Laboratory Tests for Depression and Other Psychiatric Disorders

Number: 0306

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses laboratory tests for depression and other psychiatric disorders.

1. Medical Necessity

   Aetna considers the dexamethasone suppression test (DST) medically necessary when it is requested by a psychiatrist as an aid to differentiate psychotic depression from schizophrenia. Note: Studies have indicated that individuals with psychotic depression fail to suppress cortisol after the dexamethasone challenge, whereas those with schizophrenia demonstrate suppression.

2. Experimental and Investigational

   The following tests are considered experimental and investigational because the effectiveness of these approaches has not been established:

   1. Dexamethasone Suppression Test (DST) for any of the following indications:

      1. As an aid in diagnosing major depressive disorders because the test lacks sufficient specificity and sensitivity to be useful; or
      2. For selecting medications for persons with major depressive illness; or 
      3. To diagnose or manage borderline personality disorder or post-traumatic stress syndrome;

   2. MindX Blood Tests, which uses gene expression profiling by RNA sequencing of genes collected from whole blood to assess, predict or manage mood disorders, stress disorders, suicidality, longevity/mortality, and pain associated with depression or substance use history:

      1. MindX - Longevity
      2. MindX - Mood disorders
      3. MindX - Pain
      4. MindX - Stress disorders
      5. MindX - Suicidality;
   3. Measurement of microRNAs for diagnosis of depression;
   4. Measurements of Neutrophil-to-Lymphocyte, Monocyte-to-Lymphocyte, and Platelet-to-Lymphocyte Ratios for diagnosis of depression.

3. Related Policies

   • CPB 0221 - Quantitative EEG (Brain Mapping)
   • CPB 0469 - Transcranial Magnetic Stimulation and Cranial Electrical Stimulation

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Dexamethasone suppression test (DST):
CPT codes not covered for indications listed in the CPB:
80420	Dexamethasone suppression panel, 48 hours. This panel must include the following: Free cortisol, urine (82530 x 2), cortisol (82533 x 2),and volume measurement for timed collection (81050 x 2)
MindX Blood Tests:
CPT codes not covered for indications listed in the CPB:
0290U	Pain management, mRNA, gene expression profiling by RNA sequencing of 36 genes, whole blood, algorithm reported as predictive risk score
0291U	Psychiatry (mood disorders), mRNA, gene expression profiling by RNA sequencing of 144 genes, whole blood, algorithm reported as predictive risk score
0292U	Psychiatry (stress disorders), mRNA, gene expression profiling by RNA sequencing of 72 genes, whole blood, algorithm reported as predictive risk score
0293U	Psychiatry (suicidal ideation), mRNA, gene expression profiling by RNA sequencing of 54 genes, whole blood, algorithm reported as predictive risk score
0294U	Longevity and mortality risk, mRNA, gene expression profiling by RNA sequencing of 18 genes, whole blood, algorithm reported as predictive risk score
0437U	Psychiatry (anxiety disorders), mRNA, gene expression profiling by RNA sequencing of 15 biomarkers, whole blood, algorithm reported as predictive risk score
Measurement of microRNAs:
CPT codes not covered for indications listed in the CPB::
Measurement of microRNAs- no specific code
Measurements of neutrophil to lymphocyte ratio, monocyte to lymphocyte ratio, and platelet to lymphocyte ratio:
CPT codes not covered for indications listed in the CPB:
Measurements of neutrophil to lymphocyte ratio, monocyte to lymphocyte ratio, and platelet to lymphocyte ratio – no specific code
Other CPT codes related to the CPB:
0289U	Neurology (Alzheimer disease), mRNA, gene expression profiling by RNA sequencing of 24 genes, whole blood, algorithm reported as predictive risk score
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
F01.50 – F99	Mental and behavioral disorders
G89.0	Central pain syndrome
G89.11 – G89.18	Acute pain
G89.21 – G89.29	Chronic pain
G89.4	Chronic pain syndrome
R52	Pain, unspecified
Z13.30 - Z13.39	Encounter for screening examination for mental health and behavioral disorders
Z13.89	Encounter for screening for other disorder [depression][longevity and mortality risk]

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Background

Dexamethasone Suppression Test

Guidelines from the Agency for Healthcare Policy and Research (1993) stated that the descriptive diagnosis of depression is based entirely on the patient's signs, symptoms, and personal history.  Only a limited number of basic laboratory tests to detect potential general medical causes for the depression unless specific risk factors, specific positive symptoms on the medical review of systems, unusual symptom profiles, or an atypical course of illness is present, in which case selected additional tests are called for to answer specific diagnostic questions.  The guideline stated that the dexamethasone suppression test is not recommended for routine use as a screening tool in primary care outpatients because it lacks sufficient specificity and has lower sensitivity in the less severely ill.  However, the dexamethasone suppression test can play a role in differentiating psychotic depression from schizophrenia (AHCPR, 1993).

The consensus paper of the World Federation of Societies of Biological Psychiatry (Mossner et al, 2007) stated that biological markers for depression are of great interest to aid in elucidating the causes of major depression.  The authors evaluated currently available biological markers to examine their validity for aiding in the diagnosis of major depression.  They specifically focused on neurotrophic factors, serotonergic markers, biochemical markers, immunological markers, neuroimaging, neurophysiological findings, as well as neuropsychological markers.  They delineated the most robust biological markers of major depression.  These include decreased platelet imipramine binding, decreased 5-HT1A receptor expression, increase of soluble interleukin-2 receptor and interleukin-6 in serum, decreased brain-derived neurotrophic factor in serum, hypocholesterolemia, low blood folate levels, and impaired suppression of the dexamethasone suppression test.  However, none of these markers is sufficiently specific to contribute to the diagnosis of major depression.

The dexamethasone suppession test was first developed for diagnosing Cushing Syndrome.  The Endocrine Society's clinical practice guideline on the diagnosis of Cushing's syndrome (Nieman et al, 2008) recommended initial use of one test with high diagnostic accuracy (e.g., urine cortisol, late night salivary cortisol, 1 mg over-night or 2 mg 48-hour dexamethasone suppression test [DST]).  The guideline recommended that patients with an abnormal result see an endocrinologist and undergo a second test, either one of the above or, in some cases, a serum mid-night cortisol or dexamethasone-corticotrophin releasing hormone (DEX-CRH) test.  Patients with concordant abnormal results should undergo testing for the cause of Cushing's syndrome.  Patients with concordant normal results should not undergo further evaluation.  The guideline recommended additional testing in patients with discordant results, normal responses suspected of cyclic hyper-cortisolism, or initially normal responses who accumulate additional features over time.

Reimondo et al (2008) evaluated if the combined low-dose DEX-CRH (LDDST-CRH) test may have a place in the diagnostic strategy of Cushing's syndrome.  All subjects underwent the same screening protocol including 1 mg DST, 24-hour urinary free cortisol (UFC), and mid-night serum cortisol, followed by the LDDST-CRH test whose results were not used to establish a definitive diagnosis.  Plasma dexamethasone concentration was measured 2 hour after the last dose of dexamethasone.  Patients qualified for Cushing's syndrome when at least 2 screening tests were positive.  A total of 16 patients had Cushing's syndrome; while Cushing's syndrome was excluded in the remaining 15 subjects.  Even if not statistically significant, the sensitivity and the negative predictive value of the cortisol 15 minutes after CRH were better than the other tests; on the other hand, the test specificity was lower.  All patients classified as indeterminate were correctly diagnosed by the LDDST-CRH test.  Nevertheless, the repeated assessment of the screening tests and the active follow-up gave the same correct results.  In all of the patients mis-classified by the LDDST-CRH test, the plasma dexamethasone concentrations were in the normal range.  The authors concluded that based on the present findings, they suggested that the LDDST-CRH test may still find a place as a rule-out procedure in patients who present with indeterminate results after screening and may be unavailable to repeat testing during follow-up.

Neuroendocrine studies have reported significant changes in hypothalamic-pituitary-adrenal (HPA)-axis regulation in patients with post-traumatic stress disorder (PTSD).  Based on baseline assessments and the response to dexamethasone, a hypothalamic over-drive with enhanced glucocorticoid feedback inhibition has been suggested.  Moreover, the DEX-CRH test has shown to be a more sensitive test to assess HPA-axis dysregulation in major depression and therefore may provide a useful test tool to probe HPA-axis regulation in PTSD.  de Kloet and colleagues (2008) evaluated the effect of PTSD on HPA-axis regulation.  These researchers compared the response to a DEX-CRH test between male veterans with PTSD (n = 26) and male veterans who had been exposed to similar traumatic events during their deployment but without PTSD (n = 23).  Patients and controls were matched on age, year, and region of deployment.  Additionally, these investigators compared the response of PTSD patients with (n = 13) and without co-morbid major depressive disorder (MDD) (n = 13).  No significant differences were observed in adenocorticotropic hormone (ACTH) and cortisol response to the DEX-CRH test between patients and controls.  Patients with PTSD and with co-morbid MDD showed a significantly lower ACTH response compared to patients without co-morbid MDD.  The response to the DEX-CRH test did not correlate with PTSD or depressive symptoms.  The authors concluded that the DEX-CRH test did not reveal HPA-axis abnormalities in PTSD patients as compared to trauma controls.  Furthermore, PTSD patients with a co-morbid MDD showed an attenuated ACTH response compared to PTSD patients without co-morbid MDD, suggesting the presence of subgroups with different HPA-axis regulation within the PTSD group.

Muhtz et al (2008) noted that reports about alterations of HPA function in patients with chronic PTSD are inconsistent and controversial.  More refined laboratory tests and subgrouping of PTSD patients might help to decrease variance of findings.  In a pilot study, these investigators reported the preliminary results of a combined DEX-CRH test in patients with chronic PTSD.  A total of 14 subjects with chronic PTSD and 14 healthy controls were examined between 13:00 and 17:00 using a modified combined DEX-CRH test (0.5 mg dexamethasone at 23:00, 100 microg CRH at 15:00).  Plasma ACTH, cortisol and blood pressure were measured every 15 minutes from 14:45 until 17:00.  No significant differences between patients and controls were found in the analyses of ACTH and cortisol levels, but systolic and diastolic blood pressure were significantly elevated in PTSD.  Severity of depressive symptoms had no influence.  However, explorative analyses showed that patients with a history of childhood traumatization had significantly higher post-dexamethasone-ACTH levels and a significantly lower diastolic blood pressure in comparison to patients without early trauma.  The authors concluded that in this first pilot study in a typical clinical sample of patients with chronic PTSD, they found effects of severe adverse events in childhood on HPA-axis regulation.  Maybe, childhood traumatization could influence HPA-axis findings in PTSD.  They stated that further research is needed, especially dose-response studies with different doses of dexamethasone in DEX-CRH tests in patients with PTSD.

Castinetti and colleagues (2009) stated that recurrence of Cushing's disease (CD) after trans-sphenoidal surgery (TSS) occurs in about 25 % of cases.  Twenty percent of patients with immediate post-surgical corticotroph deficiency will present late recurrence.  In a prospective bi-center study, these investigators evaluated a coupled dexamethasone-desmopressin test (CDDT) as a predictor of recurrence of CD.  They studied 38 patients treated by TSS for CD with a mean follow-up of 60 months; and evaluated 24-h urinary free cortisol, ACTH, and cortisol plasmatic levels and performed low-dose DST and CDDT 3 to 6 months after surgery and then yearly.  After CDDT, ACTH ratio (ACTHr) was defined as (PeakACTH - BaseACTH)/BaseACTH.  Cortisol ratio (Cortisolr) was defined as (PeakCortisol - BaseCortisol)/BaseCortisol.  Basal values were observed after low-dose DST.  Receiver operator characteristics curve defined ACTHr and Cortisolr giving the best sensitivity and specificity associated with recurrence.  A total of 10 patients presented recurrence; ACTHr and Cortisolr were superior or equal to 0.5 in all patients with recurrence and in 3 of 28 patients in remission (100 % sensitivity, 89 % specificity).  The test became positive in 8 of 10 patients with recurrence 6 to 60 months before classical markers of hyper-cortisolism.  Six patients with immediate post-surgical corticotroph deficiency presented recurrence.  All of them presented CDDT positivity during the 3 years after surgery, and recurrence 6 to 60 months after CDDT positivity.  The authors concluded that CDDT is an early predictor of recurrence of CD and could be of particular interest in the first 3 years after surgery, by selecting patients at high risk of recurrence despite falsely reassuring classical hormonal markers.  The findings of this small study need to be validaetd by well-designed studies.

Hori et al (2013) stated that evidence showed that depression is associated with HPA axis hyper-activation, although such findings were not entirely unequivocal.  In contrast, various psychiatric conditions, including atypical depression, are associated with hypocortisolism.  Another line of research has demonstrated that personality is associated with HPA axis alteration.  It is thus hypothesized that different personality pathology in depression would be associated with distinct cortisol reactivity.  These researchers examined the relationship of temperament and character with cortisol reactivity to the combined DEX-CRH test in depressed patients.  A total of 87 outpatients with DSM-IV major depressive disorder were recruited.  Personality was assessed by the temperament and character inventory (TCI).  Hypothalamic-pituitary-adrenal axis reactivity was measured by the combined DEX- CRH test.  According to the authors’ previous studies, 2 subgroups were considered based on their cortisol responses to the DEX-CRH test:

1. incomplete-suppressors whose cortisol response was exaggerated, and
2. enhanced-suppressors whose cortisol response was blunted. 

The analysis of co-variance, controlling for age, gender and symptom severity, revealed that incomplete-suppressors scored significantly higher on cooperativeness than enhanced-suppressors (p = 0.002).  A multi-variate step-wise logistic regression analysis predicting the cortisol suppression pattern from the 7 TCI dimensions, controlling for age, gender and symptom severity, revealed that lower cooperativeness (p = 0.001) and higher reward dependence (p = 0.018) were significant predictors toward enhanced suppression.  The authors concluded that these findings suggested that (personality-related) subtypes of depression might be differentiated based on the different pattern of cortisol reactivity.  Moreover, they stated that future studies are needed to further characterize the HPA axis alteration in relation to various subtypes of depression.

An UpToDate review on "Dexamethasone suppression tests" (Lacroix, 2015) does not mention depression, personality disorder, and post-traumatic stress syndrome as indications of dexamethasone suppression test.

Urwyler and co-workers (2017) compared the 2-mg DST with the gold-standard 1-mg DST in obese patients in order to reduce the false-positive rate for Cushing's syndrome (CS).  The primary end-point was the comparison of serum cortisol levels after 1-mg versus 2-mg DST in patients with a body mass index (BMI) greater than 30 kg/m2 and at least 1 additional feature of the metabolic syndrome.  Secondary end-points were comparison of salivary cortisol and ACTH levels, respectively.  A total of 44 obese patients were included.  Median serum cortisol levels after 1-mg DST and 2-mg DST were similar [28 nmol/L (20; 36) versus 28 nmol/L (20; 38), p = 0.53].  Salivary cortisol was 8.2 nmol/L (4.7; 11.7) after the 1-mg DST versus 6.7 nmol/L (4.2; 9.5) after the 2-mg DST, p = 0.09; ACTH levels were higher after the 1-mg DST compared to the 2-mg DST [10.0 pg/ml (7.6; 10.7) versus 5.0 pg/ml (5.0; 5.1), p < 0.0001].  The false positive rate after the 1-mg DST was 14.8 % (n = 8) and was reduced to 11.1 % (n = 6) after the 2-mg DST.  All non-suppressors (n = 8) had type 2 diabetes and most of them took a medication interacting with cytochrome P450 3A4 (CYP3A4).  The authors concluded that in individuals with obesity, the 2-mg DST was not superior to the 1-mg DST in regard to serum cortisol levels.  However, in some patients, particularly with poorly controlled diabetes or medication interacting with CYP3A4 and without adequate suppression after the 1-mg DST, the 2-mg DST might prove helpful to reduce the false-positive rate for CS.

Mojtahedzadeh and associates (2018) previously reported on the lack of utility of the 1-mg overnight DEX test in mild and/or periodic CS, as most patients with the condition suppressed to 1-mg DEX.  It is possible that a lower dose of DEX as part of an overnight DEX test might be able to distinguish between mild and/or periodic CS and those without the condition.  These investigators determined the sensitivity and specificity of a 0.25-mg overnight DST, the standard 1-mg overnight DST, and the 2-day low-dose (Liddle test) DST with and without correction for DEX levels in patients evaluated for mild and/or periodic CS.  A total of 30 patients determined to have CS by biochemical testing and 14 patients determined not to have the condition had the 0.25-mg and standard 1-mg overnight DST and the 2-day low-dose DST.  The results showed that morning serum cortisol and cortisol/DEX ratios following an overnight DST were similar in patients with CS and those not having CS.  However, a morning cortisol value above 7.6 μg/dL following a dose of DEX of 0.25 mg was found in 12 patients with CS and none in those not having CS, suggesting that a high cortisol value after this low-dose of DEX could indicate that further testing for CS is needed.  The authors concluded that these findings suggested that the traditional 1-mg overnight or the 2 mg/2 day DST should no longer be used as a screening test in patients who could have mild and/or periodic CS, while the 0.25-mg dose of DEX may pick up some patients with mild CS.

Kellner and colleagues (2018) stated that while the impact of childhood trauma on basal and dynamic cortisol regulation has widely been studied, the most abundant steroid hormones dehydroepiandrosterone (DHEA) and its sulphated derivative DHEA-S have received little attention in this context.  In this study, a total of 100 in-door patients suffering from major depression or an anxiety disorder filled in the Childhood Trauma Questionnaire.  These researchers carried out a low-dose DST measuring DHEA, DHEA-S and cortisol.  Furthermore, various cardiovascular risk parameters were measured; 46 % of the patients reported a history of substantial physical or sexual childhood abuse.  However, no significant differences in plasma DHEA or DHEA-S emerged in the DST between the traumatized group and the remaining patients.  Basal plasma cortisol was significantly lower in the childhood trauma group.  No impact of childhood trauma history on cardiovascular risk factor profile was detected.  The authors concluded that current limited data regarding DHEA or DHEA-S in patients with childhood trauma are equivocal.  They stated that further study using more sophisticated assessment of trauma history and simultaneously measuring a multitude of putative biomarkers of traumatization are needed.

MindX Blood Tests

Mood Disorders

MindX Sciences offers the MindX Blood Test - Mood, mRNA, to evaluate gene expression profiling by RNA sequencing of 144 genes, using whole blood, and an algorithm reported as a predictive risk score. The test is indicated for patients with a history of depression, a poor response to antidepressants, and occasional suicidal ideation. Blood is obtained to assess the mood state, predict short- and long-term risk of worsening mood and treatment planning. During the test, RNA is isolated from blood and 144 genes associated with mood disorders are sequenced to determine biomarker gene expression levels. A proprietary algorithm is applied. A qualified laboratory professional compiles the report that is communicated to the ordering provider detailing risk and medication suggestions. The report also gives a list of medications and nutraceuticals that are potentially effective in reversing this risk. These medications and nutraceuticals are ranked in the order of percentiles (MindX Sciences, 2021).

Le-Niculescu et al (2021) describe a novel and comprehensive effort to discover and validate blood biomarkers of relevance to mood disorders, including testing them in independent cohorts to evaluate predictive ability and clinical utility. The authors note that their early pilot studies to discover blood biomarkers for mood state were promising. The authors further used a longitudinal within-subject design and whole-genome gene expression approach to discover biomarkers which track mood state in subjects who had diametric changes in mood state from low to high, from visit to visit, as measured by a visual analog scale (SMS-7) that the authors developed. Subjects are recruited primarily from the patient population at the Indianapolis VA Medical Center. Second, the authors prioritized these biomarkers using a convergent functional genomics (CFG) approach encompassing in a comprehensive fashion prior published evidence in the field. Third, they validated the biomarkers in an independent cohort of subjects with clinically severe depression (as measured by Hamilton Depression Scale, (HAMD)) and with clinically severe mania (as measured by the Young Mania Rating Scale (YMRS)). Adding the scores from the first three steps into an overall convergent functional evidence (CFE) score, the authors ended up with 26 top candidate blood gene expression biomarkers that had a CFE score as good as or better than SLC6A4, an empirical finding which the authors used as a de facto positive control and cutoff. Notably, there was among them an enrichment in genes involved in circadian mechanisms. The authors further analyzed the biological pathways and networks for the top candidate biomarkers, showing that circadian, neurotrophic, and cell differentiation functions are involved, along with serotonergic and glutamatergic signaling, supporting a view of mood as reflecting energy, activity and growth. Fourth, they tested in independent cohorts of psychiatric patients the ability of each of these 26 top candidate biomarkers to assess state (mood (SMS-7), depression (HAMD), mania (YMRS)), and to predict clinical course (future hospitalizations for depression, future hospitalizations for mania). The authors conducted their analyses across all patients, as well as personalized by gender and diagnosis, showing increased accuracy with the personalized approach, particularly in women. Again, using SLC6A4 as the cutoff, twelve top biomarkers had the strongest overall evidence for tracking and predicting depression after all four steps: NRG1, DOCK10, GLS, PRPS1, TMEM161B, GLO1, FANCF, HNRNPDL, CD47, OLFM1, SMAD7, and SLC6A4. Of them, six had the strongest overall evidence for tracking and predicting both depression and mania, hence bipolar mood disorders. There were also two biomarkers (RLP3 and SLC6A4) with the strongest overall evidence for mania. These panels of biomarkers have practical implications for distinguishing between depression and bipolar disorder. Next, they evaluated the evidence for their top biomarkers being targets of existing psychiatric drugs, which permits matching patients to medications in a targeted fashion, and the measuring of response to treatment. The authors also used the biomarker signatures to bioinformatically identify new/repurposed candidate drugs. Top drugs of interest as potential new antidepressants were pindolol, ciprofibrate, pioglitazone and adiphenine, as well as the natural compounds asiaticoside and chlorogenic acid. Finally, they provide an example of how a report to doctors would look for a patient with depression, based on the panel of top biomarkers (12 for depression and bipolar, one for mania), with an objective depression score, risk for future depression, and risk for bipolar switching, as well as personalized lists of targeted prioritized existing psychiatric medications and new potential medications. The authors conclude that overall, their studies provide objective assessments, targeted therapeutics, and monitoring of response to treatment, that enable precision medicine for mood disorders.

Longevity and Mortality Risk

MindX Sciences offers the MindX Blood Test - Longevity, mRNA, gene expression profiling by RNA sequencing of 18 genes, using whole blood, and an algorithm reported as predictive risk score. The test is indicated for middle aged or elderly patients with past depression, stress, decreased physicial energy and concentration ability. During the test, 18 biomarker genes associated with longevity are sequenced to determine their expression levels. A proprietary algorithm is applied to generate predictive risk scores. A qualified laboratory professional compiles the report that is communicated to the ordering provider detailing mortality risk and suggested medications based on the predictive scores. The test report shows the risk of death in the first year (immediate risk) and the risk of death in future years. The report also gives a list of medications and nutraceuticals that are potentially effective in reversing this risk. These medications and nutraceuticals are ranked in the order of percentiles. The test is initially administered to establish a baseline. After the treatment plan commences, the test is repeated at 6 months and thereafter yearly to see if there is an increase or decrease of death risk scores from baseline and evaluate the effectiveness of the treatment plan (MindX Sciences, 2021).

Pain

MindX Sciences offers the MindX Blood Test - Pain, mRNA, gene expression profiling by RNA sequencing of 36 genes, using whole blood, and an algorithm reported as predictive risk score. The test is indicated for patients suffering from pain,and associated depression, and substance abuse history. Blood is obtained to assess pain intensity, predict short- and long-term risk of increasing pain and treatment planning. During the test, RNA is isolated from blood and 36 genes associated with pain are sequenced to determine biomarker gene expression levels. A proprietary algorithm is applied. A qualified laboratory professional compiles the report that is communicated to the ordering provider detailing risk and medication suggestions. The test report shows the immediate and long term risk of pain. The report also gives a list of medications and nutraceuticals that are potentially effective in reversing this risk. These medications and nutraceuticals are ranked in the order of percentiles (MindX Sciences, 2021).

Stress Disorders

MindX Sciences offers the MindX Blood Test - Stress, mRNA, to evaluate gene expression profiling by RNA sequencing of 72 genes, using whole blood, and an algorithm reported as a predictive risk score. The test is indicated for patients who present with suicidal thoughts, depression, post-traumatic stress disorder (PTSD) and chronic pain. Blood is obtained to asess stress levels, predict short- and long-term risk of increasing stress and treatment planning. During the test, RNA is isolated from blood and 72 genes associated with stress disorders are sequenced to determine biomarker gene expression levels. A proprietary algorithm is applied. A qualified laboratory professional compiles the report that is communicated to the ordering provider detailing risk and medication suggestions. The report also gives a list of medications and nutraceuticals that are potentially effective in reversing this risk. These medications and nutraceuticals are ranked in the order of percentiles (MindX Sciences, 2021).

Suicidal Ideation

MindX Sciences offers the MindX Blood Test - Suicidality, mRNA, to evaluate gene expression profiling by RNA sequencing of 54 genes, using whole blood, and an algorithm reported as a predictive risk score. The test is indicated for patients with suicidal thoughts and a history of depression, post-traumatic stress disorder (PTSD) and chronic pain or patients who have attempted suicide and have been hospitalized. Blood is obtained to assess current suicidality state, predict short- and long-term risk of suicide and treatment planning. During the test, RNA is isolated from blood and 54 genes associated with suicide risk are sequenced to determine biomarker gene expression levels. A proprietary algorithm is applied. A qualified laboratory professional compiles the report that is communicated to the ordering provider detailing risk and medication suggestions. The test report shows the immediate and long term risk of suicidality. The report also gives a list of medications and nutraceuticals that are potentially effective in reversing this risk. These medications and nutraceuticals are ranked in the order of percentiles (MindX Sciences, 2021).

MicroRNAs for Diagnosis of Depression

Li et al (2023) stated that currently, depression is diagnosed on the basis of neuropsychological examinations and clinical symptoms, and there is no objective diagnostic method.  Several studies have examined the use of microRNAs as potential biomarkers diagnostic for depression.  In a systematic review and meta-analysis, these researchers examined the diagnostic value of microRNAs for depression.  PubMed, Embase, the Cochrane Library, the Web of Science, Wanfang Database, SINOMED, China Science and Technology Journal Database and China National Knowledge Infrastructure were searched up to January 11, 2022.  Stata (version 16.0) and RevMan (version 5.3) software were used for meta-analysis.  The pooled sensitivity, pooled specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) were calculated; the summary receiver operating characteristic (SROC) curve was plotted, and the area under the curve (AUC) was calculated.  Moreover, meta-regression analyses were carried out to determine the source of heterogeneity.  Deeks' funnel plot test was used to evaluate publication bias.  A total of 677 patients were enrolled, including 364 patients with depression and 313 healthy controls.  Meta-analysis results showed that the pooled sensitivity, specificity, and DOR of microRNAs for the diagnosis of depression were 0.82 (95 % confidence intervals [CI]: 0.76 to 0.87), 0.70 (95 % CI: 0.62 to 0.77), and 11 (95 % CI: 6 to 20), respectively, and the AUC of the SROC was 0.84 (95 % CI: 0.80 to 0.87).  The authors concluded that microRNAs have high sensitivity and specificity in diagnosing depression and are potential diagnostic biomarkers for depression.

Furthermore, UpToDate reviews on “Unipolar depression in adults: Assessment and diagnosis” (Lyness, 2023), “Pediatric unipolar depression: Epidemiology, clinical features, assessment, and diagnosis” (Bonin, 2023), and “Diagnosis and management of late-life unipolar depression” (Espinoza and Unutzer, 2023) do not mention measurement of microRNAs as a management option.

Neutrophil-to-Lymphocyte Ratio (NLR) / Monocyte-to-Lymphocyte Ratio (MLR) / Platelet-to -Lymphocyte Ratio (PLR) for Diagnosis of Depression

Meng et al (2022) noted that the association of neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and monocyte to lymphocyte ratio (MLR) with depression has been examined extensively while the results were conflicting.  In a cross-sectional study, these investigators examined if NLR, PLR, and MLR are associated with depression, as well as to examine the potential non-linear relationship between them.  This trial was carried out based on representative samples of U.S. adults from the National Health and Nutrition Examination Survey 2005-2006 to 2017-2018.  Major depression was defined as a 9-item Patient Health Questionnaire of 10 or more.  Multi-variable logistic regression models were used to calculate the odds ratio (OR) of depression in relation to NLR, PLR, and MLR with the 1st quartile of their values as the reference.  Restricted cubic splines (RCS) were added to the regression model to estimate the non-linear relationship between NLR, PLR, or MLR and depression.  A total of 34,324 subjects were included in the study and 3,009 of them were diagnosed with major depression.  Only PLR was significantly associated with depression following adjustment of all co-variates in the multi-variable logistic regression analysis.  RCS showed that NLR was significantly associated with depression following adjustment of all co-variates and NLR, PLR, and MLR were associated with depression in a non-linear manner.  The authors concluded that NLR and PLR were associated with depression following adjustment of potential confounders in a non-linear manner.  Moreover, these researchers stated that prospective studies are needed to further reveal the non-linear relationships.  They also noted that the cross-sectional design did not imply any causal inferences.

Su et al (2022) stated that the possible associations between depression and NLR, PLR, and MLR have been examined in many studies; however, the results were still controversial.  In a meta-analysis, these investigators used the Web OF Science, PubMed, Embase, and Cochrane Library databases to search for eligible studies.  Standardized mean difference (SMD) and 95 % CI were used to evaluate the differences in NLR, PLR, and MLR levels between depressed patients and controls.  A total of 2,580 cases and 2,664 controls, 1,393 cases and 1,370 controls, 744 cases and 765 controls were identified in the meta-analyses for NLR, PLR, and MLR, respectively.  The pooled analyses showed that depressed subjects had significantly higher levels of NLR than healthy controls (SMD = 0.33, 95 % CI: 0.15 to 0.15, p < 0.001).  Sensitivity analysis and publication bias test confirmed the result.  Subgroup analyses suggested that the association between depression and NLR could be affected by country, study design, and anti-depressant treatment.  While no significant difference of PLR (SMD = 0.13, 95 % CI: -0.04 to 0.31, p = 0.140) and MLR (SMD = 0.02, 95 % CI: -0.24 to 0.28, p = 0.892) values was found between depressed subjects and controls.  These researchers noted high heterogeneity across studies.  The authors concluded that the present meta-analysis supported the hypothesis that depression is associated with inflammation, and NLR could be used as an indicator of depression.  Moreover, these researchers stated that further large-scale studies are needed, especially those that examine PLR or MLR in depression.

Furthermore, UpToDate reviews on “Unipolar depression in adults: Assessment and diagnosis” (Lyness, 2023), “Pediatric unipolar depression: Epidemiology, clinical features, assessment, and diagnosis” (Bonin, 2023), and “Diagnosis and management of late-life unipolar depression” (Espinoza and Unutzer, 2023) do not mention measurements of neutrophil to lymphocyte ratio, monocyte to lymphocyte ratio, and platelet to lymphocyte ratio as management options.

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References