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Issue 103, Nov 2020
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Intravenous ketamine for postmenopausal women with treatment-resistant depression (TRD): Results from Canadian Rapid Treatment Center of Excellence

Lipsitz O et al. J Psychiatr Res.2020. Aug 8; S0022-3956(20)30913-4. doi:10.1016/j.jpsychires.2020.08.002.[Epub ahead of print].

PMID:32948309

Background

Ketamine has demonstrated rapid and robust efficacy in adults with TRD, and women are disproportionately represented amongst adults with TRD. This study was designed to assess if menopausal status influenced the response to ketamine in women with TRD.

Methods

This was a post-hoc analysis. Premenopausal women were those under the age of 45 (n = 52), while postmenopausal women (n = 54) were those over the age of 51. Participants received four IV ketamine infusions over one-to-two weeks at a community-based center for adults with TRD. The primary outcome of interest was the change in depressive symptom severity as measured by the Quick Inventory of Depressive Symptomatology Self-Report 16 (QIDS-SR16) following four infusions, compared to pretreatment. The secondary outcomes were improvements in suicidal ideation (SI; i.e., QIDS-SR16 SI item), anxiety (i.e., Generalized Anxiety Disorder-7 scale), anhedonic severity (i.e., Snaith-Hamilton Pleasure Scale), and workplace and psychosocial function (i.e., Sheehan Disability Scale).

Results

Menopausal status did not influence the overall treatment response. Both premenopausal and postmenopausal participants demonstrated similar response rates (30% and 26%, respectively) and remission rates (both 13%) to four ketamine infusions. Premenopausal women experienced statistically significant improvements in social function more rapidly than postmenopausal women. Postmenopausal women experienced a reduction in SI more rapidly than premenopausal women.

Conclusions

These preliminary findings provide the impetus for future studies to investigate the moderational role of menopausal status, as defined by hormone levels, on response to IV ketamine for TRD.

Clinical Commentary

Women are 1.7 times more likely to experience a major depressive episode in their lifetime. Additionally, women are more likely to be prescribed antidepressants and have a greater likelihood of having TRD. Menopause is a vulnerable time, and 20 percent of women may experience depression during the transition. In the perimenopausal period, the gonadal hormones are in flux. There are reports that post-menopausal women have a poorer response to monoamine-antidepressants. Hence the need to look at ketamine.

The weakness of the study is using age cut-offs for menopausal status rather than biochemical assays. The study ratings did not have a blinding, and ketamine was used as an adjunct to antidepressants. No control group either.

The study simulated real-world practice and had a good sample size. This study used validated rating scales.

Estrogen receptors are protective against glutamate-induced neurotoxicity. Preclinical data suggest that estrogen enhances NMDA receptor function. This is thought to happen via the upregulation of the receptor subtypes.  Allopregnanolone, a neuroactive steroid, influences glutamatergic signaling through effects on GABA receptors.

The lack of menopausal status affecting the response to ketamine is important to note as it did not attenuate the improvement in anxiety, anhedonia, and workplace, and family function, unlike monoamine antidepressants. This is a replication of a prior study by (Freeman et. al 2019) and replicated findings are important.

The suicidal ideation (SI) finding is interesting too, a more rapid reduction in postmenopausal women (first infusion) while premenopausal women had reduction SI after the third infusion. This may be the issue related to a larger sample size of this study compared to the Freeman et. al 2019 study. The premenopausal women experienced a rapid improvement in social functioning. The transition in social roles that occurs during the menopausal transition may contribute to depression.

The important point is the finding of the lack of difference between the response to ketamine infusion in premenopausal and postmenopausal women. Previous studies have reported monoaminergic antidepressants as not being effective in postmenopausal women.  

In summary: In my opinion, these findings are interesting but not strong enough for us to make any clinical distinctions about ketamine response based on menopausal status. More prospective research is needed to validate these findings.

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Maternal use of antidepressants in early pregnancy: Risk of selected birth defects

Anderson KN et al. JAMA Psychiatry. 2020 Aug 5; e202453. doi: 10.1001/jamapsychiatry.2020.2453

PMID:32777011

Background

Antidepressants are commonly used during pregnancy, but limited information is available about individual antidepressants and specific birth defect risks. This study aimed to examine associations between individual antidepressants and specific birth defects with and without attempts to partially account for potential confounding by underlying conditions.

Methods

The population-based, multicenter case-control National Birth Defects Prevention Study (NBDPS) (October 1997-December 2011) included cases with selected birth defects identified from surveillance systems. The controls were randomly sampled infants without major birth defects. Mothers of cases and controls participated in an interview after the expected delivery date. The data were analyzed after the completion of the National Birth Defects Prevent Study's data collection. Self-reported antidepressant exposure was coded to indicate monotherapy exposure to antidepressants.

Main outcomes and measures: Statistical analyses were used to assess associations between maternal antidepressant use and birth defects. The study compared early pregnancy antidepressant-exposed women with those without antidepressant exposure and, to partially account for confounding by underlying maternal conditions, those exposed to antidepressants outside of the birth defect development critical period.

Results

This study included 30 630 case mothers of infants with birth defects and 11 478 control mothers (aged 12-53 years). Early pregnancy antidepressant use was reported by 1562 case mothers (5.1%) and 467 control mothers (4.1%), for whom elevated risk was observed for individual selective serotonin reuptake inhibitors (SSRIs) and selected congenital heart defects (CHD) (e.g., fluoxetine and anomalous pulmonary venous return). This pattern was observed for many SSRI-CHD combinations. Associations between SSRIs and non-CHD birth defects often persisted or strengthened after partially accounting for underlying conditions (e.g., citalopram and diaphragmatic hernia. Venlafaxine had elevated associations with multiple defects that persisted after partially accounting for the underlying conditions.

Conclusions

This study found associations between maternal antidepressant use and specific birth defects. Venlafaxine was associated with the highest number of defects, which needs further confirmation given the limited literature on venlafaxine use during pregnancy and risk for birth defects. The results suggest confounding by underlying conditions should be considered when assessing risk. Fully informed treatment decision-making requires balancing the risks and benefits of proposed interventions against those of untreated depression or anxiety.

Clinical Commentary

The NBDPS is a large US population (included 10 US states) based multi-site case-control study that assessed risk factors for major structural defects. The strengths include being one of the largest studies worldwide to look investigate structural birth defects with systemic case verification. This study investigated several classes of antidepressants, as well as accounted for confounding by underlying conditions. In this analysis, the researchers did not go by classes of antidepressants but took into account the commonly used ones such as individual SSRIs, venlafaxine, and bupropion and women exposed only outside of early pregnancy. There may be recall bias due to retrospective data collection.

Mothers who used fluoxetine and paroxetine in early pregnancy had the highest proportion of birth defects amongst SSRIs studied followed by citalopram and sertraline. There was no significant elevated risk with birth defects for escitalopram.

Venlafaxine had the highest proportion of elevated birth defect risk while escitalopram had the least risk.

Many SSRIs and birth defect associations particularly heart defect associations attenuated after partially accounting for the underlying condition when analysis compared mothers with early pregnancy exposure to those with exposure outside of early pregnancy. Most venlafaxine associations remained.

Summary:

In my clinical opinion, this study is a guide. I would not use venlafaxine if possible and prefer to use escitalopram or other SSRIs in pregnancy. However, the real-world issues are not so simple as patients may be well-controlled on the antidepressant they are taking and changing risks a recurrence of the depressive/ anxiety disorder which may have far worse consequences. It is important to have a discussion with the mother and father of the child (shared decision making) and then take action with good documentation. I always provide the website www.womensmentalhealth.org as part of the process. Despite the discussion, some patients may choose to be off antidepressants for the entire pregnancy. In such cases, I emphasize psychotherapy. Others might want to be off the antidepressants during the first trimester (critical period). In such cases, again, psychotherapy would be important and I would restart medications in the fourth month after obtaining consent. There is no one way to do this process but having the discussion is key. Many other scenarios can arise.

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Anhedonia a transdiagnostic symptom in major depression and bipolar disorder: Effects of ketamine.

Rodrigues NB et al. J Affect Disord. 2020 Nov 1; 276:570-575. Doi: 10.1016/j.jad.2020.07.083. {Epub2020 Jul 20].

PMID:32871688

Background

Anhedonia is a trans-diagnostic symptom that mediates patient outcomes and suicidality. This study investigated the role of ketamine in targeting anhedonia in adults with treatment-resistant depression (TRD).

Methods

This retrospective study included 203 patients receiving four infusions of intravenous (IV) ketamine at a community-based clinic in Toronto Canada. The primary outcome measure was the change in anhedonia severity, as measured by the Snaith-Hamilton Pleasure Scale (SHAPS). Secondary measures sought to determine if improvement on the SHAPS mediated the effect of repeated IV ketamine infusions on symptoms of depression and suicidal ideations, as measured by the Quick Inventory for Depression Symptomatology-Self Report 16-Item (QIDS-SR16) and anxiety, as measured using the Generalized Anxiety Disorder-7 (GAD-7).

Results

After adjusting for age, sex, primary diagnosis, concomitant medication, body mass index, and baseline depression severity, there was a statistically significant reduction in symptoms of anhedonia with IV ketamine treatment. Improvements in depressive symptoms, suicidal ideation, and anxiety symptoms with repeated-dose IV ketamine were significantly partially mediated by a reduction in anhedonic severity. Moreover, the combination of the number of infusions received and change in anhedonic severity accounted for 26% of the variance in depressive score improvements.

Conclusions

Ketamine was effective in improving measures of anhedonia in this large, well-characterized community-based sample of adults with TRD. Improvements in anhedonia also partially mediated the significant improvement in depressive symptoms, suicidality, and anxiety.

Clinical Commentary

This is a novel study targeting anhedonia specifically with ketamine infusions. Anhedonia is an extremely debilitating symptom (present in 92% of patients at baseline) in patients with mood disorders and results in significant morbidity. A week following the fourth infusion, 29% of the patients noted no clinically significant anhedonia. The authors further suggest the indirect anti-depressive action of ketamine on the reward system. The strengths include a good sample size of community-based patients, the use of symptom rating scales, and specifically targeting anhedonia. Limitations include a lack of a control group and open-label design. The hypothesis was also not predefined.

The results suggest that in addition to anhedonia there is an improvement in depression and suicidal symptoms with intravenous ketamine infusions. The effects on depression were direct as well as indirect through improvement in anhedonia.

There was an overall increase in glucose metabolism at the dorsal anterior cingulate cortex and putamen. These regions have been associated with anticipatory reward processing and suggest overlapping anhedonia targets between bipolar disorder and major depressive disorder patients.

The pharmacology research suggests that that ketamine may indirectly increase cerebral dopamine in addition to modulation of the glutamatergic system.

Summary:

In my clinical opinion, severely ill patients with major depression and bipolar depression can benefit from intravenous ketamine infusion which has been shown to have effects on anhedonia, a symptom causing severe morbidity in mood disorders. The affordability is limited by cost as it is not covered by insurance as it is not FDA approved. Based on careful case selection, IV ketamine could jump ahead of ECT (electroconvulsive therapy) in the depression treatment algorithm. ECT is limited by the need for anesthesia and the side-effect of cognitive impairment.  

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Pharmacogenomic test guided treatment for major depressive disorder (MDD) versus treatment as usual: Randomized controlled (RCT) with blinded raters

Perlis RH. et al.  Depression Anxiety. 2020 Sep;37(9):834-841. doi:10.1002/da.23029. [Epub 2020 May 7th]

PMID 32383277

Background

It has been proposed that measuring genes that influence the metabolism of drugs can influence antidepressant outcomes. This study investigated this issue using a blinded RCT sponsored by Genomind.

Methods

A multicenter randomized double-blind, controlled trial of pharmacogenomic testing among outpatients with nonpsychotic major depressive disorder (MDD). Study participants (n = 304) were randomized 1:1 to assay-guided treatment (AGT; N = 151) or treatment-as-usual (TAU; N = 153). Participants and raters were blinded to study arm; unblinded clinicians received results of a pharmacogenomic test and adjusted treatment guided by the test report. The primary outcome was the change over 8 weeks in Hamilton Depression Rating Scale (SIGH-D-17).

Results

For the primary outcome measure, change in SIGH-D-17, no significant difference was detected between the two treatment groups at Week 8. Rates of study completion also did not differ between the arms. Exploratory analyses suggested significantly fewer individuals experienced worsening of depressive symptoms following AGT, and that treatment concordant with assay results was associated with the greater likelihood of remission.

Conclusions

Pharmacogenomic testing guided treatment did not result in any statistically different response compared to treatment as usual.

Clinical Commentary

This study revealed no advantage of genomic testing for the treatment of depression using an RCT in which the raters and patients were blinded. The strengths included the design and the use of rating scales. It was essentially a negative study. The sponsor subsequently did exploratory post hoc analyses following a negative result suggesting that assay guided treatment was linked with a greater likelihood of remission. This we usually consider a limitation as it appears like a fishing expedition.

Currently, there is a significant amount of marketing by the companies doing these tests to psychiatric clinicians suggesting that one may tailor the treatment based on the genomic test. It is also marketed as "covered" meaning the tests are paid for by insurance and should be clinically used before the antidepressant prescription.

The above issues were even noted by the FDA which issued guidance based on the reality on this issue. I would like to laud the sponsor of this study Genomind for publishing this negative study.

Contact FDA at: 1-888-INFO FDA (1-888-463-6332) or (301) 796-3400. You can also email   [email protected] Additional information is available at the DDI (Division of Drug Information) Web page.

Summary:

In my clinical opinion, I do not suggest that we routinely do these expensive tests. This negative study only proves that. The science is simply not there yet. In some rare instances when patients have "sensitivity" to many medications, this testing may be tried.

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Depression in untreated obstructive sleep apnea: an examination of the predictors and a meta-analysis of prevalence rates

Jackson ML et al. Sleep Med. 2019 Oct; 62:22-28. doi: 10.1016/j.sleep.2019.03.011.  [Epub2019 Mar 27]

PMID 31525678.

Background

Patients with obstructive sleep apnea (OSA) experience daytime sleepiness, cognitive impairment, and depressive symptoms. This study aimed to examine the prevalence of clinical depression and antidepressant use in untreated OSA patients.

Methods

This study included 109 consecutive patients with diagnosed OSA (mean age 52.6 years; 43.1% female) who presented to the sleep laboratory completed a structured clinical interview for depression (SCID-IV), the Hospital Anxiety and Depression Scale, the Pittsburgh Sleep Quality Index (PSQI), the Functional Outcomes of Sleep Questionnaire (FOSQ), the Assessment of Quality of Life Questionnaire (AQoL), and the Epworth Sleepiness Scale (EES). An exploratory meta-analysis was also conducted to quantify the risk of clinical depression in untreated OSA.

Results

Twenty-five (22.7%) participants had depression based on the SCID-IV, and 24.8% were using antidepressants. Those with depression had significantly poorer sleep quality and impaired quality of life. The quality of life impairment was most strongly associated with depression. Results from the meta-analysis revealed a pooled prevalence of 23% of depression in OSA patients across seven studies.

Conclusions

Clinical depression and antidepressant use are common in patients with OSA and is associated with a reduced quality of life and poorer subjective sleep. Depression was not associated with daytime sleepiness. Whether CPAP treatment can alleviate the burden of depression needs to be determined in future studies.

Clinical Commentary

This study has important findings suggesting that depression and antidepressant use is common in sleep apnea patients. Depression is prevalent in a quarter of sleep apnea patients. The relationship is bidirectional. The strengths of this study include the use of structured instruments for assessment of depression and rating scales for sleep quality, quality of life, and other measures.

The presence of depression may exacerbate sleep apnea through weight gain, lack of exercise, and being sedentary. Also, the use of alcohol may add to the sleep apnea issue.

There are common neurobiological underpinnings involving the serotonergic system in both ailments.

Below are screening questions for sleep apnea

STOP: S-loud snoring; T-tired, fatigued, or sleepy during the day; O- anyone observed you stop breathing; P-are you being treated for high blood pressure

BANG: B- MI greater than 35 kg/m2; A-age greater than 50 years; N-neck size greater than 40 cm?  G-Is your gender male? (This additional set of questions increases the yield of diagnosis even further).

In Summary

In my clinical opinion, we in psychiatry should be thinking more about sleep apnea in our patients, as we are often prescribing sleep medications and patients often do not have an adequate response. In addition, tiredness is a sleep apnea symptom that overlaps with depression. We should be sending them for a sleep study to a neurologist or other sleep medicine specialists. This study has instigated me to ask screening questions for OSA in patients while taking a history. Please see link below to locate sleep centers.

http://www.sleepcenters.org

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Sanjay Gupta, MD
Clinical Professor of Psychiatry, SUNY Buffalo

GME Research Review is a monthly newsletter edited by Sanjay Gupta, MD, Clinical Professor of Psychiatry, SUNY Buffalo. Dr. Gupta selects, summarizes, and provides a clinical commentary on the latest published research in psychiatry. 

We are always carefully evaluating which research papers to discuss in GME Research Review. Have come across a research paper published in the last 6 months that you thought is clinically relevant? Do you want me to analyze it for you and for the benefit of others? Please email Dr. Gupta the citation at [email protected]

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