M. Jackson Group Update – December 2022 – Vitamin D and Depression

Merry Christmas and Happy New Year!

A collection of postings on a range of issues is available on our website (www.mjacksongroup.ca).  This month’s post is again from Ken Pope’s listserv, where he kindly provides daily summaries of current articles in the field.

The article is as follows:
Pharmacological Research has scheduled a study for publication in a future issue: “Vitamin D protects against depression: Evidence from an umbrella meta-analysis on interventional and observational meta-analyses.” 
The authors are Vali Musazadeh et al.

Here’s how it opens:
Depression is a mental disorder that causes disabling effects of mood and anxiety disorders. Depression has also become a leading global cause of disease burden [1], [2]. Based on the evidence from the World Health Organization, more than 264 million people are affected by depression worldwide [3]. In the wake of the COVID-19 outbreak, a number of studies have demonstrated a rise in depression psychopathology and suicide tendencies across a variety of countries [4]. Depressive symptoms were the most common mental health condition during the COVID-19 pandemic, ranging from 14.6 to 48.3% across all populations, according to a systematic review [5]. People who suffer from depression may feel sad, anxious, hopeless, helpless, irritable, worthless, guilty, or ashamed [6]. There might also be decreased appetite or overeating, and inability to exercise, or even suicide among them [7]. Antidepressants, which have been used for many years to treat depression, have raised concerns about their effectiveness and tolerance [8], [9], [10]. Furthermore, the failure of depression to respond to a wide range of pharmaceutical treatments [11] indicates that other mechanisms are involved in the pathogenesis of depression, such as those affecting neuroendocrine, immunological, neurotrophic, and metabolic systems [12]. In spite of these challenges, complementary treatments for depression appears to be helpful.

Vitamin D is a unique neurosteroid hormone that may play a role in depression [13]. Vitamin D has numerous functions in the brain such as neuroimmunomodulation, regulation of neurotrophic factors, neuroprotection, neuroplasticity, and brain development [14]. Also, vitamin D receptors can be found on the neurons and glia in many parts of the brain, including the cingulate cortex and the hippocampus [15]. Vitamin D deficiency may have played a significant role in stress-related depression during the COVID-19 pandemic, according to a growing body of literature [16]. Vitamin D is thought to influence the serotoninergic system and contribute to the maintenance of circadian rhythms, both of which are associated with depressive symptoms [16], [17]. As a result, it is biologically plausible that vitamin D might play an important role in the treatment of depressive disorders [13].

Another excerpt:
In the current study, we included meta-analyses of randomized controlled trials (RCTs) and of observational studies (cohort and cross-sectional) that investigated the effect of vitamin D supplementation on depression symptoms considering the following criteria: reporting standardized mean difference (SMD), or odds ratio (OR) and their corresponding confidence intervals (CI) for vitamin D supplementation on depression symptoms. Other studies were excluded from this review, including original experimental studies, case reports, in vitro, ex-vivo, and in vivo investigations.

Here’s how the Discussion opens:
The current umbrella meta-analysis summarized 15 meta-analyses, which inluded 65 RCTs, and 31 observational (cohort and cross-sectional) studies. According to the results, vitamin D supplementation was efficient in alleviating symptoms of depression and an inverse association was observed between higher serum levels of vitamin D intake and overall depression. Based on sub-group analyses, vitamin D supplementation in studies using dosage of > 5,000 IU/day, and intervention duration of ≤20-weeks exhibited stronger effects in lowering symptoms of depression. Morever, the inverse association between lower serum vitamin D levels and depression was stronger among participants aged ≤50 years.

Recent studies have shown a significant association between vitamin D insufficiency or deficiency and depressive disorders [32]. Receptors of vitamin D and 1-alphahydroxylase enzymes, involved in the hydroxylation of 25-hydroxy vitamin D (25OHD) to the active form 1,25-dihydroxy vitamin D, are present on neurons and glia in multiple regions of the brain, including prefrontal cortex, substantia nigra, cingulate cortex and hippocampus and hypothalamus which have an important role in the pathophysiology of depression [13], [30], [34], [39]. Vitamin D is involved in the synthesis of neurotrophic factors and neurotransmitters (serotonin, dopamine, adrenalin, and noradrenaline) through VDRs in the adrenal cortex and due to its steroidal structure, modulates the hypothalamic-pituitary-adrenal axis and GABA‐A receptors activity [30], [34].

During depression, inflammatory markers increase [34]. Meanwhile, vitamin D displays antioxidant effects in the central nervous system, enhances nerve growth factors and the gene expression of antioxidant agents, down-regulates cytokines and inflammatory mediators such as nuclear factor-kB, which is linked to psychosocial stress and depression [32]. In general, vitamin D prevents the onset of depression by taking role in sixmain pathways: 1) Controlling the expression of calcium homeostasis genes; 3) Controlling serotonin synthesis via alleviating tryptophan hydroxylase 2 (TPH2) expression and repressing tryptophan hydroxylase1 (TPH1); 4) Controlling inflammation by reducing the expression of inflammatory cytokines; 5) Controlling the expression of mitochondrial proteins that preserve normal mitochondrial respiration; and 6) Preventing the hypermethylation of gene promotors such as Jumonji domain-containing protein 1 A and 3 (JMJD1A, JMJD3) and lysine-specific demethylase 1 and 2 (LSD1, LSD2). These genes have a significant role in the activation of GABAergic neurons [29], [42]. Fig. 5 exhibits the mechanism of action of vitamin D in preventing and lowering symptoms of depression.

Another excerpt:
Fig. 5. The mechanism of action of vitamin D in preventing and declining symptoms of depression.

Here’s how the article concludes:
The present umbrella of meta-analyses confirms the potential benefits of vitamin D supplementation in reducing symptoms of depression and an inverse relationship between higher serum levels of vitamin D and overall depression. Vitamin D supplementation in studies using dosage of >5,000 IU/day and intervention duration of ≤20-weeks exhibited better effects in lower symptoms of depression. Moreover, a greater risk of depression was shown among participants aged ≤ 50 with lower serum vitamin D levels.
REPRINTS & OTHER CORRESPONDENCE: Rania A. Mekary, School of Pharmacy, MCPHS University, 179 Longwood Avenue, Boston MA, 02115 rania.mekary@mcphs.edu
Ken Pope
Hector Y. Adames, Nayeli Y. Chavez-Dueñas, Melba J.T. Vasquez, & Ken Pope:Succeeding as a Therapist: How to Create a Thriving Practice in a Changing World (APA, September, 2022)
Ken Pope, Melba J.T. Vasquez, Nayeli Y. Chavez-Dueñas, & Hector Y. Adames:
Ethics in Psychotherapy & Counseling: A Practical Guide, 6th Edition (Wiley, 2021)

Ken Pope:
Five Steps to Strengthen Ethics in Organizations and Individuals: Effective Strategies Informed by Research and Histor
y   (Routledge, 2019)

Night of the ScorpionNissim Ezekiel 

I remember the night my mother
was stung by a scorpion. Ten hours
of steady rain had driven him
to crawl beneath a sack of rice.

Parting with his poison – flash
of diabolic tail in the dark room –
he risked the rain again.

The peasants came like swarms of flies
and buzzed the name of God a hundred times
to paralyse the Evil One.

With candles and with lanterns
throwing giant scorpion shadows
on the mud-baked walls
they searched for him: he was not found.
They clicked their tongues.
With every movement that the scorpion made his poison moved in Mother’s blood, they said.

May he sit still, they said
May the sins of your previous birth
be burned away tonight, they said.
May your suffering decrease
the misfortunes of your next birth, they said.
May the sum of all evil
balanced in this unreal world

against the sum of good
become diminished by your pain.
May the poison purify your flesh

of desire, and your spirit of ambition,
they said, and they sat around
on the floor with my mother in the centre,
the peace of understanding on each face.
More candles, more lanterns, more neighbours,
more insects, and the endless rain.
My mother twisted through and through,
groaning on a mat.
My father, sceptic, rationalist,
trying every curse and blessing,
powder, mixture, herb and hybrid.
He even poured a little paraffin
upon the bitten toe and put a match to it.
I watched the flame feeding on my mother.
I watched the holy man perform his rites to tame the poison with an incantation.
After twenty hours
it lost its sting.

My mother only said
Thank God the scorpion picked on me
And spared my children.


M. Jackson Group Update – November 2022 – How Antidepressants Really Work

A collection of postings on a range of issues is available on our website (www.mjacksongroup.ca).  This month’s post is again from Ken Pope’s listserv, where he kindly provides daily summaries of current articles in the field.

The article is as follows:

The New York Times includes an article: “Antidepressants Don’t Work the Way Many People Think—The most commonly prescribed medications for depression are somewhat effective—but not because they correct a ‘chemical imbalance’” by Dana G. Smith.

Here are some excerpts:

Over the course of the Covid-19 pandemic, rates of depression and anxiety soared, and many Americans turned to antidepressant medication to help them cope. Even before the emergence of Covid, 1 in 8 American adults was taking an antidepressant drug. According to one estimate, that number rose by 18.6 percent during 2020. Zoloft is now the 12th most commonly prescribed medication in the United States.

Given this, you might assume that the question of how — and how well — these drugs work has been clearly answered. And yet recentpapers have challenged their efficacy and actions in the brain. Some researchers even say the medications are barely better than a placebo and ask whether they warrant such widespread use.

For psychiatrists, this debate is nothing new. Dr. David Hellerstein, a professor of clinical psychiatry at the Columbia University Irving Medical Center, said the question comes in many iterations but boils down to: Do antidepressants work?

“I think they do,” he said. “The best clinical trials and meta-analyses, most of them indicate that there’s some medication effect. I would say it’s less than we would like it to be.”


If you take an antidepressant or are considering one, here’s what to know about how they work and how their effectiveness is measured.

What do we know about antidepressant effectiveness?

The most commonly prescribed type of antidepressants are selective serotonin reuptake inhibitors, or S.S.R.I.s. These include Prozac, Zoloft and Celexa. 

The drugs prevent neurons from sucking up the neurotransmitter serotonin, allowing more of the chemical to float around in the brain. Other antidepressants increase circulating levels of different brain chemicals, such as norepinephrine and dopamine, in addition to serotonin. However, those drugs come with more side effects, so psychiatrists typically start people with depression on an S.S.R.I. first.

The largest study of antidepressants to date was the Sequenced Treatment Alternatives to Relieve Depression, or STAR*D, trial, which was conducted by the National Institute of Mental Health during the early 2000s. The clinical trial tested multiple antidepressants on nearly 3,000 people with depression, starting everyone on an S.S.R.I. If people didn’t respond to the S.S.R.I. after 12 weeks, they moved on to either another type of S.S.R.I. or a different class of antidepressants. Those include Effexor, a serotonin and norepinephrine reuptake inhibitor, or S.N.R.I., which boosts serotonin and norepinephrine levels; and Wellbutrin, which works similarly on norepinephrine and dopamine.

The trial continued in this way until people who weren’t responding to the medications had tried four different antidepressants. 

By the end of the study, half of the participants had significantly improved after using either the first or second medication, and nearly 70 percent of people had become symptom-free by the fourth antidepressant.

“If you look at the STAR*D, better than 60 percent of those patients actually had a very good response after going through those various levels of treatment,” said Dr. Gerard Sanacora, a professor of psychiatry at the Yale School of Medicine. 

“But it really did make people aware of the fact that these are not miracle treatments. There’s still a lot of people that are suffering despite having these treatments out there.”

One critique of the STAR*D trial is that it didn’t compare the medications against a placebo. Other research has shown that much of the benefit antidepressants provide comes not from their chemical effects in the brain but from a placebo effect. In one study, antidepressants helped people improve 9.6 points on a depression scale, while people taking a placebo improved 7.8 points, meaning that 80 percent of the benefit people experienced could be attributed to a placebo effect. Subsequent meta-analyses that combined multiple trials assessing the efficacy of several types of antidepressants have found that people are about 25 percent more likely to improve on a drug than on a placebo.

To Dr. Sanacora, what matters more than the source of the improvement — whether it’s the pharmacological action of the medication or the placebo effect, which he prefers to call the “nonspecific response” — is that patients got better after taking the drug. He points out that when you take an antidepressant, you benefit from both the drug’s chemical effects on the brain and the placebo (or nonspecific) effects, such as the daily reminder that you are doing something to help your mental health. But if you don’t take the medication, you don’t benefit at all.

“I worry that patients who are really struggling, especially now, when rates of depression are higher than ever, are going to hear this and get the idea that these drugs don’t work,” he said, referring to some of the skeptics’ claims. “That’s not true. They do work.”

Predicting who will improve on antidepressants and who won’t is virtually impossible. Attempts to use genetic screening to forecast a person’s potential treatment response haven’t panned out. Those tests provide information on how efficiently the body metabolizes the drug, but Dr. Sanacora said that is most useful for assessing adverse reactions, not effectiveness.

“I think it’s been oversold by some people that you could do a genetic test and it’s going to tell you which drug you’re going to respond to,” he said. “That has never been the case.”

How do these drugs work?

Experts initially thought that depression must be caused by low levels of neurotransmitters in the brain, in part because the first antidepressant drug — accidentally discovered in the 1950s — increased circulating amounts of the chemicals. Further research suggested that serotonin played an especially important role in mood. 

This so-called “chemical imbalance” theory gained a foothold in the cultural psyche and was promoted by ads for the medications.

However, starting in the 1990s, researchers began to understand that depression was much more complicated and that serotonin played only a nominal role. 

For one thing, S.S.R.I.s increase serotonin levels immediately, but it takes several weeks before people start to feel better. Studies also started to emerge showing that another brain system played a role: People with depression consistently have less volume in an area called the hippocampus that’s important for regulating mood.

The current prevailing theory, Dr. Hellerstein said, is that chronic stress can cause the loss of connections — called synapses — between cells in the hippocampus and other parts of the brain, potentially leading to depression. Antidepressants are now thought to work at least in part by helping the brain form new connections between cells. 

Researchers aren’t exactly sure how increasing serotonin with an S.S.R.I. causes these synapses to regrow. 

One possibility is that the medications also increase levels of other brain chemicals, called growth factors, that help those connections form and spread.

A paper published earlier this year made headlines for presenting several decades’ worth of evidence that people with depression don’t have less serotonin than people who are not depressed. To most psychiatrists, the paper didn’t reveal anything new, and it didn’t mean antidepressants aren’t effective (a widely held misinterpretation of the paper). 

Instead it revealed a fundamental disconnect between how the public viewed depression and how the experts thought about it.

“To me, that is an old theory for depression,” said Dr. Daniel Iosifescu, a professor of psychiatry at N.Y.U. Langone Health. 

“That was already invalidated 20 years ago, so we’re just essentially putting the nail in the coffin, so to speak.”

What alternatives to antidepressants are available?

Alternative treatments for depression have emerged that attempt to help the brain create new connections more efficiently — most notably ketamine and psychedelic therapy (which is not approved by the Food and Drug Administration). 

These interventions appear to be about as effective as antidepressants, improving depression scores in roughly 60 percent of the people who try them. More significant is that they are able to treat some of the people who don’t respond to the traditional medications. 

The drugs are seen as riskier and more invasive than antidepressants, though, so are meant to be used as a last resort, not a first-line treatment, Dr. Sanacora said.

Some psychiatrists have also started to recommend nonpharmaceutical treatments to help people with depression. Dr. Hellerstein said that when he evaluates a new patient, he now pays more attention to habits, such as sleep, diet and exercise, and would often recommend behavioral changes, therapy or meditation before medication. 

There’s research suggesting that exercise also may help new connections grow in the brain, and in some studies exercise has been shown to be as effective as antidepressants at treating depression.

Meditation has been found to help with feelings of stress and anxiety, and there’s a clear connection between sleep deprivation and anxiety in the brain.

“You’re making, I think, a more holistic assessment of that person’s way of living than maybe you did in the late 1980s,” Dr. Hellerstein said.

Finding the best solution for your depression, whether that’s an S.S.R.I., another antidepressant or a behavioral intervention, can take a lot of trial and error, but it’s important to remember that you do have options. And while psychiatrists acknowledge that S.S.R.I.s and other antidepressants are imperfect — and they hope a better drug will come along eventually — for the time being, they’re the best medications currently available.

“I wouldn’t write these older antidepressants completely off and say we should get rid of them,” Dr. Iosifescu said. “They do seem to work for a good number of patients.”

Ken Pope
Hector Y. Adames, Nayeli Y. Chavez-Dueñas, Melba J.T. Vasquez, & Ken Pope:Succeeding as a Therapist: How to Create a Thriving Practice in a Changing World (APA, September, 2022)
Ken Pope, Melba J.T. Vasquez, Nayeli Y. Chavez-Dueñas, & Hector Y. Adames:
Ethics in Psychotherapy & Counseling: A Practical Guide, 6th Edition (Wiley, 2021)

Ken Pope:
Five Steps to Strengthen Ethics in Organizations and Individuals: Effective Strategies Informed by Research and Histor
y   (Routledge, 2019)A Valediction Forbidding MourningAdrienne Rich  

My swirling wants.  Your frozen lips. 
The grammar turned and attacked me. 
Themes, written under duress. 
Emptiness of the nations. 
They gave me a drug that slowed the healing of wounds. I want you to see this before I leave: 
the experience of repetition as death 
the failure of criticism to locate the pain 
the poster in the bus that said: 
my bleeding is under control. 
A red plant in a cemetery of plastic wreaths. A last attempt: the language is a dialect called metaphor. 
These images go unglossed: hair, glacier, flashlight. 
when I think of a landscape I am thinking of a time. 
When I talk of taking a trip I mean forever. 
I could say: those mountains have a meaning 
but further than that I could not say. 
To do something very common, in my own way. 

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.Molecular Psychiatry includes a study: “Antidepressants for the treatment of