Focus on Depression

Another nonsensical “study” to discredit nutritional supplements

Effect of Long-term Vitamin D3 Supplementation vs Placebo on Risk of Depression or Clinically Relevant Depressive Symptoms and on Change in Mood Scores A Randomized Clinical Trial

In this randomized clinical trial that included 18353 adults aged 50 years or older without depression or clinically relevant depressive symptoms at baseline, vitamin D3 supplementation compared with placebo did not result in statistically significant differences in the incidence and recurrence of depression or clinically relevant depressive symptoms (hazard ratio, 0.97) or for change in mood scores over a 5-year treatment period.

Low levels of 25-hydroxyvitamin D have been associated with higher risk for depression later in life, but there have been few long-term, high-dose large-scale trials.

There were 18353 men and women aged 50 years or older in the VITAL-DEP (Vitamin D and Omega-3 Trial-Depression Endpoint Prevention) ancillary study to VITAL, a randomized clinical trial of cardiovascular disease and cancer prevention among 25871 adults in the US. There were 16657 at risk for incident depression (ie, no depression history) and 1696 at risk for recurrent depression (ie, depression history but no treatment for depression within the past 2 years). Randomization occurred from November 2011 through March 2014; randomized treatment ended on December 31, 2017, and this was the final date of follow-up.

The study randomized assignment in a 2×2 factorial design to vitamin D3 (2000 IU/d of cholecalciferol) and fish oil or placebo; 9181 were randomized to vitamin D3 and 9172 were randomized to matching placebo.

The primary outcomes were the risk of depression or clinically relevant depressive symptoms (total of incident and recurrent cases) and the mean difference in mood scores (8-item Patient Health Questionnaire depression scale [PHQ-8]; score range, 0 points [least symptoms] to 24 points [most symptoms]; the minimal clinically important difference for change in scores was 0.5 points).

Among the 18,353 randomized participants (mean age, 67.5 [SD, 7.1] years; 49.2% women), the median treatment duration was 5.3 years and 90.5% completed the trial (93.5% among those alive at the end of the trial). Risk of depression or clinically relevant depressive symptoms was not significantly different between the vitamin D3 group (609 depression or clinically relevant depressive symptom events; 12.9/1000 person-years) and the placebo group (625 depression or clinically relevant depressive symptom events; 13.3/1000 person-years) (hazard ratio, 0.97 [95% CI, 0.87 to 1.09]; P=.62); there were no significant differences between groups in depression incidence or recurrence. No significant differences were observed between treatment groups for change in mood scores over time; mean change in PHQ-8 score was not significantly different from zero (mean difference for change in mood scores, 0.01 points [95% CI, -0.04 to 0.05 points]).

Conclusions and Relevance Among adults aged 50 years or older without clinically relevant depressive symptoms at baseline, treatment with vitamin D3 compared with placebo did not result in a statistically significant difference in the incidence and recurrence of depression or clinically relevant depressive symptoms or for change in mood scores over a median follow-up of 5.3 years. These findings do not support the use of vitamin D3 in adults to prevent depression.

 JAMA. 2020;324(5):471-480. doi:10.1001/jama.2020.10224

Dr. Reinhardt:  Sounds all science-y, doesn’t it? This study illustrates the reason why the public increasingly does not trust the “medical science” presented in drug magazines (medical journals). No one, no naturopath, no alternative healer and no nutritionist claims the vitamin D is a drug. Only a western-trained physician would make this error.

The authors did not assess vitamin D status at baseline. Clearly, a non-biased study to determine the value of supplemental vitamin D in depression would include a study arm of subjects with low vitamin D levels who are left untreated, and an arm of subjects with low vitamin D levels at start, who receive supplemental vitamin D to reach an accepted minimum standard.

Vitamin D supplements are appropriate to establish and maintain adequate reserves of vitamin D in the body, to prevent deficiencies. Deficiencies of the vitamin have been linked to increased risks of developing hypertension, respiratory infections, cardiovascular disease and some cancers, as well as depression and anxiety.

The conflict of interest and funding disclosures for this work show significant financial interest and funding from large chemical companies, who are, so far, unable to gain patent rights to vitamin D supplements. We can look for vitamin D being hailed as the next miracle drug once they figure out a way to chemically alter the vitamin enough to secure FDA regulation, just as they have done with Vascepa, Omtryg, Lovaza and Epanova, expensive forms of omega-3 fatty acids that offer no clinical benefit over the cheapest fish oil on the market. These drugs are being aggressively marketed on the TV networks, misleading the public to believe they offer some sort of advantage.

 “Anti”depressants may cause violent criminal behavior, even post-treatment

Associations between selective serotonin reuptake inhibitors and violent crime in adolescents, young, and older adults – a Swedish register-based study

This study identified individuals ever dispensed a selective serotonin reuptake inhibitor (SSRI) aged 15–60 years during 2006–2013, using Swedish national registers. The outcome was violent crime conviction. The main statistical analyses assessed risks of violent crime during periods on compared to off SSRI treatment within individuals. Further analyses investigated risk over time in relation to treatment initiation and discontinuation.

The study identified 785,337 individuals (64.2% female), experiencing 32,203 violent crimes in 5,707,293 person-years. Between-individual analyses found statistically significantly elevated Hazard Ratios (HRs) overall (HR = 1.10), and in 15–24 and 25–34 year-olds (HR = 1.19 and 1.16), but non-significant HRs in 35–44 and 45–60-year-olds (HR = 1.02 and 1.04). In within-individual analyses, where 2.6% of SSRI users were informative, hazards were elevated overall (HR = 1.26, 95% CI = 1.19, 1.34), and across age groups (HR of 1.35 [95% CI = 1.19, 1.54] in 25–34-year-olds to 1.15 [95% CI = 0.99, 1.33] in 35–44-year-olds). In the overall cohort, the within-individual HRs were significantly elevated throughout treatment (HRs of 1.24 to 1.35) and for up to 12 weeks post-discontinuation (HRs of 1.37 and 1.20).

Conclusions:  These results indicate that there may be an increased risk of violent crime during SSRI treatment in a small group of individuals. It may persist throughout medicated periods, across age groups, and after treatment discontinuation. European Neuropsychopharmacology Volume 36, July 2020, Pages 1-9 https://www.sciencedirect.com/science/

article/pii/S0924977X20301048

“Anti”depressants may ONLY cause suicide attempts, but not completed suicides?

Antidepressants and suicidality: A re-analysis of the re-analysis

A recent study by Hengartner and Plöderl describes a strong increase for suicides (odds ratio (OR) of 2.83, 95% CI=1.13-9.67) and suicide attempts (OR=2.38 95%, CI=1.63-3.61) in antidepressant treated patients as compared to placebo. The authors re-analyzed data presented by Khan et al. who found no drug-placebo differences in suicide and suicide attempt rates.

We applied a meta-analytical approach to account for between-drug variance and conducted several statistical analyses as a sensitivity analysis.

Conclusions:  Our analysis leads to different conclusions as opposed to Hengartner and Plöderl. With the recommended method we estimate an OR of 1.98, 95% CI 0.71-5.50 for suicides and 1.63 (95%CI=1.09-2.43) for suicide attempts.

Journal of Affective Disorders Volume 266, 1 April 2020, Pages 95-99 https://www.sciencedirect.com/science/article/abs/pii/S016503271932395X

Dr. Reinhardt:  What a relief, SSRIs only make people TRY to commit suicide. Since 1988 Chemical companies have been trying to prove “anti”depressants help; all they have conclusively found is that they harm. Just like the dementia studies on chemicals to dissolve plaques:  the subjects just get worse, yet the same approach continues to be pursued.

Nasal spray approved for treating suicidal people

Johnson & Johnson’s Spravato has been approved as the first antidepressant for actively suicidal people, as doctors are becoming increasingly concerned about COVID-19’s effect on the mental health of Americans.

The Food and Drug Administration approval means the quick-acting nasal spray will be available to people with suicidal thoughts and a plan to put them into action, said Michelle Kramer, vice president of J&J’s U.S. neuroscience medical affairs unit. That constitutes 11% to 12% of as many as 17 million Americans who have major depressive disorder.

In its studies, J&J found those who got the drug had a rapid reduction in the severity of their thinking, although the results didn’t differ in a statistically significant way from patients given a placebo.

The data from studies of the drug show it “may offer clinicians a new way to provide support to patients quickly in the midst of an urgent depressive episode and help set them on the path to remission,” said Gerard Sanacora, director of Yale’s Depression Research Program and a trial investigator.

Spravato is a close chemical cousin of the anesthetic ketamine, which differs from existing antidepressants because it acts on the glutamate system in the brain rather than on serotonin or norepinepherine.

MedicalXpress August 3, 2020

Dr. Reinhardt:  The prescribing information from Janssen has some interesting findings:

Per 1,000 patients receiving an SSRI, those under 18 had 14 additional suicidal thoughts and behaviors compared to placebo, and for ages 18-24 they had 5 additional verses placebo. “It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. “ Not studied, or not published? Which is worse?

“SPRAVATO causes increases in systolic and/or diastolic blood pressure (BP) at all recommended doses. Approximately 8% to 19% of SPRAVATO-treated patients and 1% to 4% of placebo-treated patients experienced an increase of greater than or equal to 40 mmHg in systolic BP and/or 25 mmHg in diastolic BP in the first 1.5 hours after administration at least once during the first 4 weeks of treatment. A substantial increase in blood pressure could occur after any dose administered even if smaller blood pressure effects were observed with previous administrations. Approximately 8/19%. [?] Were they hampered by a small sample size, or were results not published?

“In a study in healthy volunteers, a single dose of SPRAVATO caused cognitive performance decline 40 minutes post-dose. Compared to placebo-treated subjects, SPRAVATO-treated subjects required a greater effort to complete cognitive tests at 40 minutes post-dose.

No adverse effects of SPRAVATO nasal spray on cognitive functioning were observed in a one-year open-label safety study; however, the long-term cognitive effects of SPRAVATO have not been evaluated beyond one year.” Use of an open label invalidates this defense.

“In clinical studies with SPRAVATO nasal spray, there was a higher rate of lower urinary tract symptoms (pollakiuria, dysuria, micturition urgency, nocturia, and cystitis) in SPRAVATO-treated patients than in placebo-treated patients.”

“SPRAVATO may cause fetal harm when administered to pregnant women. Advise pregnant women of the potential risk to an infant exposed to SPRAVATO in utero.” Seriously, advise your pregnant patients there is a risk? Not prescribing it to pregnant women might be a better solution.

“The most commonly observed adverse reactions in patients treated with SPRAVATO plus oral AD (incidence 5% and at least twice that of placebo nasal spray plus oral AD) were dissociation, dizziness, nausea, sedation, vertigo, hypoesthesia, anxiety, lethargy, blood pressure increased, vomiting, and feeling drunk.”41% had dissociation. 28% had nausea, 23% had vertigo. 23% had sedation.

Four studies were submitted in order to gain FDA approval, with a total of 786 subjects, including 225 receiving placebo only. This may explain the thinness of data!

“J&J found those who got the drug had a rapid reduction in the severity of their thinking, although the results didn’t differ in a statistically significant way from patients given a placebo. “Not statistically significant:  they could not reliably tell the Spravato group from the placebo group. Statistically this is clearly not the case when it came to the adverse effects.

The Psychopathology and Neuroanatomical Markers of Depression in Early Psychosis

Depression frequently occurs in first-episode psychosis (FEP) and predicts longer-term negative outcomes. It is possible that this depression is seen primarily in a distinct subgroup, which if identified could allow targeted treatments. We hypothesize that patients with recent-onset psychosis (ROP) and comorbid depression would be identifiable by symptoms and neuroanatomical features similar to those seen in recent-onset depression (ROD).

Data were extracted from the multisite PRONIA study: 154 ROP patients (FEP within 3 months of treatment onset), of whom 83 were depressed (ROP+D) and 71 who were not depressed (ROP-D), 146 ROD patients, and 265 healthy controls (HC).

Conclusions:  We conclude that depression at a symptom level is broadly similar with or without psychosis status in recent-onset disorders; however, this is not driven by a separable depressed subgroup in FEP. Depression may be intrinsic to early stages of psychotic disorder, and thus treating depression could produce widespread benefit.

Schizophrenia Bulletin, sbaa094, https://doi.org/10.1093/schbul/sbaa094

Dr. Reinhardt:  In reporting, Neuroscience news headlined this study “Patients with early onset psychosis may benefit from treatment for depression, including with anti-depressants alongside other medication, new research shows.” The study authors did not single out and recommend “anti”depressants, but treatment of depression.

It is unfortunate that psychotherapy was not even mentioned by the drug-sponsored magazines.

Prevalence of Treatment for Depression Among US Adults Who Screen Positive for Depression, 2007-2016

The researchers observed no significant change in the prevalence of U.S. adults who screened positive for depression from 2007-2008 to 2015-2016 (8.3 to 7.5 percent). From 2007-2008 to 2015-2016, there was an increase in the overall proportion of adults who received any treatment for depression, from 43.5 to 52.9 percent; with the trend mainly due to both use of antidepressant therapy and contact with a mental health professional. The likelihood of receiving treatment was increased in association with having any health insurance (adjusted odds ratio, 1.70; 95 percent confidence interval, 0.49 to 1.94); following adjustment for survey year, this association was attenuated, but remained significant (adjusted odds ratio, 1.25; 95 percent confidence interval, 1.05 to 1.49). Several authors disclosed financial ties to the biopharmaceutical industry.

 JAMA Psychiatry. Published online July 1, 2020. https://pubmed.ncbi.nlm.nih.gov/32609306/

Dr. Reinhardt:  What proportion of those positive for depression received additional medical workup for causes, such as hypothyroidism? Since most of the “treatment” was symptom suppression by “anti”depressants, how many treatable disorders were neglected?

Experts are calling for the immediate suspension of electroconvulsive therapy (ECT) for major depression.

Antipsychotics offer little or no benefit over psychotherapy

Antipsychotic medication versus psychological intervention versus a combination of both in adolescents with first-episode psychosis (MAPS): a multicentre, three-arm, randomised controlled pilot and feasibility study

The aim of this study was to establish the feasibility of a randomised controlled trial of antipsychotic monotherapy, psychological intervention monotherapy, and antipsychotics plus psychological intervention in adolescents with first-episode psychosis.

We did a multicentre pilot and feasibility trial according to a randomised, single-blind, three-arm, controlled design.

Participants were aged 14–18 years; help-seeking; had presented with first-episode psychosis in the past year; were under the care of a psychiatrist; were showing current psychotic symptoms; and met ICD-10 criteria for schizophrenia, schizoaffective disorder, or delusional disorder, or met the entry criteria for an early intervention for psychosis service. Participants were assigned (1:1:1) to antipsychotics, psychological intervention (CBT with optional family intervention), or antipsychotics of whom were randomly assigned to psychological intervention, 22 to antipsychotics, and 21 to antipsychotics plus psychological intervention.

Mean scores for PANSS total at the 6-month primary endpoint were 68.6 (SD 17.3) for antipsychotic monotherapy, 59.8 (13.7) for psychological intervention, and 62.0 (15.9) for antipsychotics plus psychological intervention. A good clinical response at 6 months (defined as =50% improvement in PANSS total score) was achieved in four (22%) of 18 patients receiving antipsychotic monotherapy, five (31%) of 16 receiving psychological intervention, and five (29%) of 17 receiving antipsychotics plus psychological intervention. In as-treated groups, serious adverse events occurred in eight [35%] of 23 patients in the combined group, two [13%] of 15 in the antipsychotics group, four [24%] of 17 in the psychological intervention group, and four [80%] of five who did not receive any treatment.

The Lancet Psychiatry July 07, 2020 DOI:https://doi.org/10.1016/S2215-0366(20)30248-0

Dr.Reinhardt:  A Lancet editorial on this study criticized the lack of diagnostic interview to break down subjects into specific ICD-10 subsets, and for lack of a psychological placebo group. On the first point, with a total of only 61 subjects, breaking down into what many consider meaningless diagnostic divisions would leave each of these “diagnoses” with so few of subjects as to raise the bar for significance beyond the practical. The ICD-10 divisions themselves are widely criticized as being without sound scientific bases. On the second point, the authors reported on “five who did not receive any treatment.” Examination of the full study found that 5 subjects who received “no treatment” were tracked, and adverse effects reported. A small group, but still can be considered a fourth arm.

According to the authors, “All three regimens were broadly safe and acceptable, with no involuntary hospital admissions and no suggestions that psychological interventions in the absence of antipsychotic medication were detrimental. All three regimens also seemed to provide benefit, with mean PANSS scores improving from baseline by approximately 6–14 points at 6 months, and 12–20 points at 12 months, most of which are within the range recognized as clinically important differences.”

I have pointed out many studies on these pages of inadequate and even nonexistent diagnostic rigor for uncovering the physical causes of first-episode, and indeed all psychosis, with a rush to administer psychotropics. Long term use of antipsychotics has been found to cause structural changes in the brain, with poorly studied impacts. According to Cochrane studies, this class of medication provides moderate or better reduction in delusions and hallucinations of only 9% of recipients versus placebo.

Why use chemicals that are so damaging, if they offer no meaningful benefit over talk therapy? A better approach might be for medical psychologists to serve as first line gatekeepers when “mental” symptoms are present, to ensure that emotional issues, nutritional deficiencies, pathogens and treatable genetic issues are addressed, with psychiatry using their bag of short term symptom suppression tricks after curable conditions are assessed and addressed.

Electroconvulsive Therapy for Depression: A Review of the Quality of ECT versus Sham ECT Trials and Meta-Analyses

Electroconvulsive therapy (ECT) is still being administered to approximately a million people annually. There have been no ECT versus simulated ECT (SECT) studies since 1985. The five meta-analyses of ECT versus SECT studies all claim that ECT is more effective than SECT for its primary target, severe depression. This review assesses the quality of those meta-analyses and of the 11 studies on which they are based.

The meta-analyses were evaluated primarily in terms of whether they considered the quality of the studies they included, but also in terms of whether they addressed efficacy beyond end of treatment. The methodological rigor of the 11 studies included by one or more of the meta-analyses was assessed using a 24-point Quality scale developed for this review.

The five meta-analyses include between 1 and 7 of the 11 studies. The meta-analyses pay little or no attention to the multiple limitations of the studies they include. The 11 studies have a mean Quality score of 12.3 out of 24. Eight scored 13 or less. Only four studies describe their processes of randomization and testing the blinding. None convincingly demonstrate that they are double-blind. Five selectively report their findings. Only four report any ratings by patients. None assess Quality of Life. The studies are small, involving an average of 37 people. Four of the 11 found ECT significantly superior to SECT at the end of treatment, five found no significant difference and two found mixed results (including one where the psychiatrists reported a difference but patients did not). Only two higher Quality studies report follow-up data, one produced a near-zero effect size (.065) in the direction of ECT, and the other a small effect size (.299) in favor of SECT.

Conclusions:  The quality of most ECT studies is so poor that the meta-analyses were wrong to conclude anything about efficacy, either during or beyond the treatment period. There is no evidence that ECT is effective for its target demographic of older women, or its target diagnostic group of severely depressed people, or for suicidal people, people who have unsuccessfully tried other treatments first, involuntary patients, or adolescents. Given the high risk of permanent memory loss and the small mortality risk, this longstanding failure to determine whether or not ECT works means that its use should be immediately suspended until a series of well designed, randomized, placebo-controlled studies have investigated whether there really are any significant benefits against which the proven significant risks can be weighed.

Ethical Human Psychology and Psychiatry.  https://connect.springerpub.com/content/sgrehpp/early/2020/04/02/ehpp-d-19-00014

Dr. Reinhardt:  What next, discredit trephination?

Effects of Antipsychotic Medication on Brain Structure in Patients With Major Depressive Disorder and Psychotic Features

To assess the effects of antipsychotics on brain structure in humans, a double-blind, randomized, placebo-controlled trial over a 36-week period was conducted.

All participants had major depressive disorder with psychotic features (psychotic depression) and were prescribed olanzapine and sertraline for a period of 12 to 20 weeks, which included 8 weeks of remission of psychosis and remission/near remission of depression. Participants were then randomized to continue receiving this regimen or to be switched to placebo and sertraline for a subsequent 36-week period. Data were analyzed between October 2018 and February 2019. The primary outcome measure was cortical thickness in gray matter and the secondary outcome measure was microstructural integrity of white matter.

There was a significant treatment-group by time interaction in cortical thickness (left, t=3.3; P=.001; right, t=3.6; P<.001) but not surface area. No significant interaction was found for fractional anisotropy, but one for mean diffusivity of the white matter skeleton was present (t=-2.6, P=.01). When the analysis was restricted to those who sustained remission, exposure to olanzapine compared with placebo was associated with significant decreases in cortical thickness in the left hemisphere, and the right hemisphere. Post hoc analyses showed that those who relapsed receiving placebo experienced decreases in cortical thickness compared with those who sustained remission.

Conclusions:  In this secondary analysis of a randomized clinical trial, antipsychotic medication was shown to change brain structure. This information is important for prescribing in psychiatric conditions where alternatives are present. However, adverse effects of relapse on brain structure support antipsychotic treatment during active illness.

 JAMA Psychiatry. 2020;77(7):674-683. https://pubmed.ncbi.nlm.nih.gov/32101271/

Dr. Reinhardt:  Subjects were not drug naive:  all had used antipsychotics for at least 3 months. The changes in brain structure may well have been much more pronounced if they would have started as drug naive, although this study shows significant brain damage even at the later stage. Given the “mushiness” of a diagnosis of “major depressive disorder with psychotic features” (a diagnosis which completely ignores brief psychosis due to a particular drug, infection or other transient physical cause) and given the findings of Cochrane that these chemicals result in only 9% of subjects being moderately or more improved, should those prescribing them be the ones taking them?

Association between naturally occurring lithium in drinking water and suicide rates: systematic review and meta-analysis of ecological studies

Lithium is widely and effectively used in pharmacological doses for the treatment and prevention of manic/depressive episodes, stabilising mood and reducing the risk of suicide. Since the 1990s, several ecological studies have tested the hypothesis that trace doses of naturally occurring lithium in drinking water may have a protective effect against suicide in the general population.

Databases were searched to identify eligible ecological studies published between 1 January 1946 and 10 September 2018. The literature search identified 415 articles; of these, 15 ecological studies were included in the synthesis. The random-effects meta-analysis showed a consistent protective (or inverse) association between lithium levels/concentration in publicly available drinking water and total (pooled ß = -0.27, 95% CI -0.47 to -0.08; P = 0.006, I2 = 83.3%), male (pooled ß = -0.26, 95% CI -0.56 to 0.03; P = 0.08, I2 = 91.9%) and female (pooled ß = -0.13, 95% CI -0.24 to -0.02; P = 0.03, I2 = 28.5%) suicide mortality rates. A similar protective association was observed in the six studies included in the narrative synthesis, and subgroup meta-analyses based on the higher/lower suicide mortality rates and lithium levels/concentration.

Conclusions:  This synthesis of ecological studies, which are subject to the ecological fallacy/bias, supports the hypothesis that there is a protective (or inverse) association between lithium intakes from public drinking water and suicide mortality at the population level. Naturally occurring lithium in drinking water may have the potential to reduce the risk of suicide and may possibly help in mood stabilisation, particularly in populations with relatively high suicide rates and geographical areas with a greater range of lithium concentration in the drinking water. All the available evidence suggests that randomised community trials of lithium supplementation of the water supply might be a means of testing the hypothesis, particularly in communities (or settings) with demonstrated high prevalence of mental health conditions, violent criminal behaviour, chronic substance misuse and risk of suicide.

The British Journal of Psychiatry (2020). DOI: 10.1192/bjp.2020.128 https://www.cambridge.org/core/journals/the-british-journal-of-psychiatry/article/association-between-naturally-occurring-lithium-in-drinking-water-and-suicide-rates-systematic-review-and-metaanalysis-of-ecological-studies/B7DDAF6E2A818C45EA64F3424E12D67A

Dr. Reinhardt:  The authors researched as far back as 1949, a date based on renewed interest in using lithium for bipolar disorder published by the psychiatrist John Cade. Lithium has been used for health improvement much longer, with published research going back over 2 centuries for both physical and mood issues.    Lithium’s use, in trace amounts, has been shown to reduce violence, depression, suicidality, mania, hyperactivity, schizophrenia symptoms and anxiety, and certain known physical malfunctions as well, including osteoarthritis, collagen production (wrinkles!) and insulin metabolism.

In reviewing all PubMed content for over 100 years on the subject, I have found significant evidence that low dose (1-15 mg) of lithium salts can be helpful. Unfortunately, I have been unable to find any published studies comparing the efficacy of low dose lithium to the massive, near fatal doses of lithium used in psychiatry today. The closest I have found was a study of low dose to high dose, with low dose set at 600 mg/day. It seems unlikely that this issue has not been explored, simply not published.

Psychiatry and pharmaceutical companies claim they do not know how lithium works and why it is helpful.

Fortunately, veterinary science is more forthcoming. Studies have been done on animals that had interesting results. Doing a PubMed search for “lithium glycine GABA calf” finds that lithium (in very small doses) promotes absorption of the amino acid glycine across cell membranes. Glycine is the major inhibitory neurotransmitter in caudal areas of the brain, spinal cord and retina, and contributes to the processing of sensory and motor information. Glycine also exerts a positive modulation on the excitatory glutamatergic neurotransmission as a co-agonist of glutamate in NMDA receptors. Further, glycine is a cofactor in release of GABA. See “Multifarious Beneficial Effect of Nonessential Amino Acid, Glycine: A Review” (Oxid Med Cell Longev. 2017; 2017: 1716701. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5350494/), also “Skeletal muscle metabolomics and blood biochemistry analysis reveal metabolic changes associated with dietary amino acid supplementation in dairy calves.” (Scientific Reports, Sept. 14 2018, https://core.ac.uk/download/pdf/227978717.pdf

The lithium-glycine-GABA connection came into interest due to field observations that in certain animals used in commerce (specifically cows, pigs and chickens) were less aggressive, healthier and developed faster when trace amounts of both glycine and lithium were added to their feed. This is now standard practice. Decrease in violence, suicides, hyperactivity and suicides in people mirrors this response.

Lithium is widely considered a micronutrient. The usual source for humans is from drinking water, which picks it up from lithium salts in the aquifer. Some water sources have almost no lithium, while others had significant amounts. Glycine, the smallest and most slowly absorbed amino acid, is primarily derived through biosynthesis of serine and other enzyme pathways. Glycine was long considered a “non-essential” amino acid until recently, when it was reclassified as conditionally essential, particularly in those with ADHD, schizophrenia, obesity, diabetes, cardiovascular disease, and cancer). Bipolar Disorder certainly belongs on this list.

Genetic variations in individuals may affect the production of vital enzymes necessary to absorb, metabolize and utilize a wide variety of nutrients, certainly lithium and glycine among them. Considerable research has been conducted, searching for early signs of disorders labeled as schizophrenia, ADHD, canter, dementia, diabetes, and many others.  many “early signs” have been discovered, yet the current medical approach is “wait and see.” If you see ANY of these ‘early signs” in your patients, or your family, perhaps a more prudent approach than “wait and see” would be to add trace mineral and more targeting nutrient supplementation early on.

Food & mood: a review of supplementary prebiotic and probiotic interventions in the treatment of anxiety and depression in adults

 A bidirectional relationship exists between the brain and the gastrointestinal tract. Foods containing bacteria that positively influence the gastrointestinal microbiome are termed, probiotics; compounds that promote the flourishing of these bacteria are termed, prebiotics. Whether microbiome influencing therapies could treat psychiatric conditions, including depression and anxiety, is an area of interest. This systematic review analyses databases and grey literature sites to investigate pre and/or probiotics as treatments for depression and/or anxiety disorders. 7 studies were identified. All demonstrated significant improvements in one or more of the outcomes measuring the of effect taking pre/probiotics compared with no treatment/placebo, or when compared to baseline measurements.

In all, 12 probiotic strains featured in the selected studies, primarily Lactobacillus acidophilus, Lactobacillus casei, and Bifidobacterium bifidium. One study looked at combined pre-probiotic treatment, while one looked at prebiotic therapy by itself.

The studies varied considerably in their design, methods used, and clinical considerations, but all of them concluded that probiotic supplements either alone or in combination with prebiotics may be linked to measurable reductions in depression.

And every study showed a significant fall or improvement in anxiety symptoms and/or clinically relevant changes in biochemical measures of anxiety and/or depression with probiotic or combined pre-probiotic use.

Of the 12 different probiotics investigated, 11 were potentially useful, the findings showed.

Conclusions:  Our results affirm that pre/probiotic therapy warrants further investigation. Efforts should aim to elucidate whether the perceived efficacy of pre/probiotic therapy in depression and/or anxiety disorders can be replicated in larger test populations, and whether such effects are maintained through continued treatment, or post cessation.

BMJ Nutrition, Prevention & Health, 2020; bmjnph-2019-000053 https://nutrition.bmj.com/content/bmjnph/early/2020/06/09/bmjnph-2019-000053.full.pdf

Dr. Reinhardt:  These were placebo controlled studies. No subjects had worsening of depression or anxiety with the treatment, unlike what is found in all ‘anti”depressant studies. All of the studies demonstrated improvement in anxiety and depression scores, unlike what is found in all ‘anti”depressant studies. No adverse effects were found, unlike what is found in all ‘anti”depressant studies.   maybe the AMA is correct, that medical schools should start teaching nutrition.

Blood homocysteine concentration and mood disorders with mixed features among patients with alcohol use disorder

Blood homocysteine concentration (BHC) is higher in patients with alcohol use disorder (AUD). Previous studies have found a relationship between depressive symptoms severity and BHC in AUD patients and recently some authors have found high BHC among patients with bipolar disorder, both during manic and depressive episodes and in euthymic state. However, BHC in patients with mixed mood episode has not yet been investigated. The aim of this study was to evaluate the BHC of patients with AUD and mixed mood episode.

The MIXED group showed greater severity of both depressive ( p < 0.001) and manic (p < 0.001) symptoms, and higher BHC (p < 0.001), than the NO MOOD group. BHC was strongly correlated to the HDRS, YMRS and AUDIT scores, just as HDRS was to YMRS, and AUDIT was to both HDRS and YMRS, in the MIXED group only (p < 0.001).

The MIXDEPRESSION subgroup showed higher BHC than the MIXMANIA subgroup (Mdn = 42.96, IQR = 10.44 vs. Mdn = 19.77, IQR = 5.93; p < 0.001).

A linear regression model conducted on the MIXED group found a significant predictive value for BHC of both HDRS (β = 0.560, t = 2.43, p = 0.026) and AUDIT (β = 0.348, t = 2.17, p = 0.044).

Conclusions:  Depressive symptoms seem to be mainly implicated in the BHC elevation among patients with both mixed features mood disorder and AUD.

BMC Psychiatry. Published online 2017 May 12. https://bmcpsychiatry.biomedcentral.com/articles/10.1186/s12888-017-1342-y

 Vitamin D ₃ reduces risk of cardiovascular and liver diseases by lowering homocysteine levels: double-blinded, randomized, placebo-controlled trial

The objective of this study was to evaluate the effect of vitamin D3 on total homocysteine (tHcy) and C-reactive protein (CRP) levels and liver and kidney function tests in overweight women with vitamin D deficiency. A randomized double-blind placebo controlled clinical trial was conducted on one hundred eligible women.

Subjects were randomly divided into two groups: the placebo (n = 50) and the vitamin D (n = 50) which received 50,000 IU vitamin D3 per week for 2 months. The participants’ 25- hydroxyvitamin D (25 (OH)D), tHcy, CRP, aspartate and alanine aminotransferases (AST, ALT), urea, creatinine and estimated glomerular filtration rate (eGFR) were measured and compared before and after treatment.

Results showed that the tHcy, CRP, AST, ALT, and eGFR levels after the second month of vitamin D3 intervention were significantly (p < 0.001) decreased and the 25(OH)D, urea, and creatinine levels were significantly (p < 0.001) increased in the treatment group. In the placebo group, no significant changes were identified throughout the follow up period.

Conclusions: The vitamin D3 intervention with a treatment dose of 50,000 IU per week for at least 2 months may help in lowering homocysteine and CRP levels and may improve liver function tests, which in turn might help in minimizing the risk of CVD and liver diseases among overweight women but negatively affect kidney function.

Br J Nutr . 2020 Jun 1;1-21.   https://pubmed.ncbi.nlm.nih.gov/32475360/

Dr. Reinhardt:  Should vitamin D supplements be first line treatment for depression?

A large effect size was found for saffron supplementation vs. placebo control in treating depressive symptoms (M ES = 1.62, p < 0.001), revealing that saffron supplementation significantly reduced depression symptoms compared to the placebo control condition. A null effect size was evidenced between saffron supplementation vs. the antidepressant groups (M ES = −0.15) indicating that both treatments were similarly effective in reducing depression symptoms. The mean JADAD score was 5 indicating high quality trials.

Conclusions:  Findings from clinical trials conducted to date indicate that saffron supplementation can improve symptoms of depression in adults with MDD.

J Integr Med. 2013 Nov; 11(6): 377–383.  https://pubmed.ncbi.nlm.nih.gov/24299602/

The effect of saffron supplement on clinical outcomes and metabolic profiles in patients with active rheumatoid arthritis: A randomized, double-blind, placebo-controlled clinical trial

Our study aimed to determine the effect of saffron supplement on clinical outcomes and metabolic profiles in patients with active RA. In this randomized, double-blind, placebo-controlled trial, 66 women older than 18?years old received 100?mg/day either saffron supplement in the intervention group (n = 33) or matched placebo in the placebo group (n = 33) for a period of 12?weeks. Sixty-one patients (30 in the control and 31 in the saffron group) remained for the final analysis.

No adverse effects were reported by the patients. Saffron supplementation significantly decreased the number of tender (-1.38±1.66 vs. 0.10±0.40, p<.001) and swollen (-2.12±2.34 vs. 0.63±2.79, p<.001) joints, pain intensity based on visual analogue scale (-18.36±15.07 vs. -2.33±5.04), p <.001), and disease activity score (DAS28) (-0.75±0.67 vs. 0.26±0.77, p<.001) at the end of intervention between the two groups and in saffron group compared with baseline values. Physician Global Assessment (p = .002) and erythrocyte sedimentation rate were significantly improved after intervention (24.06±12.66 vs. 32.00±14.75, p = 0.028). High-sensitivity C-reactive protein reduced at the end of the intervention in the saffron group compared with baseline values (12.00±7.40 vs. 8.82±7.930, p = .004). Tumor necrosis factor alpha, interferon gamma, and malondialdehyde were decreased, and total antioxidant capacity were increased, but their differences between the two groups were not significant (p>.05).

Conclusions:  According to the results, saffron supplements could positively and significantly improve clinical outcomes in RA patients.

Phytotherapy research 11 February 2020

https://onlinelibrary.wiley.com/doi/abs/10.1002/ptr.6633

Dr. Reinhardt: Given saffron’s efficacy and total lack of adverse effects, can a prescriber in good conscience order an “anti”depressant before trying saffron?  Saffron is the most expensive of herb/spices. An extract at those dose is available OTC for under $0.33 per Day. Methotrexate is the first line treatment for RA in Western medicine. Available research indicates that saffron is similar in efficacy. It primarily blocks inflammation. Methotrexate has the potential for serious toxicity. (FDA) It has many serious adverse effects, and takes a similar 12 weeks for full efficacy. Methotrexate (generic tablet) costs about the same as saffron.

Physical Exercise: Lowering Mortality Among Patients With Depression

People suffering from depression die, on average, 10 years earlier than non-depressed individuals. The premature mortality of individuals with depression is an alarming public health concern. Physical exercise may help address this concern, but it represents an underutilized intervention.

This brief article leverages recent scientific literature to provide some hints as to why premature mortality plagues those who are depressed. It also aims to show the importance of regular physical activity, or even better, physical exercise. Finally, the paper will provide advice on how to encourage patients to do so.

Psychiatric Times special report May 7, 2020.  https://www.psychiatrictimes.com/view/physical-exercise-lowering-mortality-among-patients-depression

Dr. Reinhardt:  Yes, exercise has substantial benefits. But, the 900 lb. gorilla in the room may be revealed below:

The Mortality and Myocardial Effects of Antidepressants Are Moderated by Preexisting Cardiovascular Disease: A Meta-Analysis

Antidepressants (ADs) disrupt multiple adaptive processes regulated by evolutionarily ancient biochemicals, potentially increasing mortality. We conducted a meta-analysis assessing the effects of ADs on all-cause mortality and cardiovascular events in general-population and cardiovascular-patient samples.

Two reviewers independently assessed articles from PubMed, EMBASE, and Google Scholar for AD-related mortality controlling for depression and other comorbidities. From these articles, we extracted information about cardiovascular events, cardiovascular risk status, and AD class.

Seventeen studies met our search criteria. Sample type consistently moderated health risks. In general-population samples, AD use increased the risks of mortality (HR = 1.33, 95% CI: 1.14-1.55) and new cardiovascular events (HR = 1.14, 95% CI: 1.08-1.21). In cardiovascular patients, AD use did not significantly affect risks. AD class also moderated mortality, but the serotonin reuptake inhibitors were not significantly different from tricyclic ADs (TCAs) (HR = 1.10, 95% CI: 0.93-1.31, p = 0.27).

Conclusions: The results support the hypothesis that ADs are harmful in the general population but less harmful in cardiovascular patients.

Psychother Psychosom 2017;86:268-282 https://www.karger.com/Article/Abstract/477940

Dr. Reinhardt:  Yes, depression has an effect on premature mortality. This study shows that chemical interventions with “anti”depressants play a major part in this. It is of little consequence that the “modern” chemicals are not any worse than the older ones. The benefits of ADs approach or equal zero compared to placebo; the worsening of depression by an average of 4-8% is found in all studies. Many studies have uncovered the adverse health effects of these chemicals, yet they remain on the market.

Dietary Intervention Cuts Mood Swings, Other Bipolar Symptoms

A nutritional intervention with a focus on fatty acids appears to reduce mood swings in patients with bipolar disorder (BD) when used as an adjunct to pharmacotherapy, early research suggests.

The researchers randomized 41 patients with BD to receive the nutritional intervention of high omega-3 plus low omega-6 (H3-L6) and 41 patients with BD to receive a control diet of usual US levels of omega-3 and omega-6 fatty acids.

The patients ranged in age from 20 to 75 years (mean age, 43.5 +/- 13.9 years) and 83% were women. They had similar mean levels of mood symptoms and pain.

In a single-center study, patients with BD who received a diet consisting of high omega-3 plus low omega-6 fatty acids (H3-L6), in addition to usual care, showed significant reductions in mood variability, irritability, and pain compared with their counterparts who received a diet with usual levels of omega-3 and omega-6 fatty acids commonly consumed in regular US diets.

After 12 weeks, significant reductions were seen in mood variability, energy, irritability, and pain in the H3-L6 group (P < .001). The only symptom that was significantly lowered in the control group was impulsive thoughts (P = .004).

“The best message for doctors to tell their patients at this point is one of general nutritional health and the importance of nutrition in overall body and brain health, and that that can be a very important component of mood.”

Medscape Psychiatry June 1 2020, reporting American Society of Clinical Psychopharmacology (ASCP) 2020. Abstract 3002415. Presented May 29, 2020. https://www.medscape.com/viewarticle/931499

Can Depression Be Prevented? If So, How?

Depression is highly prevalent, heterogenous, and comorbid with multiple chronic physical conditions and remains the leading cause of disability worldwide. Research and public health efforts have furthered our understanding of the cause of depression and its treatment while increasing community awareness. However, global estimates suggest that the prevalence of depression may nevertheless be on the rise. Increased awareness, subsequent diagnosis, and inadequate reach of effective therapies are potential contributors to this rise, although changing risk factors may play a role. These risk factors for depression are complex and diverse, spanning multiple individual, family, environmental, social, and other domains.

JAMA Psychiatry. June 24, 2020. https://pubmed.ncbi.nlm.nih.gov/32579156/

Dr. Reinhardt:  Obviously depression is best prevented, rather than treated. I note the author recognizes that nutrition does indeed play a part. Depletion of certain nutrients indeed does manifest as depressive symptoms, and other physical symptoms of nutrient deficiency certainly can make a person feel depressed. Articles and Viewpoints published in JAMA Psychiatry have, for over a decade, called for improved nutrition training in medical schools, yet I see no evidence that anyone is listening.

A study published in Academic Medicine in September, 2010 found, “Overall, medical students received 19.6 contact hours of nutrition instruction during their medical school careers (range: 0-70 hours); the average in 2004 was 22.3 hours. Only 28 (27%) of the 105 schools met the minimum 25 required hours set by the National Academy of Sciences; in 2004, 40 (38%) of 104 schools did so.” https://journals.lww.com/academicmedicine/fulltext/2010/09000/nutrition_education_in_u_s__medical_schools_.30.aspx  It appears nothing has changed, despite the overwhelming science revealing the link between depressive symptoms and nutrition.

There is another problem not addressed in this article on preventing depression symptoms:  treatable physical conditions, especially cardiovascular and endocrine issues, may manifest as depressive symptoms much earlier than they are diagnosed, if indeed they are diagnosed at all. As soon as a simple interview or 10 question survey unveils these symptoms, many patients are labeled “Major Depressive Disorder” (or the bizarre diagnosis “Generalized Anxiety Disorder”) and further medical diagnosis efforts often end. There is a rush to prescribe one or more psychotropics. Perhaps that is the reason that reported depression cases are soaring in the face of massive and increasing antidepressant use.

Antidepressant Prescribing and Suicide/Self-Harm by Young Australians: Regulatory Warnings, Contradictory Advice, and Long-Term Trends

In 2004, the US Food and Drug Administration (FDA) controversially issued a black box warning that antidepressants were associated with an increased risk of suicidal thoughts and behaviours in people aged under 18 years. In 2007, the warning was expanded to include young adults aged under 25 years. In 2005, the Australian Therapeutic Goods Administration responded to the FDA warning by requiring Product and Consumer Information leaflets to be updated to reflect the risk. However, there was considerable debate, and at times emotive backlash, in academic journals and the international media.

Prominent US and Australian mental health organisations and psychiatrists challenged the FDA warning. They argued that, on balance, antidepressant use was likely to reduce the risk of suicide. Several ecological studies were cited misleadingly as evidence that decreasing antidepressant use increases suicide risk. From 2008 to 2018, Australian per-capita child, adolescent and young adult antidepressant dispensing (27 years of age) and suicide (24 years) rates have increased approximately 66% and 49%, respectively. In addition, there was a 98% increase in intentional poisonings among 5 to 19 year-olds in New South Wales and Victoria between 2006 and 2016, with substantial overlap between the most commonly dispensed psychotropics and the drugs most commonly used in self-poisoning.

These results do not support claims that increased antidepressant use reduces youth suicide risk. They are more consistent with the FDA warning and the hypothesis that antidepressant use increases the risk of suicide and self-harm by young people. Causal relationships cannot be established with certainty until there is a vast improvement in post-marketing surveillance. However, there is clear evidence that more young Australians are taking antidepressants, and more young Australians are killing themselves and self-harming, often by intentionally overdosing on the very substances that are supposed to help them.

Front. Psychiatry, 05 June 2020 | https://doi.org/10.3389/fpsyt.2020.00478

Dr. Reinhardt:  “Academic Journals” and “International Media,” as stated, lead the charge to discount the warnings on suicidality. Not the actual scientists. A count of the advertising pages and their content in these publications would yield few surprises.

Renewed hope for treatment of pain and depression

Researchers at the Department of Infection and Immunity of the Luxembourg Institute of Health (LIH) have developed LIH383, a novel molecule that binds to and blocks a previously unknown opioid receptor in the brain, thereby modulating the levels of opioid peptides produced in the central nervous system (CNS) and potentiating their natural painkilling and antidepressant properties. Opioid peptides are small proteins that act as neuromodulators by interacting with four ‘classical’ opioid receptors on the surface of CNS cells, playing a key role in mediating pain relief but also emotions such as euphoria, anxiety, stress and depression.

MedicalXpress June 19, 2020.  https://medicalxpress.com/news/2020-06-renewed-treatment-pain-depression.html?utm_source=nwletter&utm_medium=email&utm_campaign=daily-nwletter

Dr. Reinhardt: The MedicalXpress review of this study is a clear example of how honest scientific work can be subverted by pharmacologically influenced reporting. This was an open source study report appearing in Nature Communications (2020). DOI: 10.1038/s41467-020-16664-0. The actual title is “The atypical chemokine receptor ACKR3/CXCR7 is a broad-spectrum scavenger for opioid peptides.”

The full study contains 2 instances of the word “depression”:  “Indeed, drugs targeting the opioid system remain among the most widely prescribed analgesics for severe pain but their use frequently leads to tolerance, dependence or depression.” Also, “These opioid receptor modulators are the most widely used analgesics in the clinic but their use is associated with severe drawbacks like tolerance, dependence, or respiratory depression…”

The researchers must be very offended to have their good work, aimed at trying to solve a problem in pain management, misrepresented to offer a promise of a chemical cure for feelings of sadness, to be coming to your psychiatrist’s office soon. Don’t bother looking for causes of the depressive symptoms, not even hypothyroidism. “Peer reviewed” or advertiser reviewed journal?

“This is a glaring example of the way fundamental research can be translated into concrete applications with tangible benefits for patients, leading to improved clinical outcomes,” says Prof Markus Ollert, Director of the LIH Department of Infection and Immunity and co-author of the study. Yes, I believe he chose the words “glaring example” carefully.