Lithium Augmentation Treatment Resistant Depression

The Course Of Unipolar Depression

Unipolar depression in its classic form is an episodic disorder with a high persisting morbidity. The first episode starts commonly around 42 years of age and can last for a period of up to 12 months or more. The episode will then remit and the patient can be symptom free for a period of several years before it is followed by a further episode in a substantial proportion of patients. Many patients will have multiple episodes the length of an episode usually does not vary but the interval between the episodes decreases. After 3 or 4 episodes, patients can spend a considerable proportion of their lives with a depressive episode . . The population attributable risk for suicide in mood disorders is 26% for males and 32% for females . In clinical populations and by 18 months, 10% of individuals with unipolar depression attempt suicide when ill particularly among patients with previous attempts, female patients, those with poor social support, and those aged 40 years or less , Similar rates were observed over 5 years in primary care . The incidence of suicide attempts during major depressive episodes was 21-fold and fourfold during partial remission compared with full remission .

A retrospective study of phenomenology and treatment course of delusional depression reported a high relapse rate of unipolar DD . It was proposed that unipolar DD will require long-term maintenance pharmacologic treatment, as 40.7% of the relapses occurred during or shortly after a medication taper.

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Search Results And Quality Assessment

Embase returned 1176, MEDLINE 646, and PsycINFO 513 results. The process of guideline selection can be seen in .

Who Should Prescribe Augmentation Treatment?

The National Institute for Health and Care Excellence guidelines stated that combinations of medications initiated in primary care should be done in consultation with a psychiatrist, and referral to specialist services/an individual with specialist interest may be appropriate. The Royal Australian and New Zealand College of Psychiatrists , Clinical Practice Guidelines in the Spanish NHS , and the World Federation of Societies of Biological Psychiatry offered similar advice.

The British Association for Psychopharmacology and the Maudsley Prescribing Guidelines recommended the initiation of certain augmenters in specialist centers with careful monitoring. The BAP included stimulants, estrogen in perimenopausal women, and testosterone in men with low levels, while the MPG specified lithium, ketamine, and triiodothyronine . The Canadian Network for Mood and Anxiety Disorders stated that their guidance was intended for psychiatrists and other mental health professionals. The Institute for Clinical Systems Improvement , American Psychiatric Association , and Texas Medication Algorithm Project did not advise.

Monitoring

Discontinuation

Pharmacological Augmentation Recommendations

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Dosing And Serum Levels

A question that may arise when considering the use of lithium as augmentation for unipolar depression is that of dosing. There are no specific recommendations for the dosing of lithium as an adjunctive therapy in unipolar depression. In a study assessing the benefit of lithium added to a tricyclic antidepressant, serum concentrations ranged from 0.41.2 mEq/L however, marked improvement in symptoms was observed at lithium concentrations of 0.40.5 mEq/L. A study by Bauer et al. suggested that lithium exerts a significant effect at a dose of 600800 mg/day and recommends target concentrations of 0.60.8 mEq/L. Coppen et al reported that a lithium trough level of 0.50.7 mEq/L was the most effective blood concentration. These levels were well-tolerated with only minor side effects. Lepkifker et al reported a significant reduction in suicidal behavior with average lithium trough concentration of 0.40.8 mEq/L. Thus the current evidence suggests that the target lithium trough levels for depression should be similar to those for lithium maintenance therapy in bipolar disorder.

The ideal serum lithium level for maintenance therapy in bipolar disorder is debated, but recent reviews and experts tend to agree that a serum concentration of 0.50.8mEq/L should be targeted to maximize efficacy while minimizing side effects.,

Lithium And Suicide Prevention In Unipolar Depression

Whilst it is well established that recurrence of unipolar depression can be significantly reduced by adequate maintenance treatment, be it by antidepressants or lithium, it is strange, therefore, that the reduction in suicide rates over the years has been relatively modest . A probable explanation of this modest reduction is that only a proportion of patients with unipolar depression are diagnosed, and only a proportion of those patients are treated, mostly with antidepressants. However, in contrast to a common belief, antidepressants do not reduce the risk of suicide . If patients are adequately treated, however, preferably with lithium, one can observe a significant reduction of up to 75% in the suicide rate, as demonstrated by 18-year mortality and suicide rate in a group of 103 patients who attended a mood disorder clinic . The majority of patients had unipolar depression which was severe and recurrent illness with a few dropouts during the first year of treatment. The standard treatment was sustainedrelease lithium given once-daily. Until 1982, the plasma lithium concentration measured approximately 12 h after dosage was maintained between 0.8 and 1.2 mmol/l. In 1982, the regiment was changed to maintain patients at the plasma lithium concentration between 0.6 and 0.8 mmol/l. Additional treatments, including antidepressants and neuroleptics, were administered as required.

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Ocr And Ecar In Response To Substrates And Adp

The addition of glucose, mitochondrial substrates, and ADP stimulates both oxidative and non-oxidative substrate utilization and is a measure of the bioenergetic capacity of a tissue. A significant interaction effect of treatment on OCR response was observed across all treatment groups . Post hoc multiple comparisons found that relative to controls, the OCR response to substrates and ADP was lower in animals treated with ketamine . Similarly, a significant interaction effect of treatment on ECAR response was observed . However, multiple comparisons revealed no differences between groups .

Fig. 2: Mitochondrial OCR and ECAR responses to stimulation.

Mitochondrial OCR and ECAR responses were determined following initial exposure to substrate and ADP challenge and following exposure to biomarkers TNF Wnt3a ). OCR oxygen consumption rate, ECAR extracellular acidification rate, ACTH adrenocorticotropic hormone, BDNF brain-derived neurotrophic factor, Wnt3a WNT family member 3a, TNF tumor necrosis factor , ADP adenosine diphosphate. *p< 0.05.

Indications For Commencing Prophylaxis In Unipolar Depression

A crucial decision for the clinician is when to start lithium prophylaxis. A detailed and profound discussion of this topic was published by Angst . He analysed the course of the illness in 159 unipolar patients probably diagnosed in a traditional European manner and decided that it would be desirable to start prophylaxis if the patients were likely to suffer 2 further episodes in the subsequent 5 years. He examined numerous criteria to see which identified those patients at risk. His conclusions were surprisingly simple. He found that if the patient had had one episode or more in the previous 5 years in addition to the present one, then he was likely to have 2 further episodes in the following 5 years. He also reported that at least 40% of unipolar patients would require prophylactic treatment. Of course, more than one episode in the previous 5 years would be a strong indication for starting prophylactic therapy. He could find no good criteria for discontinuing lithium therapy which should be continued indefinitely provided that patients adherence is satisfactory and serious adverse drug effects do not occur.

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Data Collection And Analyses

Article review and data extraction

All search results were evaluated against inclusion criteria independently by pairs of review authors , with disparities addressed by consensus with additional review authors . Following inclusion, data extraction was conducted by authors as above.

Quality assessment

The methodological quality assessment was examined using the Scottish Intercollegiate Guidelines Network8 and the Cochrane Risk of Bias Reference Higgins and Green9 tools. Studies were assessed by two reviewers for nine domains: sequence generation, allocation concealment, blinding of outcome assessors, use of intention-to-treat analysis, comparability of randomised groups at baseline, inter-site differences in findings, the potential for selective outcome reporting and presence of for-profit bias . Using individual criterion ratings, each study was given an overall RoB rating of low, moderate or high .

Measures of treatment effect

Continuous data describing treatment effectiveness were extracted and presented as a standardised mean difference . Using a random-effects model, meta-analyses computed a pooled ES with 95% confidence intervals , P-values and the I2 statistic. Statistical heterogeneity was considered important if I2 exceeded 60%Reference Higgins and Green9 and explored using subgroups. The following comparisons were planned to assess the primary outcome:

Statistical Methods For Analysing Primary And Secondary Outcomes

A full statistical analysis plan will be drawn up prior to completion of data collection. The main analysis will follow an intention to treat principle, whereby patient data are analysed by treatment group, regardless of the medication status of patients throughout the follow-up period.

Participant flow will be presented in a CONSORT diagram. For analysis of the listed primary and secondary outcomes, missing baseline data will be filled in using imputation . Models will covary for randomisation stratification factors throughout. For the self-report QIDS-SR score a linear mixed model, covarying by baseline score, will be used for the estimation of the mean treatment difference and 95% confidence interval over the course of the trial. Full information maximum likelihood methods will be used for analysis, which will account for missing data under the missing at random assumption. Error distributions will be checked using Q-Q plots. Time to discontinuation will be calculated from first prescription date to treatment discontinuation, and will be analysed using Kaplan-Meier methods and Cox regression models, providing the hazard ratio for treatment discontinuation in lithium versus quetiapine, and associated 95% CI.

For measures where missingness is above 5% and where the absence of repeated measurement gives less confidence in the adequacy of the missing data properties of maximum likelihood, we may undertake a sensitivity analysis within a multiple imputation framework .

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Lithium Augmentation Beneficial In Treatment

Lithium augmentation could be a potential treatment optionfor older patients with treatment-resistant depression, according to a studypublished in the Journal ofAffective Disorders.

Researchers of this prospective, multicenter cohort studyevaluated the efficacy of lithium augmentation in patients with unipolardepression with insufficient response to current antidepressantpharmacotherapy. This study included separate cohorts with patients aged 65years and another with patients aged < 65 years. All participants received tailoreddoses of lithium carbonate based on individual lithium serum levels andcompleted the Hamilton Depression Rating Scale questionnaire and the CharlsonComorbidity Score at baseline and again over the course of the 4-weekfollow-up.

Lithium Prophylaxis In Unipolar Depression

The first systematic study of lithium prophylaxis in recurrent affective illness using a mirror or before and after design was reported by Baastrup and Schou . Before lithium treatment, the patients spent 3.88 months per year with an affective episode and this fell to 0.27 months per year during the period of lithium treatment. Other investigations using a similar before and after design also produced similarly encouraging reports . There followed prospective double-blind placebo-controlled studies in which patients were randomly allocated to receive either lithium or placebo for a fixed period during which time they were regularly assessed. Relapses were treated by conventional antidepressant measures, but the prophylactic measures were not changed. This enables a sensitive measure of benefit to be obtained either in terms of the time spent with an episode or as the Affective Morbidity Index . The AMI is a composite measure both of duration and severity of affective episodes , and is calculated by measuring the area under the curve made by joining all the points representing ratings of severity of affective disturbance at each assessment. Such a measure is invaluable in calculating reduction of morbidity where, as is often the case, there is not a complete abolition of morbidity.

Long-term naturalistic studies strongly supported the effectiveness of lithium prophylaxis for unipolar depression disorder in clinical practice.

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Specific Interventions Included In The Review

Lithium at daily doses of 250-1,200mg ), for a duration of 2-42 days, was added to pre-study treatment regimens of conventional antidepressants , desipramine , mianserin , imipramine or equivalent , phenelzine , maprotiline , fluvoxamine , dibenzepine , fluoxetine , lofepramine and citalopram ). All studies compared placebo addition in place of lithium.

Lithium Augmentation For Treatment

• Psychology, Medicine
• Journal of Geriatric Psychiatry and Neurology

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• The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry
• 2013

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• Psychology
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• The American journal of psychiatry
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Discussion And Expert Opinion

use of appropriate TRD definition, more homogeneous populations, as well as rating scales for the evaluation of severity of depression in order to allow pooled analyses and meta-analytical approaches of large samples of patients

more clarity in defining whether certain symptoms are part of depression or the result of comorbid psychiatric conditions

How Were Differences Between Studies Investigated

The variance of the pooled estimate was calculated . Although no statistically significant heterogeneity was found, clinically relevant heterogeneity was investigated. Cumulative meta-analyses were performed with respect to lithium dosage and duration of lithium therapy .

As a further sensitivity analysis, the pooling of the odds ratios was also performed using other methods .

Nine RCTs were included in the meta-analysis. A study by Cournoyer et al was not included in the meta-analysis because no response criteria were given. In this study, 12 patients with major depressive disorder were considered tricyclic antidepressant-resistant after 21 days of treatment with amitriptyline or trimipramine and entered a 48-hour double-blind cross-over study. Significant improvement occurred with lithium, but not with placebo.

The trials included in the meta-analysis achieved quality scores ranging from 39 to 93%.

Combining three studies that used a minimum dose of 800mg/day, or a dose sufficient to reach lithium serum levels greater than or equal to 0.5 mEq/L, and a minimum treatment duration of 2 weeks indicated that the response rate during lithium administration was greater than during placebo treatment, pooled odds ratio 3.31 . No significant heterogeneity was found . The corresponding relative risk was 2.14 , the risk difference was 27% , and the number needed to be treat was 3.7 .

Research: The authors do not state any recommendations for further research.

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Why Lithium Isnt Used For Standard Depression

Lithium isnt used in cases of standard depression because it doesnt generally have antidepressant properties as a standalone treatment. It is a mood stabilizer, and thus is heavily utilized to help keep people stable. In cases of bipolar disorder, this treatment is extremely beneficial for preventing manic mood swings.

Another reason that Lithium is generally avoided is because 75% of people who take it have side effects. Although most side effects are minor, for some individuals they are pretty extreme. Obviously you should determine whether the side effects outweigh the depression. In most cases people that are put on this medication to help their treatment-resistant depression need it.

• Mood stabilizer It isnt an antidepressant by itself it simply works to stabilize the mood. However when supplementing it, it may be beneficial to help keep someone calm.
• Side effects Many of the side effects associated with this medication can be unbearable. These include things like tremors, frequent urination, diarrhea, weight gain, memory issues, muscle weakness, and thyroid problems.

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A Review Of The Evidence Supporting The Use Of Lithium Augmentation Therapy For The Reduction Of Suicidal Behavior In Patients With Unipolar Depression: Revisiting An Overlooked Benefit Of An Older Medication

Elizabeth Jackson, Rene A. Endow-Eyer A review of the evidence supporting the use of lithium augmentation therapy for the reduction of suicidal behavior in patients with unipolar depression: Revisiting an overlooked benefit of an older medication. Mental Health Clinician 1 September 2014 4 : 221225. doi:

Major depressive disorder is a serious, recurrent condition with significant impact on a person’s quality of life and functioning, which carries a significant risk of premature death due to suicide. There is evidence that supports the effectiveness of lithium as an augmentation strategy for treatment-resistant depression, as well as for reducing suicidality in this population. This review introduces several theories regarding the proposed mechanism behind lithium’s anti-suicidal effects and summarizes a selection of the pertinent literature supporting lithium’s beneficial effects on suicidality.