Sundaresh, Vishnu

Thyroid hormone (TH) augmentation, although commonly used for major depression, is sparingly used for bipolar disorder (BD) after the failure of mood-stabilizing agents. While the exact mechanisms of thyroid hormone action in BD remains unclear, central thyroid hormone deficit has been postulated as a mechanism for rapid cycling. This systematic review—conducted in accordance with the PRISMA guidelines—of eight studies synthesizes the evidence for TH augmentation in BD. A systematic search of the Ovid MEDLINE, Embase, PsycINFO, and Cochrane databases was conducted for randomized controlled trials (RCT), open-label trials, and observational studies of levothyroxine (LT4) and triiodothyronine (T3) for BD. Open-label studies of high dose LT4 augmentation for bipolar depression and rapid cycling showed improvement in depression outcomes and reduction in recurrence, respectively. However, an RCT of high-dose LT4 did not show benefit in contrast to placebo. An RCT comparing LT4, T3, and placebo showed benefit only in rapid-cycling bipolar women. A meta-analysis could not be completed due to significant differences in study designs, interventions, and outcomes. Our systematic review shows mixed evidence and a lack of high-quality studies. The initial promise of supratherapeutic LT4 augmentation from open-label trials has not been consistently replicated in RCTs. Limited data are available for T3. The studies did not report significant thyrotoxicosis, and TH augmentation were well tolerated. Therefore, TH augmentation, especially with supratherapeutic doses, should be reserved for highly treatment-resistant bipolar depression and rapid-cycling BD.

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Abstract Introduction: Hypothyroidism is implicated in the pathophysiology and clinical course of mood disorders. This study aimed to investigate the association between TSH and severe depression. Methods: The historical cohort included all consecutive adult patients (≥ 18 years) who had a TSH and PHQ-9 questionnaire data within 6 months of index visit, between October 2016 and July 2019, at the University of Utah Health. Data on demographics, hypothyroidism, TSH, PHQ-9, thyroid hormone replacement (THR), and antidepressant medications were extracted electronically. T-test and chi-square were used to compare continuous and categorical variables respectively. Logistic regression and one-way ANOVA were used to evaluate the association between TSH and depression severity. A sub-group analysis was performed among mood disorder patients without a diagnosis of overt hypothyroidism, comparing euthyroid patients (TSH 0.3-4) and patients with sub-clinical hypothyroidism based on TSH 4-10. Results: The cohort included 26,722 patients, mean age 46.3 years, 79.5% Caucasian, 68% females, and mean BMI 30. Mean PHQ-9 score was 8.2, 10% patients had severe depression (PHQ-9 ≥20), and 51% were on antidepressants and 26% on mood stabilizers. Mean TSH was 2.85, 19% patients had a diagnosis of hypothyroidism, and 20% patients were on THR. Patients with severe depression were more likely to have a higher mean TSH (p=0.06), be on antidepressants (p= <0.0001), and have a higher BMI (p=0.0003). There was a positive correlation between TSH and PHQ-9 score (p= 0.04). TSH was associated with severe depression, odds ratio 1.006 (1.003-1.009), after adjusting for potential co-variates. Hypothyroid patients who were on THR had a lower mean PHQ-9 score (p= <0.0001) as compared to hypothyroid patients not on THR. Patients with TSH from 7-10 had a higher PHQ-9 score as compared to those who had a TSH from 4-7 (p= <0.003). Conclusion: Severe depression was associated with higher TSH. Subclinical hypothyroidism with TSH above 50th percentile was associated with higher PHQ-9 scores. Future RCTs should evaluate the effect of THR in (a) patients with severe depression and (b) patients with mood disorders who have subclinical hypothyroidism.

Abstract Context The extent to which some pharmacological interventions reduce or increase the risk of biochemical conversion to type 2 diabetes mellitus (T2DM) in at-risk individuals is unclear. Methods We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and Scopus through 24 August 2017 for randomized controlled trials evaluating the effect of drugs suspected to modify the risk of biochemical conversion to T2DM. Results We included 43 trials with 192,156 subjects (mean age, 60 years; 56% men; mean body mass index, 30.4 kg/m2). α-Glucosidase inhibitors, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, metformin, orlistat, phentermine/topiramate, and pioglitazone significantly reduced the risk of biochemical conversion to T2DM, whereas statins and nateglinide increased the risk. There was insufficient direct evidence regarding the effects of sulfonylureas, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, and sodium-glucose cotransporter-2 inhibitors. Most trials were brief and evaluated this outcome during treatment without a withdrawal or washout period. Conclusions Several drugs modify the risk of biochemical conversation to T2DM, although whether this effect is persistent and clinically relevant is unclear. Future studies need to focus on cardiovascular disease prevention, mortality, and patient-important outcomes instead of biochemical conversion to T2DM.

Context: Polycystic ovary syndrome (PCOS) is a prevalent disorder that affects women of childbearing age and may be related to obesity and insulin resistance. Objective: The purpose of this systematic review was to appraise the evidence of the impact of lifestyle modification (LSM) interventions on outcomes of women with PCOS. Data Sources: Sources included Ovid Medline, OVID Embase, OVID Cochrane Library, Web of Science, Scopus, PsycINFO, and CINAHL (up to January 2011). Study Selection: We included randomized controlled trials that enrolled woman of any age with PCOS who received LSM and compared them against women who received no intervention, minimal intervention, or metformin. Data Extraction: Two authors performed the data extraction independently. Data Synthesis: We included 9 trials enrolling 583 women with a high loss to follow-up rate, lack of blinding, and short follow-up. Compared with minimal intervention, LSM significantly reduced fasting blood glucose (weighted mean difference, −2.3 mg/dL; 95% confidence interval, −4.5 to −0.1, I2 = 72%, P = .04) and fasting blood insulin (weighted mean difference, −2.1 μU/mL, 95% confidence interval, −3.3 to −1.0, I2 = 0%, P < .001). Changes in body mass index were associated with changes in fasting blood glucose (P < .001). Metformin was not significantly better than LSM in improving blood glucose or insulin levels. We found no significant effect of LSM on pregnancy rate, and the effect on hirsutism was unclear. Conclusions: The available evidence suggests that LSM reduces fasting blood glucose and insulin levels in women with PCOS. Metformin has similar effects. Translation of these short-term effects to patient-important outcomes, beyond diabetes prevention, remains uncertain.