients. Mean K(D) for the platelet 5HT(2A) receptor and MAO-B activity were significantly lower in suicidal patients as compared to nonsuicidal depressed patients and healthy controls. The observed differences in peripheral serotonergic markers between groups are partially due to a significant gender effect. A lower MAO-B activity was observed only in suicidal females, while the higher V(max) of 5HT uptake in washed platelets of suicidal patients was due to suicidal males.
In view of conflicting observations made by other authors and the present findings on suicidal patients with adjustment disorder it remains doubtful whether and if so to which extent platelet studies can provide valid information on serotonergic mechanisms related to suicidal behaviour.
Treatment of depression in palliative care must take into account expected benefits and risks of antidepressants in patients with potentially limited life expectancy, poor medical condition, advanced ...age and higher risk to suffer from side effects and drug interactions. This systematic review assesses evidence of the efficacy and safety of different classes of antidepressants depending on the type and severity of the physical illness.
A systematic database search (Medline, EMBASE) for clinical studies was carried out and references of identified literature were checked. To be included in the review studies had to be performed in illnesses that were part of in the search strategy, such as multiple sclerosis, Parkinson's disease, Alzheimer's disease, HIV/AIDS, cancer, COPD and heart failure. Considered were controlled studies comparing the efficacy of antidepressants to placebo, other classes of antidepressants, benzodiazepines, psychostimulants or psychotherapy. In a first step only studies with patients meeting established diagnostic criteria of depression and where depression was a primary endpoint were included. In a second step, additional studies were included that did not meet both of the latter criteria but were performed in patients at the end of life.
A total of 40 trials (mostly using SSRI or NSMRI) were included, 16 studies were performed in neurological, 24 in general medical conditions and 9 studies were performed in patients at the end of life or in advanced disease stages. Due to heterogeneous study designs no conclusions can be drawn if efficacy or tolerability is dependent on disease severity. In most cases, studies might have been too small to detect limited treatment effects. As a lack of efficacy was predominantly shown in larger trials, publication bias might have been present. In most of the reviewed general medical conditions study results were heterogeneous. In contrast to the popularity of the treatment approach, results suggest that SSRIs are not effective in Alzheimer's disease. In Parkinson's disease, negative studies are too small to prove lack of efficacy of SSRIs as present in the majority of trials.
This review of the evidence allows only limited conclusions concerning the use of antidepressants in physical illness disorders at the end of life. The reviewed evidence does not allow direct conclusions to be drawn concerning the use of antidepressants in different disease severities and its benefits compared to other treatment options (psychotherapy, benzodiazepines etc.). The English full text version of this article will be available in SpringerLink as of November 2012 (under "Supplemental").
Suicidality represents a frequent phenomenon in affective and psychotic disorders but the treatment of acute and chronic suicidality is still a controversial issue. Especially the efficacy of ...antidepressant and neuroleptic drugs for prevention of suicide continues to be debated. There is a lack of evidence due to limitations of methodological studies and ethical concerns are a major issue. Considering methodological problems in the conducted studies the often insufficiently valued differentiation between suicidal thoughts and actual suicidal behavior has to be emphasized. With the exception of lithium and clozapine suicide-preventing effects of antidepressants and neuroleptics could not yet be demonstrated. Regarding new antidepressant drugs, such as selective serotonin reuptake inhibitors (SSRI) and serotonin-norepinephrine reuptake inhibitors (SNRI) even the possible new onset of suicidal thoughts and ideations as an adverse effect needs to be stressed. Considering the frequent occurrence of suicidality the currently available evidence is undoubtedly insufficient. The improvement of study concepts and especially a more differentiated consideration of the vague term "suicidality" seems to be essential. An underrepresentation of the evidence-based therapeutic options with lithium and clozapine in the treatment of suicidal patients needs to be avoided.
Lithium and with restrictions, carbamazepine, valproic acid, lamotrigine, olanzapine, aripiprazole and quetiapine, are approved in Germany for maintenance treatment of bipolar disorder. Lithium is ...the only drug that (I) proved to be effective for the prevention of depressive as well as manic episodes in state-of-the-art studies without an enriched design and that (II) is approved for the maintenance treatment of bipolar disorders without restrictions. It (III) is also the only drug which is recommended for maintenance treatment by the current German S3 guidelines on bipolar disorders with the highest degree of recommendation (A) and (IV) is the only drug with a well proven suicide preventive effect. Hence, lithium is the mood stabilizer of first choice. No patient should be deprived of lithium without a specific reason. Side effects and risks are manageable if both the physician and the patient are well informed. Detailed and practical information on a safe use of lithium can be found in the S3 guidelines on bipolar disorders. For patients who do not respond sufficiently to lithium, have contraindications or non-tolerable side effects, other mood stabilizers should be used. Restrictions in their respective approval as well as specific side effects and risks have to be taken into account. Because maintenance treatment is a long-term treatment, particular concern should be paid to drugs with the potential risk of a metabolic syndrome, particularly atypical antipsychotics.
Background: Abnormal changes in platelets used as peripheral markers of central serotonergic functions are said to be associated with suicidality and depression, but this association has not been ...supported by consistent findings.
Aim: This review based on selected, often quoted publications in this area focuses firstly, on obviously contradictory findings and, secondly, on potential methodological flaws explaining these discrepancies.
Results: The platelet 5-HT transporter has been found to have an inconsistent association with suicidality; furthermore, the specificity of imipramine for the 5-HT transporter is most likely low, since the number of platelet impramine binding sites has not been reliably associated with platelet serotonin uptake (
V
max). Significant changes of platelet serotonin content in suicidal individuals, as described in various studies, are most likely due to washout periods that are too short to eliminate the effects of a previous drug intake, or, in violent suicide attempters, due to blood loss and dilution. Similar methodological shortcomings might account for an often-reported elevated number of platelet 5-HT
2 receptor binding sites in suicidal individuals. In many studies, the results have not been sufficiently controlled for drug effects on platelet 5-HT
2 receptors, and associations of platelet 5-HT
2 binding with selective classifications of suicidal behavior are often generalized as further evidence for an association of platelet 5-HT
2 receptors with ‘suicidality’. Finally, changes in platelet MAO-B-activity in suicidal patients have not been reproducibly found, and the impact of smoking on MAO-B activity has not been controlled in any studies.
Conclusion: Methodological flaws such as small sample sizes, insufficient matching criteria for controls, use of inadequate ligands in binding experiments, nonconsideration of comorbidity etc. and considerable methodological differences between studies limit their validity and comparability. It does not seem possible, at present, to integrate published findings and concepts into a plausible biological model of suicidality.
In a randomized, prospective, multicenter study with an observation period of 2.5 years, the differential prophylactic efficacy of lithium versus carbamazepine was compared in 171 patients fulfilling ...DSM-IV criteria for bipolar disorder. Serum drug levels were 0.6+/-0.1 mmol/L for lithium and 6.1+/-1.3 microg/mL for carbamazepine. Patients were subdivided into a classical subgroup (bipolar I patients without mood-incongruent delusions and without comorbidity, N = 67) and a nonclassical subgroup including all other patients (N = 104). Classical bipolar patients had a lower rehospitalization rate with lithium than with carbamazepine prophylaxis (p = 0.005). For the nonclassical group, a trend in favor of carbamazepine was found. In the lithium group, there was a positive association between hospitalization rate and number of nonclassical features (bipolar II/not otherwise specified, mood-incongruent delusions, comorbidity; p = 0.035). For carbamazepine, this association was negative (p = 0.033). Analyses including mixed states as an additional nonclassical feature confirmed the results. In conclusion, lithium seems to be superior to carbamazepine in treating classical bipolar cases. Patients with nonclassical features might profit more from prophylaxis with carbamazepine, which seems to have a broader spectrum of activity.
Treatment of patients with suicidal behaviour is one of the most challenging tasks for health care professionals. Due to the high mortality, morbidity and costs related to suicide, the development of ...treatment and preventive strategies for suicidal behaviour have been a focus of psychiatric research. For lithium, one of the oldest pharmacological agents used in psychiatry, anti-suicidal effects have been found since the early 90s in many international studies. Despite this unambiguous evidence and corresponding recommendations in national and international guidelines for the acute and maintenance therapy of affective disorders, the use of lithium is still underrepresented. The following article provides a review of studies investigating the anti-suicidal effects of lithium in affective disorders. Clinical implications for the treatment of affective disorders are discussed.
Drugs can cause a variety of blood dyscrasias, e. g., by interfering with hematopoiesis in the bone marrow or damaging mature blood cells by antibodies. Although numerous reports on the risks of ...adverse hematological effects associated with psychotropic drugs have led to stringent monitoring requirements for some compounds, particularly neuroleptics, it is still difficult to estimate the true prevalence of such risks. Sixteen episodes of thrombocytopenia, 63 of neutropenia, 22 of agranulocytosis, 4 episodes of severe neutro- and thrombocytopenia, and 2 of pancytopenia were documented by the drug safety program in psychiatry AMSP (Arzneimittelsicherheit in der Psychiatrie) in a population of 122,562 patients between 1993 and 2000. All cases were related to the epidemiological data provided for this population and systematically analyzed as regards history of medication, co-medication, and the clinical course. Putative risk rates for the main groups of medications and a number of drugs could be estimated with this database. Most changes in the white blood cell counts, which were rated as probably or definitely drug-induced, were attributed to clozapine (0.18 % of patients exposed), carbamazepine (0.14 %) and perazine (0.09 %). In patients on newer atypical neuroleptics, we documented neutropenia assumed to be probably or definitely drug-related in five patients during treatment with olanzapine and in one case with risperidone. In all five olanzapine-related cases, the drugs were the sole cause of the adverse drug reactions. All surveyed patients who received clozapine showed no difference in age and gender distribution from those who developed hematological changes. Incidences of hematological changes for antidepressants were much lower (about 0.01 %). Although the methodological accuracy of these findings has to be critically discussed these data could be of considerable clinical relevance and should be helpful in making clinical treatment decisions.
