The Depressing State of Antidepressants by Jeffrey Dach MD

Mary, a 65-year-old retired accountant has been a patient in my office for 15 years. For the past 20 years, she has been taking two different SSRI antidepressant drugs prescribed by her primary care doctor. Mary’s physical examination showed hyperactive reflexes, dilated pupils, and fine hand tremors, all from the SSRI drugs. One day, Mary told me she wanted to get off the SSRI drugs. Since her doctor would not help, would I help her to get off the SSRI drugs? I replied, yes of course, I am always happy to provide an SSRI tapering schedule. Without the gradual tapering, withdrawal effects can be quite severe, so we try to gradually taper down the dosage over 12 weeks or more before discontinuing them altogether. In Mary’s case, since she is on two separate SSRI drugs, we taper them one at a time.  Caution: DO NOT STOP YOUR SSRI DRUG without gradual tapering under the supervision of your physician. (1-6)

Header image: Paris Street in Rainy Weather, 1877  by Gustave Caillebotte (1848–1894) oil on canvas, public domain, courtesy of wikimedia commons.

In 2023, Dr. James Davies a PhD in medical anthropology from the University of Oxford and  a practicing psychotherapist, reviewed SSRI drug use between the years 2011 to 2023 in the United Kingdom. During this time, SSRI prescriptions doubled to 85 million, and nearly 20 percent of the adult population is now taking an SSRI antidepressant drug. How can we explain the disconnect between widespread use despite the lack of meaningful clinical benefit? The medical literature on SSRI antidepressants reveals these drugs have no meaningful clinical benefit, except for the most severe depression where any treatment is better than a placebo. Dr. James Davies writes:

Over the past decade, antidepressant prescriptions have almost doubled in England, rising from 47.3 million in 2011 to 85.6 million in 2022-23. Over 8.6 million adults in England are now prescribed them annually (nearly 20% of adults) …Multiple meta-analyses have shown antidepressants to have no clinically meaningful benefit beyond placebo for all patients but those with the most severe depression. (7)

SSRI Antidepressants Are Dangerous

SSRI antidepressant drugs are dangerous for two reasons. Firstly, they are addictive drugs causing morphological changes in the terminal ends of the neurons. The SSRI drug is a serotonin reuptake inhibitor which means the drug blocks the serotonin transporters which are microscopic pumps, protein machines located at the outer membrane of the pre-synaptic neuron. Their job is to take up serotonin from the synaptic cleft and return it to the pre-synaptic neuron. Blocking the transporter inhibits the reuptake of serotonin from the synaptic cleft, increasing the amount of neurotransmitter available in the synaptic space, thus increasing the neurotransmitter signal. There are many classes of such reuptake inhibitors. Cocaine inhibits the reuptake of dopamine, serotonin, and norepinephrine by blocking all three transporters. Amphetamines block the dopamine transporters. Tiagabine (Gabitril) is a GABA reuptake inhibitor. Desvenlafaxine (Pristiq), duloxetine (Cymbalta) and venlafaxine (Effexor) are SNRI drugs, both serotonin and norepinephrine reuptake inhibitor drug. Note: SNRI is Serotonin and Norepinephrine Reuptake Inhibitor. What happens after prolonged use of the SSRI drug? The brain compensates by upregulating and increasing the number of transporters, thus creating drug tolerance. As in all addictive drugs, once drug tolerance is achieved, higher doses are needed for the same effect. What happens if the drug is stopped? This will mimic serotonin deficiency syndrome and will trigger drug withdrawal symptoms. Withdrawal symptoms are both psychological and physical. Psychological withdrawal symptoms are worsening anxiety and depression, insomnia, despair, panic, suicidal thoughts, and possible psychotic breakdown. Physical symptoms are autonomic nervous system dysfunction, sweating, flushing, fatigue, irritable bowel syndrome, vertigo, loss of balance, greater sensitivity to pain, and binge eating. This is not good. Recovery from drug withdrawal may take a few months, the time it takes for the neurons to down-regulate the transporters. Eventually, withdrawal symptoms abate, meaning the brain has restored normal serotonin concentrations at the synaptic cleft. For the stronger SNRI drugs such as Effexor (venlafaxine), a drug that inhibits both serotonin and norepinephrine reuptake, its withdrawal effects include electric shock-like “brain zaps” or “shivers” which may take months to resolve. (8)

Akathisia and Psychosis

The second reason SSRI drugs are dangerous is an adverse effect called akathisia; a form of agitation often described as a feeling like scraping your fingernails across the blackboard at the front of the classroom. Akathisia and manic psychosis are known side effects of SSRI drugs, cocaine, methamphetamine, ADHD stimulants (methylphenidate), and antipsychotic drugs. Akathisia is a form of psychomotor psychosis that drives the drug user to violence, suicide, homicide, and or other bizarre behaviors. Many of the mass shootings reported in the media are the result of SSRI-induced akathisia. The link between SSRI drugs and mass shootings, suicide, and homicide has been known for decades. Yet this information is largely ignored or intentionally suppressed by mainstream media to preserve massive drug company profits from this class of drugs. (9-18)

One Percent of SSRI Users Become Violent

Most people seem to tolerate SSRI drugs without becoming psychotic. Why do SSRI drugs cause a small number of people to exhibit suicidal thoughts, hostility, and violent behavior? In 2021, Dr. Eikelenboom-Schieveld examined this question, finding genetic mutations in drug metabolism in one percent of the population, leading to the accumulation of excess SSRI drug levels. This could account for aggressive, hostile, violent, and psychotic behavior of people on SSRI drugs, and other neuro-psychiatric drugs such as amphetamines, ADHD stimulants, anti-psychotics, etc. This mutation involves the CYP450 enzyme system in the liver which is responsible for metabolizing and removing drugs and chemicals from the body. If the CYP450 is mutated and not working properly, then the SSRI drug accumulates, reaching toxic blood levels. Note: ADHD= attention deficit hyperactivity disorder. Dr. Eikelenboom-Schieveld says violence is a known side effect of psychoactive medication, writing:

There is an association between prescription drugs, most notably antidepressants and other psychoactive medication; having variant alleles for CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4; and the occurrence of an altered emotional state or acts of violence. Based on these results, genotyping [genetic testing] patients for these six CYP450s would provide information as to who might be susceptible to adverse drug reactions, e.g., the development of an altered emotional state or assault/suicide/homicide. This would be an improvement to personalized medicine…. Violence is a known side effect of psychoactive medication, as is recognized in the literature. Psychoactive medication is mainly metabolized by enzymes generated by CYP450 genes. Reduced or non-functional alleles will have an effect on the blood levels of drugs and can cause side effects, e.g., acts of violence…This might explain why millions of people take prescription drugs and only around 1% commit acts of violence, a number the FDA nevertheless considers “frequent”. When either the variant alleles or the amount of medication increase, one might develop an altered emotional state. This should be taken as a warning sign. From the medical histories, such emotional states are often considered as a sign that the medication is not working enough. A typical result is to add more or different medication, elevating a patient to a level with an increased risk of acts of violence. (19-20)

Depression is More Complicated

Amphetamines are performance-enhancing drugs. In the 1940s, amphetamines were handed out freely to WWII soldiers on both sides. After the war in the 1950s, amphetamines made their way into civilian life. They were the first drugs marketed for the treatment of depression. Amphetamines do work quite well as a pick-me-up brain stimulant. However, it was discovered that people on amphetamines eventually had psychotic episodes, addiction, and withdrawal effects. This eventually led to the 1965 FDA restrictions on amphetamine use. For SSRI and amphetamine drugs that block neurotransmitter re-uptake, the neurons eventually adapt to the drug requiring higher doses to reach the same effect. This is called drug tolerance in which the brain has reached an equilibrium state. The drug dosage is no longer effective. Many SSRI users will continue the drug to avoid the uncomfortable withdrawal effects of insomnia and anxiety. A similar scenario is found with many amphetamine users who eventually find themselves in a rehabilitation clinic undergoing drug withdrawal. SSRI drugs (Serotonin Reuptake Inhibitor Drugs) are based on the theory that depression is due to a deficiency of serotonin, a brain neurotransmitter. Recent studies show that depression is much more complicated, and not caused by lack of serotonin. Causes of depression include menopausal hormone deficiency, endocrine disorders, HPA dysfunction, low thyroid, low testosterone, low estrogen, inflammatory conditions such as leaky gut, diabetes, etc. as described by Dr. Angelos Halaris below. Note HPA= Hypothalamic Pituitary axis. (21)

Serotonin Theory of Depression Falsified

In 2023, Dr. Joanna Moncrieff did a systematic review of the medical literature finding no basis for the serotonin theory of depression. Even worse, long-term use of SSRI antidepressants reduces brain serotonin, a compensating effect associated with drug tolerance as mentioned above.  Dr. Joanna Moncrieff writes:

The main areas of serotonin research provide no consistent evidence of there being an association between serotonin and depression, and no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations. Some evidence was consistent with the possibility that long-term antidepressant use reduces serotonin concentration. (22)

In a second article in 2023, Dr. Joanna Moncrieff rebuts criticism by her psychiatric colleagues saying the clinical trials of “SSRI antidepressants show marginal differences from placebo and do not fulfill criteria for clinical relevance. SSRI drugs perturb brain chemistry in unpredictable ways, and emotional blunting has emerged as a clear drug effect”, writing:

whether antidepressants produce a genuine and useful pharmacological effect that is independent of the placebo effect, has not been established. Antidepressants show marginal differences from placebo, which do not fulfil criteria for clinical relevance, and may represent amplified placebo effects due to unblinding. It is hard to reconcile even the most generous appraisal of their efficacy with the vast numbers of people now taking them…Antidepressants produce varied and more or less subtle effects on arousal, sensations, thoughts and feelings, commonly including numbing of emotions, now demonstrated even in healthy volunteers …From the public’s point of view, taking a drug that is believed to reverse an underlying chemical imbalance or other brain abnormality is quite a different prospect from taking a drug that perturbs brain chemistry in incompletely known and potentially unpredictable ways, with poorly researched effects on mood and behaviour, with emotional numbing emerging as a clear effect. Yet, this approach to marketing drugs by drawing on unproven, implausible single neurotransmitter hypotheses to provide biological justifications for their use continues apace. (23)

Sexual Dysfunction, Emotional Blunting

In addition to increased violence and suicide, adverse side effects of SSRI antidepressants include sexual dysfunction and emotional blunting, two inconvenient truths that have been largely ignored. A medical literature search for SSRI antidepressant sexual dysfunction returns 40,000 articles. In 2024, Dr. Judith J. Stephenson reported sexual dysfunction from SSRI drug use in 19 percent of patients which may be irreversible after discontinuing the drug. (24)

In 2024, David Cox discusses the sexual consequences of SSRI drugs, writing: “Long-term sexual dysfunction is a recognized side-effect for some patients who take these widely prescribed antidepressants, and can leave sufferers devastated.” In this same article appearing in the Guardian, Rosie Tilli says her SSRI drug use has eliminated her ability to have a sexual response:

I reassured myself that I would be fine as soon as I fully ceased the [SSRI] medication, but I wasn’t,” she says. “Now nearly four years on, I’ve learned to put on a sunny disposition, but internally I am riddled with psychological grief and anguish. I can’t experience any physiological sexual response. No arousal even when physically touched. It’s as if the entire electrical hardwiring of the sexual system has been short-circuited. My clitoris feels like my elbow now, and there’s nothing I can do to reverse it. (25)

Emotional Blunting and Personality Changes

One might speculate that emotional blunting may represent the main clinical benefit of SSRI drugs for people with emotional disturbances or difficult-to-control emotional responses. In my personal experience as a clinician, I find that people on long-term SSRI drugs have characteristic personality changes. They tend to be more aggressive, hostile, talkative, and self-centered than the control population. People are unaware that the SSRI drug transforms them into an unpleasant, obnoxious, argumentative personality type. Surprisingly, the medical literature supports this viewpoint. (26-28)

What Causes Depression and What Are the Treatments?

Current pharmacological interventions with SSRI antidepressants provide remission in only 30 percent of patients. With the failure of the drug industry serotonin hypothesis, you might ask the next logical question. What is the real cause of depression and what are the treatments? In 2021, Angelos Halaris, MD, a board-certified psychiatrist, and Professor of Psychiatry at Loyola University Medical School addresses this question. Dr. Halaris finds endocrinological aberrations, notably hypothalamic-pituitary-adrenal (HPA) axis dysregulation, thyroid disorders, and menopausal hormone deficiency most common. Dr. Angelos Halaris discusses how low Vitamin D contributes to depression. He suggests the medical evaluation of depression should include genetic testing for Single Nucleotide Polymorphisms (SNPs) in Cytochrome P450, Serotonin Transporter, COMT, and folate conversion to methyl-folate (the MTHFR test). He also mentions the role of immune system dysregulation and generalized inflammation, and the value of testing for CRP (C reactive Protein) an inflammatory marker. He mentions salivary cortisol testing, and the dexamethasone suppression test useful for adrenal dysfunction. He acknowledges that methyl-folate, estrogen and testosterone can serve as highly effective antidepressant treatments. Note: COMT= catechol-O-methyl transferase enzyme. MTHFR=methylenetetrahydrofolate reductase.  Dr. Angelos Halaris writes:

Major Depressive Disorder (MDD) is a highly prevalent psychiatric disorder worldwide. … Current pharmacologic interventions fail to produce at least partial response to approximately one third of these patients, and remission is obtained in approximately 30% of patients. This is known as Treatment-Resistant Depression (TRD)… We discuss endocrinological aberrations, notably, hypothalamic-pituitary-adrenal (HPA) axis dysregulation and thyroid and gonadal dysfunction. We address the role of Vitamin D in contributing to depression. Pharmacogenomic testing is being increasingly used to determine Single Nucleotide Polymorphisms in Cytochrome P450, Serotonin Transporter, COMT, folic acid conversion (MTHFR). As the role of immune system dysregulation is being recognized as potentially a major contributory factor to TRD, the measurement of C-reactive protein (CRP) and select immune biomarkers, where testing is available, can guide combination treatments with anti-inflammatory agents (e.g., selective COX-2 inhibitors) reversing treatment resistance…As mentioned above, among the most consistent biological changes in MDD [Major Depressive Disorder] patients is increased plasma cortisol and overall dysregulation of the HPA axis …Salivary cortisol appears to be the most accurate measurement of cortisol because it reflects non-protein-bound cortisol in blood…but how do we measure HPA axis function? HPA axis function can be measured using challenge tests. One such challenge test is the dexamethasone-suppression test (DEX), which was among the first tests used to assess stress-related psychiatric disorders…Testosterone and Estrogen act as antidepressants…Vitamin D Studies of Vitamin D supplementation show no adverse effects even at high doses of up to 10,000 IU daily, and doses of 800 IU are generally sufficient to reach a 25(OH)D level of at least 50 nmol/L (or 20 ng/mL)…Folic Acid, L-methylfolate, MTHFR…Numerous studies have demonstrated the association between depression and folate deficiency. L-methylfolate, the active form of vitamin B9, is the only form that can cross the blood–brain barrier. Low levels of L-methylfolate are associated with multiple neuropsychiatric diseases, including MDD, schizophrenia and Alzheimer’s… Studies have shown the effectiveness of both folic acid and L-methylfolate as both a monotherapy and as an adjunctive therapy, suggesting the importance of assessing folate status in patients that appear to be “treatment resistant”. In fact, L-methylfolate is among the only medical foods licensed by the FDA for the treatment of depression …it is also essential to consider the MTHFR gene; individuals may have genetic polymorphisms that affect the conversion of synthetic or dietary folate to L-methylfolate, the biochemically active form. If someone is homozygous for the T variant (TT), studies suggest that they have about 30% of the enzyme activity of people with the wild-type (CC) variant [100,101]. Heterozygous (CT) individuals have about 65% of the enzyme activity of CC individuals. In Caucasian North Americans, 8–20% of the population has the TT genotype…Recommendation: perform measurement of blood level folic acid and genomic test for MTHFR, preferably as part of a more comprehensive pharmacogenomic profile as available on the market in your country…Anti-Inflammatory Treatments in Affective Disorders…Recommendations: Investigate the presence of an inflammatory process anywhere in body and take corrective action to reduce or eliminate this source of inflammation. Measurement of hsCRP may be a useful marker of an inflammatory process in the body. (21) (29-32)

In my opinion, depression is not a disease. Rather, depression is a symptom of an underlying disorder, most related to low thyroid disorders, menopausal hormone deficiency, inflammatory disorders, and mitochondrial dysfunction disorders. Note an overlap between two disorders, chronic fatigue, and depression. For all practical purposes in the clinic, they frequently overlap and can sometimes be regarded as identical syndromes. In 2011, Dr. Michael Maes, Professor, Department of Neuropsychiatry, University of Ghent, Belgium says depression and chronic fatigue “should be regarded as ‘co-associated disorders’ that are clinical manifestations of shared pathways.” Dr. Michael Maes writes:

There is a significant ‘comorbidity’ between depression and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Depressive symptoms frequently occur during the course of ME/CFS. Fatigue and somatic symptoms (F&S), like pain, muscle tension, and a flu-like malaise, are key components of depression. At the same time, depression and ME/CFS show major clinical differences, which allow to discriminate them with a 100% accuracy… Numerous studies have shown that depression and ME/CFS are characterized by shared aberrations in inflammatory, oxidative and nitrosative (IO&NS) pathways, like systemic inflammation … dysfunctional mitochondria; lowered antioxidant levels, like zinc and coenzyme Q10; autoimmune responses to neoepitopes formed by O&NS; …and increased translocation of gram-negative bacteria. …Depression and ME/CFS are not ‘comorbid’ disorders, but should be regarded as ‘co-associated disorders’ that are clinical manifestations of shared pathways. (32-33)

Estrogen Treats Menopausal Depression

In 2001, Dr. Claudio de Novaes Soares from Brazil ran a double-blind placebo-controlled trial in 50 women with perimenopausal depression treated with an estradiol skin patch (100 mcg), finding excellent efficacy, writing:

Perimenopausal women (aged 40-55 years, with irregular menstrual periods and serum concentrations of follicle-stimulating hormone >25 IU/L), meeting criteria for major depressive disorder, dysthymic disorder, or minor depressive disorder, according to DSM-IV, were randomized to receive transdermal patches of 17beta-estradiol (100 µg) or placebo in a 12-week, double-blind, placebo-controlled study…Fifty women were enrolled in the study; 26 met DSM-IV criteria for major depressive disorder, 11 for dysthymic disorder, and 13 for minor depressive disorder…Remission of depression was observed in 17 (68%) women treated with 17beta-estradiol compared with 5 (20%) in the placebo group (P = .001). Conclusion: Transdermal estradiol replacement is an effective treatment of depression for perimenopausal women. (34)

In 2001, Dr. Uriel Halbreich from Buffalo, New York found that estrogen was effective for treatment of depression in postmenopausal women, writing:

There is growing evidence suggesting that estrogen may be efficacious as a sole antidepressant for depressed perimenopausal women. (35-39)

In 2024, Dr. Louise Newsome, an OB/Gyne practitioner in the U.K. suggests that psychiatrists are missing the opportunity to prescribe HRT (hormone replacement therapy) instead of SSRI antidepressants for their depressed post-menopausal patients. However, the typical psychiatrist lacks the training and expertise to prescribe HRT to menopausal women. It would be unrealistic to expect them to do so. It would also be unrealistic to expect the psychiatrist to refer these patients out to another doctor who has expertise in HRT. This would mean losing a lucrative source of income, as the patient on an SSRI drug becomes a patient for life. At the end of the day, the patient must vote with their feet, flee the psychiatrist’s office, and seek out a doctor with expertise in bioidentical hormone replacement. A doctor with expertise in thyroid disorders is an added plus. Dr. Louise Newsome says SSRI antidepressants are unnecessary and inappropriate, writing:

However, far too many women are being offered or prescribed antidepressants instead of HRT [hormone replacement therapy] which is often unnecessary and inappropriate. Most psychiatrists do not prescribe HRT which is a massive missed opportunity for women. (40)

On November 5, 2024, in her weekly podcast, Dr. Louise Newsome was joined by Dr. Marty Makary, a pancreatic cancer surgeon at Johns Hopkins Medical Center and newly appointed commissioner for the U.S. Food and Drug Administration (FDA). Dr. Makary is the author of the best-selling book, Blind Spots in Medicine. In this podcast, Dr. Marty Makary discusses how menopause is ignored in medical education. Women seeking menopausal hormone replacement are more likely to be prescribed an SSRI antidepressant. This is an error and tragedy of modern medicine. Dr. Marty Makary speaks:

[00:21:29] You know, tragically because of this Women’s Health initiative dogma 22 years ago, medical schools just kind of concluded, well, there’s nothing you can do for menopause, so why teach it? …And so we ignored menopause altogether in medical education. So today, tragically, at least in the United States, a woman is more likely to be prescribed an antidepressant for menopause than they are hormone replacement. (41)

My Clinical Experience

In my office, I frequently see post-menopausal women with depression caused by estrogen deficiency. These patients typically report dramatic improvement after treatment with bio-identical hormone replacement with a combination of estrogen, progesterone, testosterone, and DHEA. We also use nutritional supplements such as cordyceps, lithium orotate, 5-HTP, and theanine. Many of these women arrive in my office currently taking multiple anti-depressant drugs for their post-menopausal symptoms of depression. Typically, we try to taper these women off the SSRI antidepressants, once they start treatment with bio-identical hormone replacement and are feeling better. The correct treatment for the post-menopausal female with depressive symptoms is bioidentical hormone replacement, not an SSRI drug. Progesterone is excellent for relief of anxiety-type mood disturbance. I would venture to say testosterone therapy could very well be the most effective anti-depressant known to mankind. (42-47)

Estrogen Enhances Mitochondrial Respiration in the Brain

Estrogen controls mitochondrial energy production working in synergy with thyroid and testosterone hormones, all three binding to receptors in nuclear and mitochondrial DNA, regulating the structure and function of the mitochondrial respiratory chain and generating new mitochondria. Estrogen upregulates energy production and is required by the high energy demands of brain and heart. Thus, it is not difficult to understand menopausal estrogen deficiency as a major cause of clinical depression, and menopausal estrogen replacement therapy as a highly effective treatment. It is important to remember that if clinical depression is caused by a deficiency in mitochondrial energy production, SSRI drugs are ineffective, since they do not improve mitochondrial energy production. In 2023 by Dr. Matej Luptak from Prague studied pig brain-isolated mitochondria showing all SSRI antidepressants harm mitochondrial function by inhibiting the mitochondrial electron transport chain. Quite the opposite, in 2023, Dr. Jing Zhu found estrogen upregulates energy production by enhancing the respiratory function of the mitochondrial electron transport chain, writing:

Furthermore, the E2 [estradiol] signal has been identified as one of the major signals that converge upon mitochondria to exert its neuroprotective effect. Mitochondria malfunction may cause many neurocognitive and neurodegenerative disorders, such as AD [alzheimer’s disease], depression, and anxiety, which show a sex-specific prevalence. Proteomic analysis of brain mitochondria of female rats indicates that E2 regulates the expression of pyruvate dehydrogenase (PDH), a pivotal enzyme that transforms the pyruvate to acetyl CoA, provides substrate in the citric acid cycle, concomitantly increases oxidative phosphorylation and ATP synthase, and decreases beta-oxidation. According to another in vivo data, E2 [estradiol] and progesterone treated rat brain mitochondria display enhanced respiratory function coupled with increased expression of the electron transport chain complex IV (cytochrome C oxidase). (48-54)

Depression Caused by Leaky Gut, LPS, Microglia Activation in the Brain

A major cause of depression/chronic fatigue is “leaky gut” that releases inflammatory cytokines into the blood stream which then cross the blood-brain barrier entering the brain causing inflammation and immune activation. This immune-inflammatory activation in the brain causes activation of microglia and clinical depression and chronic fatigue. Dr. Allesio Fasano, chief of Pediatric Gastroenterology at Mass General Children’s Hospital has revealed that, in susceptible individuals, the ingestion of wheat gluten triggers the release of Zonulin, a hormone that opens the “tight junctions” between epithelial cells of the GI mucosa. This is called “leaky gut.” For people with gluten sensitivity, the prolonged opening of channels between the epithelial cells makes the gut lining permeable to undigested food particles and gut bacteria which “leak” into the bloodstream, thus we have a “leaky gut.” This is also called low-level endotoxemia, or LPS, short for Lipo-Poly-Saccharide, the outer membrane of enteric gram-negative bacteria which activates macrophages and immune cells, releasing inflammatory cytokines into the bloodstream. This slurry of LPS and inflammatory mediators eventually reaches the cerebral circulation causing inflammation in the brain with activation of micro-glia. This inflammatory response disturbs the autonomic nervous system, and neurotransmitter production, resulting in autonomic dysfunction, depression, and chronic fatigue. In 2021, Dr. Michael Maes reviews this immune-inflammatory response as fundamental in the pathophysiology of depression and chronic fatigue, writing:

In the last three decades, the robust scientific data emerged, demonstrating that the immune-inflammatory response is a fundamental component of the pathophysiology of major depressive disorder (MDD).… The gastrointestinal (GI) tract, along with gut-associated lymphoid tissue (GALT), constitutes the largest lymphatic organ in the human body and forms the biggest surface of contact with the external environment. It is also the most significant source of bacterial and food-derived antigenic material. …A broad range of factors, including psychological stress, inflammation, dysbiosis and other, may compromise the permeability of this barrier. This leads to excessive bacterial translocation [leaky gut] and the excessive influx of food-derived antigenic material that contributes to activation of the immune-inflammatory response and depressive psychopathology. (55-62)

Depression Caused by Mitochondrial Dysfunction

Let us go to the next category of Depression/Chronic Fatigue. This category is caused by mitochondrial dysfunction with deficient cellular energy production. These are very treatable disorders which include hypothyroidism, post-menopausal estrogen deficiency, low testosterone in males, HPA dysfunction with low cortisol, and genetic mutations such as MTHFR. Mitochondrial toxins such as NSAIDS, certain antibiotics, statins, anti-diabetics and SSRI antidepressants (themselves) cause mitochondrial dysfunction resulting in deficient energy production. Antibiotics that impair mitochondrial function include fluoroquinolones, erythromycin, doxycycline, etc. Statin drugs deplete CoQ10, a key intermediate in the electron transport chain, thus acting as a mitochondrial toxin. Mitochondrial dysfunction may be caused by deficiencies in vitamin B12, folate, alpha lipoic acid, thiamine, Co-Q10, iron, selenium, and other co-factors involved in the electron transport chain (ETC). In 2018 Dr. Josh Allen says that the serotonin theory of depression has fallen out of favor, and instead suggests mitochondrial dysfunction should be regarded as the true etiology of depression, writing:

For more than 50 years, the dominant theory for the pathogenesis of depression was the monoamine hypothesis (Schildkraut, 1965), which arose from observations that [SSRI] antidepressant drugs work by inhibiting the reuptake of monoamines such as serotonin and norepinephrine. However, this theory has largely fallen out of favor due to a number of discrepancies, such as the fact that the therapeutic effects of antidepressants take weeks to develop even though monoamine levels are elevated within hours of administration, and the fact that only about 40% of patients respond satisfactorily to treatment (Trivedi et al., 2006)…Human and animal studies suggest an intriguing link between mitochondrial diseases and depression… Mitochondria are the cellular powerhouse of eukaryotic cells, and they also regulate brain function through oxidative stress and apoptosis. In this paper, we make the case that mitochondrial dysfunction could play an important role in the pathophysiology of depression. Alterations in mitochondrial functions such as oxidative phosphorylation (OXPHOS) and membrane polarity, which increase oxidative stress and apoptosis, may precede the development of depressive symptoms. However, the data in relation to [SSRI] antidepressant drug effects are contradictory: some studies reveal they have no effect on mitochondrial function or even potentiate dysfunction… Overall, the data suggest an intriguing link between mitochondrial function and depression that warrants further investigation. (63-68)

Natural Products for Depression

We have found natural products useful in depression. These include berberine, cordyceps, maca, lithium and 5-HTP. Testosterone is perhaps nature’s best antidepressant. Also, do not forget caffeine in coffee and tea serve as brain stimulant and excellent antidepressant. Caffeine and methylxanthines in chocolate have antidepressant effects. For assisting mitochondrial energy production, we have Coenzyme Q10, D-ribose and L-carnitine, alpha lipoic acid, and benfothiamine. Low B12 and low iron may cause fatigue and depression, which resolves upon taking B12 and iron supplements. A leaky gut with elevated inflammatory cytokines has been linked to depression. Leaky gut can be addressed with berberine, food sensitivity testing, gluten-free diet, probiotics, and glutamine to heal the gut. (69-79)

SSRI Withdrawal and Return to Normalcy

Long-term use of SSRI drugs induces adaptive, morphological changes in the serotonergic neurons to compensate for the inhibition of serotonin transporters and resulting excess serotonin within the synaptic cleft. In the SSRI drug user, their brain quickly compensates for the SSRI drug effect by increasing the number of serotonin transporters, thus removing the excess serotonin from the synaptic cleft. Once serotonin levels return to equilibrium, this is called drug tolerance. What happens when the patient suddenly stops the SSRI drug? With no SSRI drug to maintain serotonin levels in the synaptic cleft, the upregulated serotonin transporters quickly deplete serotonin from the synaptic cleft, leading to withdrawal symptoms identical to serotonin deficiency syndrome. Withdrawal effects include insomnia, anxiety, dizziness, vertigo, electric shock sensations in the head, and flu-like symptoms. Gradually over time, the SSRI neurons decrease the number of serotonin transporters at the terminal synapse, and withdrawal symptoms abate as normal brain chemistry is restored. (80-82)

Many people can withdraw from SSRI drugs uneventfully if the drug is tapered down gradually over 3-6 months. This is true for the younger patient on the drug for less than 1-2 years. However, it is not unusual to see patients on two or three different SSRI drugs for many years, as well as taking a benzodiazepine drug for sleep. These patients on higher doses or multiple SSRI drugs over 10 to 20 years may not be able to taper off their SRRI drug, even with a gradual taper, because of severe withdrawal effects. Also, SSRI drugs vary in ease or difficulty to withdraw from them. And, there is variation in  severity of withdrawal symptoms. Perhaps the most severe withdrawal symptoms are found with the combined serotonin/norepinephrine reuptake inhibitors (SNRIs). These are notorious for causing electric shock-like “brain zaps” during withdrawal. To help ameliorate the withdrawal effects, progesterone is especially useful helping to reduce symptoms of anxiety, depression, and insomnia associated with SSRI drug withdrawal. In 2024, Dr. Julia Stimpfl discussed deprescribing SSRI antidepressants in adolescents, writing:

Antidepressant withdrawal symptoms are related to the pharmacokinetics of the medication, which vary across antidepressants and may include irritability, palpitations, anxiety, nausea, sweating, headaches, insomnia, paresthesia, and dizziness. These symptoms putatively involve changes in serotonin transporter expression and receptor sensitivity, impacting the serotonin, dopamine, and norepinephrine pathways. (83-85)

Dr. James Greenblatt’s Adjunctive SSRI Withdrawal Program

In the above discussion, oral micronized progesterone was mentioned as adjunct to SSRI tapering. In 2022, Dr. James Greenblatt, a Johns Hopkins-trained child and adolescent psychiatrist suggests a basket of supplements helpful for SSRI tapering: B12, methyl-folate, vitamin D3, B6, Zinc, 5-HTP, lithium orotate, B-complex, magnesium, curcumin, N-acetylcysteine (NAC), and cannabidiol (CBD). Lithium is especially useful because it increases the volume of the hippocampus, the brain area involved in neurogenesis, memory, and spatial learning. Lithium is a mineral ubiquitous in our water supply. Lithium was added to popular soft drinks from the 1930s to the 1950s, such as lithiated 7-Up. In 2014, Anna Fels writes in the New York Times, “Should we all take a bit of lithium?” (86-94)

Do Antidepressants Cause More Harm Than Good?

In 2012, Dr. Paul Andrews asked the question: do antidepressants do more harm than good? After an exhaustive study of the medical literature, Dr. Andrews concludes that SSRI antidepressants are neither safe nor effective, and do more harm than good:

it is widely believed that antidepressant medications are both safe and effective; however, this belief was formed in the absence of adequate scientific verification. The weight of current evidence suggests that, in general, antidepressants are neither safe nor effective; they appear to do more harm than good. (95)

Dr. Paul Andrews also states the evidence of harm is greatest in the elderly where SSRI use is associated with increased risks of falling, hyponatremia, bleeding, stroke, and death, writing:

Patients should be informed that current research suggests that unless they have very severe depression, the symptom reducing effects of antidepressants are modest and are not considered clinically significant. Unless there are rapid-onset adverse side effects, antidepressant therapy usually lasts for months. Patients should be advised that prolonged use might cause mild cognitive impairment and interfere with tasks that require highly focused concentration, such as driving, which may increase the risk of accidents. Patients should also be advised that antidepressants might trigger even more severe depressive episodes when they are discontinued. All patients should be advised of the possible bleeding risks, and physicians should exercise particular caution in prescribing these drugs in conjunction with other diuretic or anti-thrombotic medications. The evidence of harm is strongest in the elderly, who should be advised of the risks of falling, hyponatremia, bleeding, stroke, and death…In fact, antidepressants cause neuronal damage and mature neurons to revert to an immature state, both of which may explain why antidepressants also cause neurons to undergo apoptosis (programmed death). Antidepressants can also cause developmental problems, they have adverse effects on sexual and romantic life, and they increase the risk of hyponatremia (low sodium in the blood plasma), bleeding, stroke, and death in the elderly. Our review supports the conclusion that antidepressants generally do more harm than good by disrupting a number of adaptive processes regulated by serotonin…Antidepressants perturb monoamine levels through a variety of mechanisms, the most common of which is by binding to monoamine transporters. In the normally functioning rodent brain, transporter blockade prevents the reuptake of monoamines into the presynaptic neuron, which causes extracellular monoamines to increase from equilibrium levels in forebrain regions within minutes to hours of administration. With prolonged antidepressant use, however, the brain’s homeostatic mechanisms buffer this effect by making a number of compensatory changes, including an inhibition of synthesis that causes the entire pool of serotonin in the forebrain (intracellular plus extracellular) to decline. Consequently, extracellular levels in the forebrain return to equilibrium levels with prolonged treatment. There are other changes that take place with chronic antidepressant use to maintain homeostasis, including alterations in the density and functioning of serotonin receptors, transporters, and enzymes …Effects of Prolonged Antidepressant Treatment…Even among those who respond to antidepressant treatment, longer-term use is associated with a loss of symptom reducing efficacy – sometimes causing a full-blown relapse. This is also consistent with the brain pushing back against the symptom reducing effect of antidepressants. In an early review, studies showed that 9–57% of long-term antidepressant users met formal criteria for a relapse or a recurrence. More recent studies have found similarly high rates of relapse among those who initially remitted on the drug. In one study of fluoxetine, 35.2% met relapse criteria after 6 months of continuous treatment, increasing to 45.9% after 12 months. In another study, 68% of patients who initially met remission criteria, and were exposed only to continuous antidepressant treatment, had a relapse over a 2 year period. Of course, these studies only report increases in symptoms that meet formal criteria for a relapse. A more general loss of efficacy with prolonged antidepressant use must be substantially higher…Three recent, large, prospective epidemiological studies have found that, even after controlling for depressive symptoms, antidepressant use is associated with an increased risk of death in the elderly ….out of 1000 elderly people taking antidepressants, the number of deaths per year caused by antidepressants was estimated to be 10.8 (for TCAs), 35.7 (for SSRIs), and 43.9 (for other antidepressants). (95)

Conclusion: One of the tragic errors of modern medicine is the refusal to prescribe bioidentical hormone replacement for menopausal depression. Some patients may need thyroid medication in addition to HRT. Instead, the postmenopausal patient is given an ineffective SSRI antidepressant causing loss of libido, drug tolerance, and addiction. Rather than improving mitochondrial energy production, studies show SSRI drugs harm the mitochondria. (103-106)

Estrogen, testosterone and thyroid hormones all increase mitochondrial biogenesis and function, thus are superior to SSRI drugs in depression when caused by mitochondrial dysfunction. A small percentage of patients on SSRIs exhibit akathisia, a form of psychomotor psychosis that drives the patients to perform aggressive, homicidal, suicidal, and violent activities, such as mass shootings. The falsification and abandonment of the serotonin theory of depression has been largely ignored by mainstream medicine which considers the SSRI antidepressant drug “the standard of care” for depression, anxiety, and a wide variety of neuropsychiatric symptoms. The SSRI drug market in the U.S. is lucrative with an annual growth rate of 3.1 percent, with sales of 8.6 billion dollars in 2024. The sad reality is that SSRI and SNRI drugs are dangerous, addictive, and mostly ineffective for depression. Depression is more complicated than handing out an SSRI drug, as described by Dr. Angelos Halaris, who reminds us the diagnosis and treatment of depression, much like the practice of medicine, requires a complex diagnostic thought process to uncover the underlying cause and devise a treatment program. Perhaps that is why the busy doctor will quickly prescribe an SSRI antidepressant drug and move on to the next patient, a simplification of medicine required by the health insurance business model. In my office, we do not use SSRI drugs. We offer a tapering schedule for those who wish to get off them. This drug tapering schedule is accompanied by an adjunct program that includes progesterone, 5HTP, lithium orotate, and theanine. For new patients presenting with depression/chronic fatigue, instead of mindlessly dispensing an SSRI drug, we use diagnostic testing to uncover the underlying cause of depression and treat it appropriately as described above.

What is the mechanism of estrogen as antidepressant, in eliminating anxiety and depression? Estrogen receptors have been found in the brain, and estrogen increases the expression of an enzyme in the brain called tryptophan hydroxylase-2 (TPH2). This enzyme’s job is to convert tryptophan to serotonin, and other neurotransmitters responsible for anti-anxiety and calming effects in the brain. In 2024, Dr. Peyton Christine Bendis provides evidence that estradiol enhances serotoninergic, dopaminergic and glutamatergic neurotransmission, writing:

In conclusion, we provide a comprehensive review of the many effects of E2 [estradiol] on neurotransmitter systems and more specifically we provide evidence supporting the hypothesis that E2 may enhance serotoninergic, dopaminergic and glutamatergic neurotransmission. Investigating animal, human, and cellular data has proven beneficial in understanding how, where, and why E2 exerts its effects on both the male and female brain. (96-102)

Articles with related Interest:

SSRI Drugs No Better than Placebo

SSRI Drugs and Suicide in the Military

SSRI Drugs and Overcome Depression Naturally

Protect Your Family from Bad Drugs

Jeffrey Dach MD
7450 Griffin Road, Suite 190
Davie, Fl 33314
954-792-4663
my blog: www.jeffreydachmd.com 

References for Chapter 25 The Depressing State of Antidepressants

1) Badar, Ahmed. “Serotonin Syndrome: An Often-Neglected Medical Emergency.” Journal of Family and Community Medicine 31.1 (2024): 1-8.

2) Scotton, William J., et al. “Serotonin Syndrome: Pathophysiology, Clinical Features, Management, And Potential Future Directions.” International Journal of Tryptophan Research 12 (2019): 1178646919873925.

3) Horowitz, Mark Abie, and David Taylor. “Tapering of SSRI Treatment to Mitigate Withdrawal Symptoms.” The Lancet Psychiatry 6.6 (2019): 538-546.

4) Palmer, Emilia G., et al. “Withdrawing from SSRI Antidepressants: Advice for Primary Care.” British Journal of General Practice 73.728 (2023): 138-140.

5) McLaren, Niall. “Clarifying Deprescribing.” Australasian Psychiatry (2024): 10398562241303398.

6) Looi, Jeffrey CL, et al. “Deprescribing Antidepressants for Depression–What Is the Evidence for And Against?” Australasian Psychiatry (2024): 10398562241282377.

7) Davies, James, et al. “Politicians, Experts, and Patient Representatives Call for The UK Government to Reverse the Rate of Antidepressant Prescribing.” BMJ 383 (2023).

8) Cortes, Jose A., and Rajiv Radhakrishnan. “A Case of Amelioration of Venlafaxine-Discontinuation” Brain Shivers” With Atomoxetine.” The Primary Care Companion for CNS Disorders 15.2 (2013): 26751.

9) Fox News: SSRI Antidepressants Causing School Shootings? With Dr. Peter Breggin. https://www.youtube.com/watch?v=WAO5_Hk06Mc

10) Healy, David, Andrew Herxheimer, and David B. Menkes. “Antidepressants and Violence: Problems at The Interface of Medicine and Law.” PLoS Medicine 3.9 (2006): e372.

11) Lagerberg, Tyra, et al. “Associations Between Selective Serotonin Reuptake Inhibitors and Violent Crime in Adolescents, Young, And Older Adults–A Swedish Register-Based Study.” European Neuropsychopharmacology 36 (2020): 1-9.

12) The Decades of Evidence That Antidepressants Cause Mass Shootings As we have seen with the vaccines, almost no social cost can keep a lucrative pharmaceutical off the market. A Midwestern Doctor. Mar 29, 2023. https://www.midwesterndoctor.com/p/the-decades-of-evidence-that-antidepressants

13) Moran, Lauren V., et al. “Risk of Incident Psychosis and Mania with Prescription Amphetamines.” American Journal of Psychiatry 181.10 (2024): 901-909.

14) Lucire, Yolande, and Christopher Crotty. “Antidepressant-Induced Akathisia-Related Homicides Associated with Diminishing Mutations in Metabolizing Genes of The CYP450 Family.” Pharmacogenomics and Personalized Medicine (2011): 65-81.

15) Kalniunas, Arturas, et al. “The Relationship Between Antipsychotic-Induced Akathisia and Suicidal Behavior: A Systematic Review.” Neuropsychiatric Disease and Treatment (2021): 3489-3497.

16) Knoll IV, James L. “Warning: Antidepressants May Cause Bank Robbery.” Psychiatric Times, September 27 (2013).

17) Adshead, Gwen. “Antidepressants and Murder: Case Not Closed.” BMJ 358 (2017).

18) Reeves, Roy R., and Mark E. Ladner. “Antidepressant‐Induced Suicidality: An Update.” CNS Neuroscience & Therapeutics 16.4 (2010): 227-234.

19) Eikelenboom-Schieveld, Selma JM, and James C. Fogleman. “Cytochrome P450 genes: Their Role in Drug Metabolism and Violence.” Handbook of Anger, Aggression, and Violence. Cham: Springer International Publishing, 2022. 1-29.

20) Eikelenboom-Schieveld, Selma JM, and James C. Fogleman. “Psychoactive Medication, Violence, And Variant Alleles for Cytochrome P450 Genes.” Journal of personalized medicine 11.5 (2021): 426.

21) Halaris, Angelos, Emilie Sohl, and Elizabeth A. Whitham. “Treatment-Resistant Depression Revisited: A Glimmer of Hope.” Journal of Personalized Medicine 11.2 (2021): 155.

22) Moncrieff, Joanna, et al. “The Serotonin Theory of Depression: A Systematic Umbrella Review of The Evidence.” Molecular psychiatry 28.8 (2023): 3243-3256.

23) Moncrieff, Joanna, et al. “The Serotonin Hypothesis of Depression: Both Long Discarded and Still Supported?” Molecular Psychiatry 28.8 (2023): 3160-3163.

24) Stephenson, Judith J., et al. “Antidepressant Use and Treatment-Emergent Sexual Dysfunction Among Patients with Major Depressive Disorder: Results from an Internet-Based Survey” Journal of Affective Disorders Reports (2024): 100750.

25) The Observer Mental Health: ‘It Feels Like We’ve Been Lobotomised’: The Possible Sexual Consequences of SSRIs by David Cox the Guardian. Mar 2, 2024. https://www.theguardian.com/society/2024/mar/02/ssri-antidepressants-sexual-dysfunction-side-effects-consequences-libido

26) Knutson, Brian, et al. “Selective Alteration of Personality and Social Behavior by Serotonergic Intervention.” American Journal of Psychiatry 155.3 (1998): 373-379.

27) Harmer, C. J., et al. “Acute SSRI Administration Affects the Processing Of Social Cues In Healthy Volunteers.” Neuropsychopharmacology 28.1 (2003): 148-152.

28) Tang, Tony Z., et al. “Personality Change During Depression Treatment: A Placebo-Controlled Trial.” Archives Of General Psychiatry 66.12 (2009): 1322-1330.

29) Jain, Rakesh, et al. “Good, Better, Best: Clinical Scenarios For The Use of L-Methylfolate In Patients With MDD.” CNS spectrums 25.6 (2020): 750-764.

30) Altaf, Rabail, et al. “Folate as Adjunct Therapy To SSRI/SNRI For Major Depressive Disorder: Systematic Review & Meta-Analysis.” Complementary therapies in medicine 61

31) Tunio, Ali Gul, et al. “Efficacy of Sertraline with L. Methyl Folate and Without L. Methyl Folate in The Treatment of Major Depressive Disorder: A Comparative Study.” Journal of Population Therapeutics and Clinical Pharmacology 31.2 (2024): 313-321.

32) Maes, Michael. “An Intriguing and Hitherto Unexplained Co-Occurrence: Depression And Chronic Fatigue Syndrome Are Manifestations Of Shared Inflammatory, Oxidative And Nitrosative (IO&NS) Pathways.” Progress in Neuro-Psychopharmacology and Biological Psychiatry 35.3 (2011): 784-794.

33) Harvey, Samuel B., et al. “The Relationship Between Fatigue and Psychiatric Disorders: Evidence For The Concept Of Neurasthenia.” Journal of psychosomatic research 66.5 (2009): 445-454.

34) de Novaes Soares, Cláudio, et al. “Efficacy of Estradiol for The Treatment of Depressive Disorders in Perimenopausal Women: A Double-Blind, Randomized, Placebo-Controlled Trial.” Archives Of General Psychiatry 58.6 (2001): 529-534

35) Halbreich, Uriel, and Linda S. Kahn. “Role of Estrogen in The Aetiology and Treatment of Mood Disorders.” CNS drugs 15 (2001): 797-817.

36) Gnanasegar, Rahavi, et al. “Does Menopause Hormone Therapy Improve Symptoms of Depression? Findings From a Specialized Menopause Clinic.” Menopause 31(4) (2024):320-325

37) Herson, Megan, and Jayashri Kulkarni. “Hormonal Agents for The Treatment of Depression Associated with The Menopause.” Drugs & Aging 39.8 (2022): 607-618.

38) Gordon, Jennifer L., and Susan S. Girdler. “Hormone Replacement Therapy in The Treatment of Perimenopausal Depression.” Current Psychiatry Reports 16 (2014): 1-7.

39) Rasgon, Natalie L., et al. “Estrogen Replacement Therapy in The Treatment of Major Depressive Disorder in Perimenopausal Women.” The Journal of Clinical Psychiatry 63 (2002): 45-48.

40) Newsome, Louise, Oct 26, 2024. https://x.com/drlouisenewson/status/18500507632857415835)

41) The Dr. Louise Newson Podcast 281 – Blind spots in modern medicine, with Dr. Marty Makary. Nov. 5, 2024. https://www.balance-menopause.com/menopause-library/blind-spots-in-modern-medicine-with-dr-marty-makary/

42) Wieland, Scott, et al. “Anxiolytic Activity of The Progesterone Metabolite 5α-Pregnan-3α-Ol-20-One.” Brain Research 565.2 (1991): 263-268.

43) Picazo, O., and A. Ferna. “Anti-Anxiety Effects of Progesterone and Some of Its Reduced Metabolites: An Evaluation Using the Burying Behavior Test.” Brain Research 680.1-2 (1995): 135-141.

44) Studd, John, and N. Panay. “Hormones and Depression in Women.” Climacteric 7.4 (2004): 338-346.

45) Walther, Andreas, et al. “Association of Testosterone Treatment with Alleviation of Depressive Symptoms in Men: A Systematic Review and Meta-analysis.” JAMA psychiatry 76.1 (2019): 31-40.

46) Sun, Qihan, et al. “Role of Estrogen in Treatment of Female Depression.” Aging (Albany NY) 16.3 (2024): 3021.

47) Kulkarni, Jayashri. “Estrogen–a Key Neurosteroid in The Understanding and Treatment of Mental Illness in Women.” Psychiatry Research 319 (2023): 114991.

48) Zhu, Jing, et al. “Role of Estrogen in The Regulation of Central and Peripheral Energy Homeostasis: From A Menopausal Perspective.” Therapeutic Advances in Endocrinology and Metabolism 14 (2023): 20420188231199359.

49) Luptak, Matej, et al. “Different Effects of SSRIs, Bupropion, And Trazodone on Mitochondrial Functions and Monoamine Oxidase Isoform Activity.” Antioxidants 12.6 (2023): 1208.

50) Irwin, Ronald W., et al. “Progesterone and Estrogen Regulate Oxidative Metabolism in Brain Mitochondria.” Endocrinology 149.6 (2008): 3167-3175.

51) Klinge, Carolyn M. “Estrogens Regulate Life and Death in Mitochondria.” Journal of Bioenergetics and Biomembranes 49 (2017): 307-324.

52) Klinge, Carolyn M. “Estrogenic Control of Mitochondrial Function.” Redox biology 31 (2020): 101435.

53) Ahmad, Irshad, and Annie E. Newell-Fugate. “Role of Androgens and Androgen Receptor in Control of Mitochondrial Function.” American Journal of Physiology-Cell Physiology (2022).

54) Sagliocchi, Serena, et al. “The Key Roles of Thyroid Hormone in Mitochondrial Regulation, At Interface of Human Health and Disease.” Journal of Basic and Clinical Physiology and Pharmacology 35.4-5 (2024): 231-240.

55) Rudzki, Leszek, and Michael Maes. “From “Leaky Gut” To Impaired Glia-Neuron Communication in Depression.” Major Depressive Disorder: Rethinking and Understanding Recent Discoveries. Singapore: Springer Singapore, 2021. 129-155.

56) Maes, Michael. “Leaky Gut In Chronic Fatigue Syndrome: A Review.” Activitas Nervosa Superior Rediviva 51.1-2 (2009): 21-8.

57) Fasano, Alessio. “Zonulin, Regulation of Tight Junctions, And Autoimmune Diseases.” Annals of the New York Academy of Sciences 1258.1 (2012): 25-33.

58) Batey, L., et al. “Lipopolysaccharide Effects on Neurotransmission: Understanding Implications for Depression.” ACS Chemical Neuroscience (2024).

59) Troubat, Romain, et al. “Neuroinflammation and Depression: A Review.” European Journal of Neuroscience 53.1 (2021): 151-171.

60) Kim, Yong-Ku, et al. “The Role of Pro-Inflammatory Cytokines in Neuroinflammation, Neurogenesis and The Neuroendocrine System in Major Depression.” Progress in Neuro-Psychopharmacology and Biological Psychiatry 64 (2016): 277-284.

61) Hurley, Laura L., and Yousef Tizabi. “Neuroinflammation, Neurodegeneration, And Depression.” Neurotoxicity Research 23 (2013): 131-144.

62) Qin L, Wu X, Block ML, et. al. Systemic LPS Causes Chronic Neuroinflammation and Progressive Neurodegeneration. Glia. 2007;55(5):453-62.

63) Allen, Josh, et al. “Mitochondria and Mood: Mitochondrial Dysfunction as A Key Player in The Manifestation of Depression.” Frontiers in Neuroscience 12 (2018): 386.

64) Gardner, Ann, and Richard G. Boles. “Beyond the Serotonin Hypothesis: Mitochondria, Inflammation and Neurodegeneration in Major Depression and Affective Spectrum Disorders.” Progress in Neuro-Psychopharmacology and Biological Psychiatry 35.3 (2011): 730-743.

65) Klinedinst, N. Jennifer, and William T. Regenold. “A Mitochondrial Bioenergetic Basis of Depression.” Journal of Bioenergetics and Biomembranes 47 (2015): 155-171.

66) Bansal, Yashika, and Anurag Kuhad. “Mitochondrial Dysfunction in Depression.” Current neuropharmacology 14.6 (2016): 610-618.

67) Zielińska, Magdalena, et al. “Dietary Nutrient Deficiencies and Risk of Depression (Review Article 2018–2023).” Nutrients 15.11 (2023): 2433.

68) Du, Jing, et al. “The Role of Nutrients in Protecting Mitochondrial Function and Neurotransmitter Signaling: Implications for The Treatment of Depression, PTSD, And Suicidal Behaviors.” Critical Reviews in Food Science and Nutrition 56.15 (2016): 2560-2578.

69) Noori, Tayebeh, et al. “The Role of Natural Products in Treatment of Depressive Disorder.” Current Neuropharmacology 20.5 (2022): 929-949.

70) Liu, Jiawen, et al. “Natural Products for The Treatment of Depression: Insights into Signal Pathways Influencing the Hypothalamic–Pituitary–Adrenal Axis.” Medicine 102.44 (2023): e35862.

71) Levine, Bruce. Psychiatry’s Discredited Theories and Drugs Versus a Sane Model and Approach. Mad in America (2024). https://www.madinamerica.com/2024/02/psychiatrys-discredited-theories/

72) Stone, Marc B., et al. “Response to Acute Monotherapy For Major Depressive Disorder In Randomized, Placebo Controlled Trials Submitted To The US Food And Drug Administration: Individual Participant Data Analysis.” BMJ 378 (2022).

73) Chen, Guang, et al. “Enhancement of Hippocampal Neurogenesis by Lithium.” Journal of neurochemistry 75.4 (2000): 1729-1734.

74) Kim, Jin Seuk, et al. “Lithium Selectively Increases Neuronal Differentiation of Hippocampal Neural Progenitor Cells Both In Vitro And In Vivo.” Journal of neurochemistry 89.2 (2004): 324-336.

75) Yan, Xue-Bo, et al. “Lithium Regulates Hippocampal Neurogenesis by ERK Pathway and Facilitates Recovery of Spatial Learning and Memory in Rats After Transient Global Cerebral Ischemia.” Neuropharmacology 4.53 (2007): 487-495.

76) Quiroz, Jorge A., et al. “Novel Insights into Lithium’s Mechanism of Action: Neurotrophic and Neuroprotective Effects.” Neuropsychobiology 62.1 (2010): 50.

77) Dach, Jeffrey. “Gut–Brain: Major Depressive Disorder, Hypothalamic Dysfunction, and High Calcium Score Associated with Leaky Gut.” Alternative Therapies in Health and Medicine 21 (2015): 10-15.

78) Twardowska, Agata, et al. “Preventing Bacterial Translocation in Patients with Leaky Gut Syndrome: Nutrition and Pharmacological Treatment Options.” International Journal of Molecular Sciences 23.6 (2022): 3204.

79) Li, Ning, et al. “Berberine Attenuates Pro-Inflammatory Cytokine-Induced Tight Junction Disruption in An In Vitro Model of Intestinal Epithelial Cells.” European Journal of Pharmaceutical Sciences 40.1 (2010): 1-8.

80) Sghendo, Lino, and Janet Mifsud. “Understanding the Molecular Pharmacology of The Serotonergic System: Using Fluoxetine as A Model.” Journal of Pharmacy and Pharmacology 64.3 (2012): 317-325.

81) Kalia, Madhu, et al. “Comparative Study of Fluoxetine, Sibutramine, Sertraline and Dexfenfluramine on The Morphology of Serotonergic Nerve Terminals Using Serotonin Immunohistochemistry.” Brain research 858.1 (2000): 92-105.

82) Collins, Helen M., et al. “Rebound Activation of 5-HT Neurons Following SSRI Discontinuation.” Neuropsychopharmacology (2024): 1-10.

83) Stimpfl, Julia N., et al. “Deprescribing Antidepressants in Children and Adolescents: A Systematic Review of Discontinuation Approaches, Cross-Titration, and Withdrawal Symptoms.” Journal of Child and Adolescent Psychopharmacology (2024).

84) Cosci, Fiammetta, and Guy Chouinard. “Acute and Persistent Withdrawal Syndromes Following Discontinuation of Psychotropic Medications.” Psychotherapy and psychosomatics 89.5 (2020): 283-306.

85) Sharp, Trevor, and Helen Collins. “Mechanisms of SSRI Therapy and Discontinuation.” Emerging Neurobiology of Antidepressant Treatments (2023): 21-47.

86) Greenblatt, James, and Winnie Lee. Integrative Medicine for Depression: A Breakthrough Treatment Plan that Eliminates Depression Naturally. Friesen Press, 2019.

86) Greenblatt, James, Functional Medicine for Antidepressant Withdrawal: An Integrative and Functional Medicine Approach to The Treatment and Prevention of Antidepressant Withdrawal, Friesen Press, June 27, 2022

87) Li, Hongfu, et al. “Lithium-Mediated Long-Term Neuroprotection in Neonatal Rat Hypoxia-Ischemia Is Associated with Antiinflammatory Effects and Enhanced Proliferation and Survival of Neural Stem/Progenitor Cells.” Journal of Cerebral Blood Flow & Metabolism 31.10 (2011): 2106-2115.

88) Diniz, Breno Satler, et al. “Lithium and Neuroprotection: Translational Evidence and Implications For The Treatment Of Neuropsychiatric Disorders.”Neuropsychiatric disease and treatment 9 (2013): 493.

89) Gray, Jason D., and Bruce S. McEwen. “Lithium’s Role In Neural Plasticity And Its Implications For Mood Disorders.” Acta Psychiatrica Scandinavica 128.5 (2013): 347-361.

90) Hajek, T., et al. “Neuroprotective Effect of Lithium on Hippocampal Volumes in Bipolar Disorder Independent of Long-Term Treatment Response.” Psychological Medicine 44.3 (2014): 507-517.

91) Kim, Jin Seuk, et al. “Lithium Selectively Increases Neuronal Differentiation of Hippocampal Neural Progenitor Cells Both In Vitro And In Vivo.” Journal of Neurochemistry 89.2 (2004): 324-336.

92) Yan, Xue-Bo, et al. “Lithium Regulates Hippocampal Neurogenesis by ERK Pathway and Facilitates Recovery of Spatial Learning and Memory in Rats After Transient Global Cerebral Ischemia.” Neuropharmacology 4.53 (2007): 487-495.

93) Quiroz, Jorge A., et al. “Novel Insights into Lithium’s Mechanism of Action: Neurotrophic and Neuroprotective Effects.” Neuropsychobiology 62.1 (2010): 50

94) Fels, Anna. “Should we all take a bit of lithium.” New York Times 14 (2014). https://www.openphilanthropy.org/wp-content/uploads/Opinion-_-Should-We-All-Take-a-Bit-of-Lithium_-The-New-York-Times.pdf

95) Andrews, Paul W., et al. “Primum Non Nocere: An Evolutionary Analysis of Whether Antidepressants Do More Harm Than Good.” Frontiers in Psychology 3 (2012): 117.

96) Bendis, Peyton Christine, et al. “The impact Of Estradiol on Serotonin, Glutamate, And Dopamine Systems.” Frontiers in Neuroscience 18 (2024): 1348551.

97) Plöderl, Martin, et al. “Observational Studies of Antidepressant Use and Suicide Risk Are Selectively Published in Psychiatric Journals.” Journal Of Clinical Epidemiology 162 (2023): 10-18.

98) Turner, Erick H., et al. “Selective publication of antidepressant trials and its influence on apparent efficacy: Updated comparisons and meta-analyses of newer versus older trials.” PLoS medicine 19.1 (2022): e1003886.

99) Paludan-Müller, Asger Sand, et al. “Extensive Selective Reporting of Quality of Life In Clinical Study Reports And Publications Of Placebo-Controlled Trials Of Antidepressants.” International Journal of Risk & Safety in Medicine 32.2 (2021): 87-99.

100) Mnie-Filali, Ouissame, et al. “Long-Term Adaptive Changes Induced by Antidepressants: From Conventional to Novel Therapies.” Mood Disorders (2013).

101) Pan, Lisa A., et al. “Neurometabolic Disorders: Potentially Treatable Abnormalities in Patients with Treatment-Refractory Depression and Suicidal Behavior.” American Journal of Psychiatry 174.1 (2017): 42-50.

102)  Why Are Antidepressants So Harmful? Exploring The Common Side Effects of SSRIS And the Nightmare of Quitting Them. A Midwestern Doctor. Nov 26, 2023, the Forgotten Side of Medicine. https://www.midwesterndoctor.com/p/why-are-antidepressants-so-harmful

103) Then, Chee-Kin, et al. “Antidepressants, Sertraline, And Paroxetine, Increase Calcium Influx And Induce Mitochondrial Damage-Mediated Apoptosis Of Astrocytes.” Oncotarget 8.70 (2017): 115490.

104) Li, Yan, et al. “Mitochondrial Dysfunction Induced By Sertraline, An Antidepressant Agent.” Toxicological Sciences 127.2 (2012): 582-591.

105) Hroudová, Jana, and Zdeněk Fišar. “In Vitro Inhibition of Mitochondrial Respiratory Rate By Antidepressants.” Toxicology letters 213.3 (2012): 345-352.

Jeffrey Dach MD
7450 Griffin Road, Suite 190
Davie, Fl 33314
954-792-4663

my blog: www.jeffreydachmd.com 
Natural Thyroid Toolkit by Jeffrey Dach MD
Cracking Cancer Toolkit by Jeffrey Dach MD
Heart Book by Jeffrey Dach MD
www.naturalmedicine101.com
www.bioidenticalhormones101.com
www.truemedmd.com
www.drdach.com

Click Here for: Dr Dach’s Online Store for Pure Encapsulations Supplements
Click Here for: Dr Dach’s Online Store for Nature’s Sunshine Supplements

Web Site and Discussion Board Links:

jdach1.typepad.com/blog/
disc.yourwebapps.com/Indices/244066.html
disc.yourwebapps.com/Indices/244067.html
http://sci.med.narkive.com/covV2Qo2/jeffrey-dach-book-announcment-natural-medicine-101

Disclaimer

The reader is advised to discuss the comments on these pages with his/her personal physicians and to only act upon the advice of his/her personal physician. Also note that concerning an answer which appears as an electronically posted question, I am NOT creating a physician — patient relationship. Although identities will remain confidential as much as possible, as I can not control the media, I can not take responsibility for any breaches of confidentiality that may occur.

Link to this Article

Copyright © 2024 Jeffrey Dach MD All Rights Reserved. This article may be reproduced on the internet without permission, provided there is a link to this page and proper credit is given. See Repost Guidelines.

FAIR USE NOTICE: This site contains copyrighted material the use of which has not always been specifically authorized by the copyright owner. We are making such material available in our efforts to advance understanding of issues of significance. We believe this constitutes a ‘fair use’ of any such copyrighted material as provided for in section 107 of the US Copyright Law. In accordance with Title 17 U.S.C. Section 107, the material on this site is distributed without profit to those who have expressed a prior interest in receiving the included information for research and educational purposes.

Serving Areas of: Hollywood, Aventura, Miami, Fort Lauderdale, Pembroke Pines, Miramar, Davie, Coral Springs, Cooper City, Sunshine Ranches, Hallandale, Surfside, Miami Beach, Sunny Isles, Normandy Isles, Coral Gables, Hialeah, Golden Beach ,Kendall,sunrise, coral springs, parkland,pompano, boca raton, palm beach, weston, dania beach, tamarac, oakland park, boynton beach, delray,lake worth,wellington,plantation

Published on February 28th, 2025 by Jeffrey Dach MD