The SSRI Antidepressant Hoax, by Jeffrey Dach MD

Mary is a 65 year old retired accountant has been a patient in my office for about 15 years. For the past 20 years she has been taking two different SSRI antidepressant drugs prescribed by her primary care doctor. One day, Mary told me she wanted to get off the SSRI drugs. Since her doctor would not help, would I help her get off the drugs ? I replied, yes of course, I am always happy to provide an SSRI tapering schedule. Without gradual tapering, withdrawal effects can be quite severe, so we try to gradually taper dosage down over least 12 weeks before discontinuing. In Mary’s case, since she is on two separate SSRI drugs, we taper them one at a time.

Header Image: Depression, Selbstporträt (1932) Karl Wiener (Austrian, 1901-1949) The Artist died in 1949 so this work is in the public domain in its country of origin and other countries where the copyright term is the Artist’s life plus 70 years or fewer. Image Courtesy of Artvee.

Caution: DO NOT STOP YOUR SSRI DRUG without gradual tapering under the supervision of your physician.

SSRI Antidepressants Increase Risk for Suicide and Violent Behavior

In my opinion, SSRI antidepressant drugs are dangerous for two reasons. Firstly, they are addictive drugs with mechanism of action similar to cocaine and amphetamines, as they prevent reuptake of neurotransmitters, causing morphological changes in the terminal ends of the neurons. Once the drug is stopped, it takes time for the neurons to recover, thus accounting for the withdrawal effects. For the stronger SSRI drugs such as Effexor (Venlafaxine) which inhibits reuptake of both serotonin and norepinephine, withdrawal effects can include a symptom described as “brain zaps”, electric shock like sensations. These can last for months or years after discontinuing the drug.

Akathisia

The second reason SSRI drugs are dangerous. Similar to amphetamines and other psych drugs, SSRI drugs can cause an adverse effect called Akathisia, a form of agitation often described as a feeling like scraping your fingernails across the blackboard in the classroom. Akathisia is a form of psychomotor psychosis which drives the drug user to suicide, homicide and other violent and bizarre behaviors. Many of the mass shootings reported in the media are the result of Akathisia.(1-2)

Here is video report from 2003 showing one such example:

Fox News: SSRI Antidepressants Causing School Shootings? With Dr. Peter Breggin

The link between SSRI drugs and mass shootings, suicide and homicide has been known for decades, yet largely ignored and even suppressed to preserve the massive drug company profits from this class of drugs.(1-7)

Why Only One Percent of People Become Violent on SSRI drugs?

One might ask the obvious question: most people seem to tolerate SSRI drugs fairly well. Why do SSRI drugs cause a small number people to exhibit suicidal thoughts, hostility and violent behavior ?

In 2021, Dr. Eikelenboom-Schieveld examined this question, finding genetic mutations in the ability to metabolize drugs in one per cent of the population accounts for these people becoming aggressive, hostile, violent and psychotic on SSRI drugs (and other psych drugs as well). 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 drug accumulates, reaching toxic levels in the blood stream. Dr. Eikelenboom-Schieveld writes:

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 [2,18]. Psychoactive medication is mainly metabolized by enzymes generated by CYP450 genes [19]. 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” [2,3,32]. 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.

Why SSRI Drugs Don’t Always Work for Depression?

Amphetamines were the first drugs marketed in the 1950’s as highly effective treatment for depression. The negatives were related to induction of psychotic episodes, and amphetamine addiction with severe drug withdrawal effects. Amphetamines did work quite well as a “pick me up brain stimulant”, which serves quite well as an anti-depressant. Ultimately the neurons adapt to chronic drug use leading to the need for higher doses to reach the same effect. The amphetamine users eventually find themselves in a rehab clinic undergoing drug withdrawal. (3-4)

Serotonin Deficiency and SSRI Drugs

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 than that, and in many cases not caused by lack of serotonin. Causes of depression include endocrine disorders such as HPA dysfunction, low thyroid, low testosterone or low estrogen, inflammatory conditions such as leaky gut, diabetes, etc as described by Dr. Angelos Halaris below. Note HPA= Hypothalamic Pituitary axis.

SSRI Drugs Do Not Work As Marketed – Serotonin Deficiency Not the Cause of Depression

In 2023, Dr. Joanna Moncrieff did a systematic review of the medical literature finding no basis for the serotonin theory of depression, writing:

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. (7)

In a second article in 2023, Dr. Joanna Moncrieff rebuts criticism of her findings, 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 [31,32,33]. 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 [36], now demonstrated even in healthy volunteers [37]…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 [36, 37]. Yet, this approach to marketing drugs by drawing on unproven, implausible single neurotransmitter hypotheses to provide biological justifications for their use continues apace.(8)

Sexual Dysfunction, Emotional Blunting

In addition to increased violence and suicide, adverse side effects of SSRI antidepressants include sexual dysfunction and emotional blunting, two bothersome effects which have largely been ignored by drug researchers and clinicians.

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. In some cases the sexual dysfunction is irreversible after discontinuing the SSRI drug(21)

The author of The Guardian : Observer Mental Health: ‘It feels like we’ve been lobotomised’: the possible sexual consequences of SSRIs , writes:

Long-term sexual dysfunction is a recognised side-effect for some patients who take these widely prescribed antidepressants, and can leave sufferers devastated.  (43)

In a recent interview appearing in the Guardian Observer, Rosie Tilli says:

“I reassured myself that I would be fine as soon as I fully ceased the 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.” end quote Rosie Tilli, emphasis mine. (43)

Dr. McFilin discusses PSSD (Post SSRI Sexual Dysfunction) video below:

In Alex Clark’s (@yoalexrapz) latest podcast, @DrMcFillin mentions #PSSD and its profound impact on sufferers.

He also discusses patients he sees, who lack sexual desire but don’t make the connection to antidepressants that they took as children. pic.twitter.com/Xqb2ulKcDc

— PSSD Network | Post-SSRI Sexual Dysfunction (@PSSDNetwork) January 3, 2024

Emotional Blunting and Personality Changes

One might speculate the 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 people not taking SSRI drugs. SSRI drugs may transform the personality into an unpleasant and obnoxious personality type, a viewpoint supported by the medical literature. (7-8) (18-22)(43)

What Causes Depression and What Are the Treatments?

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, Dr. Angelos Halaris addressed this question writing that current pharmacological intervention (SSRI antidepressants) obtain remission in only 30 percent of patients.

Dr. Angelos Halaris then listed the varied causes of depression as endocrinological aberrations, notably, hypothalamic-pituitary-adrenal (HPA) axis dysregulation and thyroid and gonadal dysfunction. Dr. Angelos Halaris discusses low Vitamin D as contributing to depression, and the utility of genetic testing for Single Nucleotide Polymorphisms in Cytochrome P450, Serotonin Transporter, COMT, folic acid conversion (MTHFR). She also mentions the role of immune system dysregulation and generalized inflammation, and utility of testing for CRP (C reactive Protein) an inflammatory marker, writing:

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)… In this review article, we present new approaches to identify and correct potential causes of TRD, thereby reducing its prevalence and with it the overall burden of this disease entity. We will address potential contributory factors to TRD, most of which can be investigated in many laboratories as routine tests. 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. We focus on established and emerging test procedures, potential biomarkers and non-biologic assessments and interventions to apply personalized medicine to effectively manage treatment resistance in general and TRD specifically…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 [27,28]…Among the most important aspects of the HPA axis that is implicated in MDD is the negative feedback loop in which cortisol starts to act as a suppressor of the HPA axis once it is carried back to the hypothalamus and pituitary via the blood stream. As part of this negative feedback loop, cortisol binds to mineralocorticoid and glucocorticoid receptors (MRs & GRs), inhibiting the release of CRH and ACTH…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 [38]. Dexamethasone is a synthetic glucocorticoid that binds to the GR [gludocorticoid receptor]  in the CNS [central nervous sytem], specifically the hypothalamus and the pituitary gland. Normally, administering synthetic glucocorticoids should activate negative feedback and slowly decrease cortisol levels. If there is HPA axis dysfunction, then cortisol levels will fail to decrease and may actually increase. In the case of MDD and potential characterization of TRD, we suggest that this failure to activate the negative feedback is indicative of HPA axis dysfunction, potentially due to receptor insensitivity [20]. Most studies have demonstrated that severely depressed patients often show non-suppression and impaired feedback inhibition by dexamethasone, which is indicative for dysfunction of corticosteroid receptors, especially GR [39,40]. Other challenge tests include the CRH [corticotropin releasing hormone] test; the combined DEX-CRH test; and the newest test, the prednisolone suppression test (PST). The PST is the gold standard for assessing HPA axis function [20,41] because it is able to measure both the MR and the GR, unlike the other challenge tests…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 [98,99,108,109,110,111]. L-methylfolate, the active form of vitamin B9, is the only form that can cross the blood–brain barrier [112]. Low levels of L-methylfolate are associated with multiple neuropsychiatric diseases, including MDD, schizophrenia and Alzheimer’s. Studies also show that individuals with a deficiency may exhibit inadequate response to antidepressants, perhaps leading to the label of “treatment-resistant”…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” [99,108,110,111]. In fact, L-methylfolate is among the only medical foods licensed by the FDA for the treatment of depression [113,114]…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. Use of an anti-inflammatory agent, preferably a COX-2 inhibitor, may assist in converting TRD to treatment response. (12)

In my opinion, Depression is not a disease. Rather, depression is a symptom of underlying disorder, most commonly inflammatory disorders and mitochondiral dysfunction disorders. Note an overlap between two disorders, Chronic Fatigue and Depression. For all practical purposes they can be regarded as identical syndromes.

Estrogen Replacement for Menopausal Depression

In my office, I frequently see depression symptoms in post-menopausal women 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. Many of these women arrive in my office having been prescribed SSRI anti-depressants for their post-menopausal symptoms of depression. For these women, they are gradually tapered off the SSRI antidepressants while starting treating with bio-identical hormone replacement. Post-menopausal women with depression symptoms do not need SSRI antidepressant drugs. They need hormone replacement which is the correct treatment. Anxiety type mood disturbance is relieved by progesterone. Testosterone replacement may be most efficacious anti-depressant for both men and women. (45-53)

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

The first category of depression/chronic fatige is “Leaky Gut” with elevated inflammatory cytokines which cross the blood-brain barrier causing activation of microglia (inflammation) in the brain.

Left image of activated microglia after LPS infusion from: Qin L, Wu X, Block ML, et. al. Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia. 2007;55(5):453-62.

As recent work by Allesio Fasano has revealed, in susceptible individuals, the ingestion of wheat gluten triggers the release of Zonulin, a hormone which opens the “tight junctions” between epithelial cells of the GI mucosa. 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 blood stream, 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 to release of inflammatory cytokines into the blood stream. This slurry of LPS and inflammatory mediators eventually reaches the cerebral circulation causing inflammation in the brain with activation of micro-glia, disturbance of the autonomic nervous system and neurotransmitter production causing depression, chronic fatigue, autonomic dysfunction and other disorders. See my previous articles on this topic: Depression and Leaky Gut from Michael Maes  and  Low Level Endotoxemia, Depression, Endocrinopathy and Coronary Artery Disease.

Depression Caused by Mitochondrial Dysfunction

The second category of Depression/Chronic Fatigue is caused by disturbance in cellular energy production due to mitochondrial dysfunction or toxicity. These are treatable. These causes include: hypothyroidism, post-menopausal estrogen deficiency, low testosterone in males, HPA dysfunction with low cortisol, and genetic mutations such as MTHFR. Another cause is exposure to mitochondrial toxins such as antibiotics, statins and other drugs. Antibiotics which impair mitochondrial function include flouroquinolones, erythromycin, doxycycline etc. Statin drugs deplete CoQ10, thus acting as a mitochondrial toxin.

Vitamin / Mineral Deficencies: Mitochondrial dysfunction may be caused by deficiencies in vitamin B12, folate, alpha lipoic acid, thiamine, Co-Q10, Iron, selenium and deficiencies in many other co-factors needed for mitochondrial function. These topics are discussed in my previous article: The non-mystery of chronic fatigue syndrome.

Natural Products for Depression

We have found natural products useful in depression. These include Berberine, Cordyceps, Maca, Lithium and 5HTP. (24-26)
Testosterone is perhaps nature’s best antidepressant. Also do not forget caffeine is a commonly used brain stimulant and excellant as an antidepresssant. 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 after taking supplements. Leaky gut with inflammatory cytokines have been linked to depression. We use Food sensitivity testing, gluten free diet, probiotics, and glutamine to heal the gut.

Conclusion: The falsification and abandonment of the serotonin theory of depression has been largely ignored by mainstream medicine which still dispenses SSRI antidepressants as “standard of care”. The SSRI drug market very lucrative, expected to grow to 20 billion annually with 4-8 percent annual growth. The reality is SSRI and SNRI drugs are dangerous, addictive and mostly ineffective for depression. Depression is more complicated than handing out an SSRI drug, as aptly described by Dr. Angelos Halaris (above) 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 simplicfication 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. 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 appropriately as described above.

Articles with Related Content:

Health Benefits of Hormone Replacement

The Non-Mystery of Chronic Fatigue Syndrome

Depression and Leaky Gut from Michael Maes

Low Level Endotoxemia, Depression, Endocrinopathy and Coronary Artery Disease

Berberine Antidote for a Modern Epidemic

SSRI induced Suicide in the Military

SSRI Antideprssants No Better Than Placebo Says Jama

Get OFF SSRI Drugs and Overcome Depression Naturally

Getting Off SSRI Antidepressants

Why Are One in Six on Psych Meds?

Jeffrey Dach MD
7450 Griffin Road Suite 180/190
Davie, Florida 33314
954-792-4663

Links and References:

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Update: 4/16/24: Header Image removed and replaced.   Happy and sad pills in a glass bottle on blue background Author Jernej Furman from Slovenia Copyright Creative Commons

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In case there was any doubt that the purpose of Creative Commons licenses is to facilitate sharing and reuse, and not speculative invoices and lawsuits, it is this: in 2015, the CC organization released the current licenses, Version 4.0, including a “cure provision” that gives people who make attribution mistakes the legal right to a 30-day grace period after notification of the error to make it right.

Also see Flikr Guidelines: On March 31, 2023, Flikr updated their Guidelines giving 30 days “Grace Period” to good-faith users to correct any error in attribution without penalty to prevent “the malpractice of so-called copyright trolls using the threat of litigation to generate income.” (see below link to Flickr updated Community Guidelines). This is the link to the Flickr Guideline: https://www.flickr.com/help/forum/en-us/72157721759096699/

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Emphasis mine

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image: courtesy of midwestern doctor. (6)

1) https://www.youtube.com/watch?v=WAO5_Hk06Mc

Fox News: SSRI Antidepressants Causing School Shootings? With Dr. Peter Breggin

Jan 2, 2013: This clip appears to be from 2003. @ 0:16 the Reporter says “2 yrs ago…” – the reference was to 4/15/2001 when 16yr old Cory Baadsgaard took a gun to school. So why the reluctance to question a possible link now? Or for the past few years? Trivia: The Reporter is Douglas Kennedy, Robert F Kennedy’s 10th child.

2) 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.

“Both clinical trial and pharmacovigilance data point to possible links between these drugs and violent behaviours… Many jurisdictions appear not to have considered the possibility that a prescription drug may induce violence…more

…In these trials, hostile events are found to excess in both adults and children on paroxetine compared with placebo & are found across indications, & both on therapy & during withdrawal. The rates were highest in children with obsessive-compulsive disorder (OCD), where the odds ratio of a hostile event was 17 times greater…more

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3) 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.

4) 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.

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;

From the start of the use of psychoactive prescription medications in the 1950s, physicians reported paradoxical adverse reactions, ranging from newly developing depressions to an increase in existing mood disorders, and extremely violent and bizarre acts of suicide and homicide. It is hypothesized that interactions between the drugs and the enzymes that are primarily responsible for their metabolism (cytochrome P450s) could cause these reactions.

Most psychoactive medication is metabolized by enzymes produced by the P450 family (CYP450 or P450). Certain allelic variants for CYP450 genes cause deviation in the rate at which prescription medication is metabolized. Most of the alternate alleles produce enzymes with reduced or no metabolic capability, although some enzymes metabolize substrates faster than normal to super-fast. Variant alleles can lead to toxic drug levels and adverse drug reactions in some patients, or to subtherapeutic levels and non-treatment responses in others [1]. By genotyping the polymorphisms at certain P450 loci, it might be possible to predict if an individual is susceptible for adverse drug reactions.

Violence is a known side effect of psychoactive medication, as is recognized in the literature [2,18]. Psychoactive medication is mainly metabolized by enzymes generated by CYP450 genes [19]. 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” [2,3,32]. 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.

In summary, this research identified four risk factors for acts of violence and/or an altered emotional state:

More than four variant alleles for the six tested CYP450s;
More than two drugs, especially when an antidepressant or other psychoactive medication is prescribed;
Having an intermediate metabolizer (IM) phenotype at CYP3A4;
Fluctuations in the levels of psychoactive medication in the blood.

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 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.

There is an association between prescription drugs (most notably antidepressants and other psychoactive medication), having variant alleles for CYP450 genes, and altered emotional states or acts of violence.

5) 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.

6) 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

Selective serotonin reuptake inhibitors (SSRIs) have a similar primary mechanism of action to cocaine. SSRIs block the reuptake of Serotonin, SNRIs, also commonly prescribed block the reuptake of Serotonin and Norepinephrine (henceforth “SSRI refers to both SSRI and SNRI), and Cocaine blocks the reuptake of Serotonin, Norepinephrine, and Dopamine.

Once the first SSRI entered the market in 1988, Prozac quickly distinguished itself as a particularly dangerous medication and after nine years, the FDA received 39,000 adverse event reports for Prozac, a number far greater than for any other drug. This included hundreds of suicides, atrocious violent crimes, hostility and aggression, psychosis, confusion, distorted thinking, convulsions, amnesia, and sexual dysfunction (long-term or permanent sexual dysfunction is one of the most commonly reported side effects from anti-depressants, which is ironic given that the medication is supposed to make you less, not more depressed).

Lastly, for anyone who reads this article that is presently taking any SSRI or SNRI, it is critically important to NOT suddenly stop taking them. These addictive drugs produce very strong withdrawal symptoms, and there are many cases of catastrophic events that followed the abrupt discontinuation of an SSRI. If this is something you ever wish to do, you need to gradually taper down the dosage with a physician who has experience in this area.

Akathisia (and psychosis) are known side effects of cocaine, methamphetamine, SSRIs, antipsychotics, and ADHD stimulant medications.

Individuals with a mutation in the gene that metabolizes psychiatric drugs are much more vulnerable to developing excessive levels of these drugs and triggering severe symptoms such as akathisia and psychosis. There is a good case to be made that individuals with this gene are responsible for many of the horrific acts of iatrogenic (medically induced) violence that occur, however to my knowledge, this is never considered when psychiatric medications are prescribed.

FDA insert explicitly lists the following as side effects of Effexor (an SNRI): intentional injury, malaise, suicide attempt, depersonalization, abnormal thinking, akathisia, apathy, ataxia, CNS stimulation, emotional lability, hostility, manic reaction, psychosis, suicidal ideation, abnormal behavior, adjustment disorder (which became a psychiatric diagnosis for her, although it was a side effect), akinesia, increased energy, homicidal ideation, and impulse control difficulties.

violent actions following the usage of SSRIs may be explained by their tendency to trigger akathisia, emotional blunting, and manic or psychotic reactions.

SSRI caused violence was repeatedly detected in the clinical trials for these drugs, but covered up by both the pharmaceutical industry and the FDA. As discussed in the above article, it only became known because lawsuits forced the manufactures to reveal it.

but do not attempt to stop taking an SSRI without the assistance of a physician who understands how to taper them. Very bad things can happen if you do not follow that advice.

SSRI Drugs Do Not Work As Marketed – Serotonin Deficiency Not the Cause of Depression

7) Moncrieff, Joanna, et al. “The serotonin theory of depression: a systematic umbrella review of the evidence.” Molecular psychiatry 28.8 (2023): 3243-3256.

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.

8)  Moncrieff, Joanna, et al. “The serotonin hypothesis of depression: both long discarded and still supported?.” Molecular Psychiatry (2023): 1-4.

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 [31,32,33]. 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 [36], now demonstrated even in healthy volunteers [37].

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 [36, 37]. Yet, this approach to marketing drugs by drawing on unproven, implausible single neurotransmitter hypotheses to provide biological justifications for their use continues apace.

9) Mnie-Filali, Ouissame, et al. “Long-term adaptive changes induced by antidepressants: From conventional to novel therapies.” Mood Disorders (2013).

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Depression: The 5 Biotypes

10) The 5 Depression Biotypes

Undermethylation
The most common biotype, these folks tends to see improvement with SSRI’s. The problem in these cases is low activity at serotonin receptors due to rapid reabsorption after serotonin is released into a synapse; as well as high blood levels of histamine, another neurotransmitter. It’s actually not so much a serotonin deficiency, but an inability to keep serotonin in the synapse long enough.

Pyrrole Disorder

\\\\\\This biotype also tends to see improvement with SSRI’s. Pyrolurics exhibit a combination of impaired serotonin production and extreme oxidative stress. These individuals have elevated urine pyrroles coupled with severe zinc and vitamin B-6 deficiency. …This type is the fastest to respond to treatment.

Copper Overload
High copper folks cannot properly metabolize metals. Most of these people say that SSRI’s do not have much of an effect either way, but they report benefits from normalizing their copper levels through nutrient therapy.

Overmethylation (folate deficiency)
This biotype tends to get worse on SSRIs, while folic acid supplements help. A study of 50 school shootings over the past five decades showed that most shooters probably had this type of depression, as SSRI’s can cause suicidal or homicidal ideation in these people.

Toxic Metal Overload
Food Intolerances (gluten, dairy, and naturally occurring plant-based chemicals such as salicylates and oxalates, to name a few)
Blood Sugar Dysregulation (hypo or hyperglycemia)
Gut pathogens (such as yeast and bacterial overgrowth)
Thyroid diseases and imbalances

Depression: The 5 Biotypes By Samantha Gilbert, FNC, CHNP, CNC / May 20, 2014

Born with epigenetic disorders, I struggled with depression for most of my life.

Over the years I’ve tried a variety of antidepressants such as Prozac and Zoloft, as well as amino acid therapy (5-HTP, etc.), and other herbal remedies such as St. John’s Wort.

Some helped a bit, which was a clue to my undermethylation status, but they had nasty side-effects and over time, actually made me feel worse.

11) 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.

low CSF 5-methyltetrahydrofolate (5-MTHF) levels. All patients with cerebral folate deficiency, including one with low CSF levels of 5-MTHF and tetrahydrobiopterin intermediates, showed improvement in depression symptom inventories after treatment with folinic acid; the patient with low tetrahydrobiopterin also received sapropterin.

12) Halaris, Angelos, Emilie Sohl, and Elizabeth A. Whitham. “Treatment-resistant depression revisited: a glimmer of hope.” Journal of personalized medicine 11.2 (2021): 155.

Major Depressive Disorder (MDD) is a highly prevalent psychiatric disorder worldwide. It causes individual suffering, loss of productivity, increased health care costs and high suicide risk. 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). The burden of TRD exponentially increases the longer it persists, with a higher risk of impaired functional and social functioning, vast losses in quality of life and significant risk of somatic morbidity and suicidality. Different approaches have been suggested and utilized, but the results have not been encouraging. In this review article, we present new approaches to identify and correct potential causes of TRD, thereby reducing its prevalence and with it the overall burden of this disease entity. We will address potential contributory factors to TRD, most of which can be investigated in many laboratories as routine tests. 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. We focus on established and emerging test procedures, potential biomarkers and non-biologic assessments and interventions to apply personalized medicine to effectively manage treatment resistance in general and TRD specifically.

As mentioned above, among the most consistent biological changes in MDD patients is increased plasma cortisol and overall dysregulation of the HPA axis [27,28].
Among the most important aspects of the HPA axis that is implicated in MDD is the negative feedback loop in which cortisol starts to act as a suppressor of the HPA axis once it is carried back to the hypothalamus and pituitary via the blood stream. As part of this negative feedback loop, cortisol binds to mineralocorticoid and glucocorticoid receptors (MRs & GRs), inhibiting the release of CRH and ACTH.

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 [38]. Dexamethasone is a synthetic glucocorticoid that binds to the GR in the CNS, specifically the hypothalamus and the pituitary gland. Normally, administering synthetic glucocorticoids should activate negative feedback and slowly decrease cortisol levels. If there is HPA axis dysfunction, then cortisol levels will fail to decrease and may actually increase. In the case of MDD and potential characterization of TRD, we suggest that this failure to activate the negative feedback is indicative of HPA axis dysfunction, potentially due to receptor insensitivity [20]. Most studies have demonstrated that severely depressed patients often show non-suppression and impaired feedback inhibition by dexamethasone, which is indicative for dysfunction of corticosteroid receptors, especially GR [39,40]. Other challenge tests include the CRH test; the combined DEX-CRH test; and the newest test, the prednisolone suppression test (PST). The PST is the gold standard for assessing HPA axis function [20,41] because it is able to measure both the MR and the GR, unlike the other challenge tests.

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 [98,99,108,109,110,111]. L-methylfolate, the active form of vitamin B9, is the only form that can cross the blood–brain barrier [112]. Low levels of L-methylfolate are associated with multiple neuropsychiatric diseases, including MDD, schizophrenia and Alzheimer’s. Studies also show that individuals with a deficiency may exhibit inadequate response to antidepressants, perhaps leading to the label of “treatment-resistant”

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” [99,108,110,111]. In fact, L-methylfolate is among the only medical foods licensed by the FDA for the treatment of depression [113,114].

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. Use of an anti-inflammatory agent, preferably a COX-2 inhibitor, may assist in converting TRD to treatment response.

13) Jain, Rakesh, Sloan Manning, and Andrew J. Cutler. “Good, better, best: clinical scenarios for the use of L-methylfolate in patients with MDD.” CNS spectrums 25.6 (2020): 750-764.

Recent clinical trials have highlighted the involvement of folate in MDD pathophysiology, and
the benefits of supplemental use of L-methylfolate, the biologically active form of folate, in
patients with depression.
• Adjunctive therapy with L-methylfolate may be of particular benefit for patients with SSRIresistant
MDD, low folate levels, and/or identified biologic markers associated with inflammation/
obesity and/or folate metabolism gene polymorphisms

14) Lam, Nelson Siu Kei, et al. “The potential use of folate and its derivatives in treating psychiatric disorders: A systematic review.” Biomedicine & Pharmacotherapy 146 (2022): 112541.

15) Altaf, Rabail, et al. “Folate as adjunct therapy to SSRI/SNRI for major depressive disorder: Systematic review & meta-analysis.” Complementary therapies in medicine 61 (2021): 102770.

16) 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.

It was concluded that L-methyl folate with Sertraline was more successful in relieving depression symptoms and function than mono-therapy group led to substantial symptomatic improvement faster and better tolerated than single drug.

17) https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2022.1054726/full
Sun, Yilu, Jia Zhao, and Jianhui Rong. “Dissecting the molecular mechanisms underlying the antidepressant activities of herbal medicines through the comprehensive review of the recent literatures.” Frontiers in Psychiatry 13 (2022): 1054726.

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https://ajp.psychiatryonline.org/doi/full/10.1176/ajp.155.3.373

18) Knutson, Brian, et al. “Selective alteration of personality and social behavior by serotonergic intervention.” American Journal of Psychiatry 155.3 (1998): 373-379.

19) Harmer, C. J., et al. “Acute SSRI administration affects the processing of social cues in healthy volunteers.” Neuropsychopharmacology 28.1 (2003): 148-152.

20) https://jamanetwork.com/journals/jamapsychiatry/fullarticle/210469
Tang, Tony Z., et al. “Personality change during depression treatment: a placebo-controlled trial.” Archives of general psychiatry 66.12 (2009): 1322-1330.

The efficacy of SSRIs in mild or moderate cases has been disputed. A 2010 meta-analysis states that “The magnitude of benefit of antidepressant medication compared with placebo … may be minimal or nonexistent, on average, in patients with mild or moderate symptoms.

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21) https://www.sciencedirect.com/science/article/pii/S2666915324000350
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.

∼19% of respondents reported treatment-emergent sexual dysfunction with ≥1 AD

22) Antidepressants Increase the Risk of Suicide and Violence at All Ages By Peter C. Gøtzsche, MD – November 16, 2016

Although the drug industry, our drug regulators and leading psychiatrists have done what they could to obscure these facts(2), it can no longer be doubted that antidepressants are dangerous and can cause suicide and homicide at any age(2,10,11). Antidepressants have many other important harms and their clinical benefit is doubtful(2). Therefore, my conclusion is that they shouldn’t be used at all. It is particularly absurd to use drugs for depression that increase the risk of suicide when we know that psychotherapy decreases the risk of suicide(12). The psychotherapy trials have been criticised for lack of blinding(12) but it is difficult to blind such trials. Furthermore, suicidality is a pretty hard outcome.

We should do our utmost to avoid putting people on antidepressant drugs and to help those who are already on them to stop by slowly tapering them off under close supervision. People with depression should get psychotherapy and psychosocial support, not drugs.

Natural Products for Depression

!!!!!!!!!!!!!!!!!!!!!!!!!! good !!!!!!!!!!!!!!!!!!!!!!!

23) Noori, Tayebeh, et al. “The role of natural products in treatment of depressive disorder.” Current neuropharmacology 20.5 (2022): 929-949.

24) 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.

25) Depression: Psychiatry’s Discredited Theories and Drugs Versus a Sane Model and Approach By Bruce Levine, PhD – February 24, 2024

26) 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).

A 2022 large study, lead-authored by Marc Stone at the FDA’s Center for Drug Evaluation and Research, examined 232 drug-company trials on antidepressants submitted to the FDA between 1979 and 2016. Even in these drug-company studies, Stone and his co-researchers found that only “15% of participants have a substantial antidepressant effect beyond a placebo effect.”

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Lithium

27) Trujillo-Estrada, Laura, et al. “Lithium, as a neuroprotective therapy for Alzheimer’s disease pathology, modifies abeta plaque toxicity.” (2014).
Lithium, as a neuroprotective therapy for Alzheimer’s disease pathology, modifies abeta plaque toxicity Author: Trujillo-Estrada, Laura; De Castro, Vanesa; Jimenez, S; Sanchez-Varo, Raquel; Sanchez-Mejias, Elisabet; Vizuete, Marisa; Vitorica, Javier; Gutierrez, Antonia Abstract: BACKGROUND: Despite the relatively large information about the Alzheimer’s disease (AD) pathology, no effective disease-modifying treatment has been yet developed. Lithium, a primary drug to treat bipolar disorder, has been suggested as a potential treatment against AD. In this work we have evaluated whether lithium treatment could ameliorate the neuropathology progression of the transgenic PS1M146L/APPSwe-London mice. Unlike most transgenic animal models, which do not exhibit the neurodegenerative spectrum of disease observed in the patient population, this AD model exhibits a prominent amyloid pathology along with a selective and significant neuronal loss in the hippocampus and entorhinal cortex. Therefore, this model is highly valuable for evaluating the effectiveness of potential neuroprotective therapies for AD. METHODS: For lithium treatment, PS1/APP mice (3 month old at the beginning of treatment) were fed, ad libitum, with diet supplemented with lithium carbonate (1.2g/kg, Harlan, Spain). The treatment lasts 6 months. After behavioural studies, mice were anesthetized and brains dissected out (hippocampus and cortex). Hemibrains were processed for immunohistochemistry, stereological and image analysis quantification, and the other hemibrains for RT-PCR and Western blot studies. RESULTS: Our data demonstrate that chronic oral administration of lithium, before the pathology onset, resulted in less toxic plaque formation that significantly ameliorated the degenerative processes and behavioural/memory deficits occurring during disease progression in our PS1/APP model. Specifically, and of great relevance for AD prevention, early lithium intervention was able to arrest neuronal loss in hippocampus and entorhinal cortex of highly vulnerable populations. Besides, lithium reduced the axonal dystrophic pathology, associated to amyloid plaques, by increasing the Abeta compaction. Moreover, a significant lower accumulation of phospho-tau, LC3-II and ubiquitinated proteins was detected. Our study highlights that the switch of plaque quality by lithium could be mediated by astrocyte activation and the release of heat shock proteins, which concentrated in the core of the plaques. – See more at: http://dspace.uma.es/xmlui/handle/10630/7753#sthash.Oq7YigW6.dpuf

28)
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.
In summary, lithium conferred impressive, morphological long-term protection against neonatal HI, at least partly by inhibiting inflammation and promoting NSPC proliferation and survival.

29) Leeds, Peter R., et al. “A new avenue for lithium: intervention in traumatic brain injury.” ACS chemical neuroscience 5.6 (2014): 422-433.
lithium has been shown to reduce neuronal death, microglial activation, cyclooxygenase-2 induction, amyloid-ß (Aß), and hyperphosphorylated tau levels, to preserve blood-brain barrier integrity, to mitigate neurological deficits and psychiatric disturbance, and to improve learning and memory outcome. Given that lithium exerts multiple therapeutic effects across an array of CNS disorders, including promising results in preclinical models of TBI, additional clinical research is clearly warranted to determine its therapeutic attributes for combating TBI. Here, we review lithium’s exciting potential in ameliorating physiological as well as cognitive deficits induced by TBI.

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30) Forlenza, Orestes Vicente, Vanessa de Jesus Rodrigues De-Paula, and B. S. O. Diniz. “Neuroprotective effects of lithium: implications for the treatment of Alzheimer’s disease and related neurodegenerative disorders.” ACS chemical neuroscience 5.6 (2014): 443-450.
Conclusions:
Converging lines of evidence derived from preclinical and clinical models support the rationale for the study of the protective effects of lithium in neuropsychiatric conditions associated with chronic degeneration of the central nervous system.

31) Diniz, Breno Satler, Rodrigo Machado-Vieira, and Orestes Vicente Forlenza. “Lithium and neuroprotection: translational evidence and implications for the treatment of neuropsychiatric disorders.” Neuropsychiatric disease and treatment 9 (2013): 493.
In the last two decades, a growing body of evidence has shown that lithium has several neuroprotective effects. Several neurobiological mechanisms have been proposed to underlie these clinical effects. Evidence from preclinical studies suggests that neuroprotection induced by lithium is mainly related to its potent inhibition of the enzyme glycogen synthase kinase-3ß (GSK-3ß) and its downstream effects, ie, reduction of both tau protein phosphorylation and amyloid-ß42 production. Additional neuroprotective effects include increased neurotrophic support, reduced proinflammatory status, and decreased oxidative stress. More recently, neuroimaging studies in humans have demonstrated that chronic use is associated with cortical thickening, higher volume of the hippocampus and amygdala, and neuronal viability in bipolar patients on lithium treatment. In line with this evidence, observational and case registry studies have shown that chronic lithium intake is associated with a reduced risk of Alzheimer’s disease in subjects with bipolar disorder. Evidence from recent clinical trials in patients with mild cognitive impairment suggests that chronic lithium treatment at subtherapeutic doses can reduce cerebral spinal fluid phosphorylated tau protein. Overall, convergent lines of evidence point to the potential of lithium as an agent with disease modifying properties in Alzheimer’s disease.

32) 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.

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33) Suwalska, A., et al. “Neuroprotective effect of lithium on hippocampal volumes in bipolar disorder independent of long-term treatment response.”

Among BD participants with substantial illness burden, the group with no or limited lifetime exposure  to Li had smaller hippocampal volumes than the Li-treated BD participants, who had hippocampal volumes comparable to controls. These results
raise the possibility that the effects of Li on hippocampal
volumes may generalize to patients with neuropsychiatric illnesses other than BD.

http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-10-131
34) Khasraw, Mustafa, et al. “Using lithium as a neuroprotective agent in patients with cancer.” BMC medicine 10.1 (2012): 131.

Lithium exerts neuroprotective effects and is associated with less cognitive loss in various brain-injury models, including after cranial irradiation [30, 31]. In addition, neural stem/progenitor cells positively respond to lithium treatment under basal conditions [32, 33]. In addition to evidence from animal studies, neuroimaging research in humans supports the observation that lithium exerts neuroprotective effects. One study used three-dimensional magnetic resonance imaging and brain segmentation to evaluate increases in the effect of lithium on grey-matter volume in patients with bipolar mood disorder. The use of 4 weeks of lithium treatment was shown to increase brain grey-matter content [34] and hippocampal volume [35]. The authors concluded that increases in grey matter probably occurred as a result of neurotrophic effects.

Lithium was found to protect irradiated hippocampal neurons in mice from apoptosis, resulting in better performance in learning and memory function [31]. Lithium is known to reduce oxidative stress, specifically via the glutathione system [36]. In bipolar disorder, lithium has been shown to prevent the loss of cortical grey matter that occurs as part of the neuroprogressive cascade in the disorder [37].

Lithium-induced neural progenitor proliferation in vitro suggests that similar effects might occur in vivo, and this action could also be related to its clinical efficacy [39]. In animal studies, the effect of lithium treatment is partly mediated by inhibiting inflammation and by promoting proliferation and survival of neural stem and progenitor cells [44]. Lithium was shown to increase progenitor, rather than stem-cell, proliferation in both non-ischemic and ischemic rat brains [44].

Glycogen synthase kinase (GSK)-3 has been shown to be an essential mediator of neural progenitors during brain development.

Clinical data on the potential neuroprotective effect of lithium

There are limited prospective clinical data on the use of lithium as a neuroprotectant. Several small imaging studies have shown that patients with bipolar disorder treated with long-term lithium therapy have fewer structural changes on brain imaging compared with patients with bipolar disorder of at least 2 years in duration who received lithium for less than 3 months. Patients with bipolar disorder who were not treated with lithium were found to have smaller left hippocampal volumes than controls (corrected P<0.05). The study included 17 patients with bipolar disorder who had at least 2 years of lithium therapy, compared with 12 patients with bipolar disorder who had less than 3 months of lifetime lithium exposure. The group treated with lithium had hippocampal volumes similar to those of 11 healthy controls and of young, lithium-naïve patients [56]. In a similar study, measurement of left prefrontal N-acetyl aspartate (NAA) levels was performed using magnetic resonance spectroscopy at 1.5 T. The study included 27 participants treated with lithium, 16 participants not treated with lithium (<3 months exposure) and 21 healthy controls. The non-lithium group had lower prefrontal NAA levels than the lithium-treated group (P<0.01) or control group (P<0.05) [57].

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35) Falk, Anna, and Jonas Frisén. “New neurons in old brains.” Annals of medicine 37.7 (2005): 480-486.

Altman and colleagues suggested in the 1960s, contrary to the dogma posed by the founding fathers of neuroscience, that neurons were added in the olfactory bulb and the hippocampus of adult rodents (1).

It was not until the 1990s, with the introduction of novel techniques and the unequivocal demonstration of adult-born neurons by many laboratories that this concept gained full acceptance.

About fifteen years ago the thymidine analogue 5-bromo-3’-deoxyuridine (BrdU) was introduced BrdU is also incorporated in the DNA of the dividing cell and can be visualized with immunohistochemical techniques.

Imaging studies have demonstrated changes in the volume of distinct brain areas in response to, for example, training of a certain task (15) and in major depression (16).

In a seminal study in 1998 Eriksson and colleagues for the first
time demonstrated neurogenesis in the adult human hippocampus by BrdU labeling (17).

Therefore, the time of birth of a population of cells can be established retrospectively by the analysis of 14C in genomic DNA (7).

Stem cells in the adult brain The neurons generated in adulthood derive from stem or progenitor cells. Neural stem cells are
immature cells that have the potential to generate the main cell types of the central nervous system: neurons, astrocytes and oligodendrocytes (23,24).

The neurons that continuously are added to the hippocampus derive from local resident stem cells present in the subgranular zone of the dentate gyrus (24,34–36). The neurons that are added to the olfactory bulb derive from stem cells residing in the
lateral wall of the lateral ventricles, from where they migrate along the rostral migratory stream to the olfactory bulb (37–39).

Learning, enriched environment and physical activity stimulate the generation of adult born neurons in the hippocampus (48–50). Upon stress and ageing the level of glucocorticoids is raised, and high levels of adrenal steroids decrease the number of proliferating cells in the dentate gyrus (51–54).

neurogenesis may be important for certain aspects of memory formation (59). Moreover, it was suggested that depression leads to reduced neurogenesis in the hippocampus, and that
the behavioral effects of many antidepressants may
be mediated by the stimulation of neurogenesis in
the hippocampus (16).

Our view of the adult brain has changed with the realization of the presence of endogenous stem cells and continuous neurogenesis in certain regions.’

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36) Neuropharmacology. 2012 Jan;62(1):21-34. doi: 10.1016/j.neuropharm.2011.09.003. Epub 2011 Sep 19. The neurogenesis hypothesis of affective and anxiety disorders: are we mistaking the scaffolding for the building?  Petrik D1, Lagace DC, Eisch AJ.
Hypotheses are scaffoldings erected in front of a building and then dismantled when the building is finished. They are indispensable for the workman; but you mustn’t mistake the scaffolding for the building. Johann Wolfgang von Goethe. The neurogenesis hypothesis of affective disorders – in its simplest form – postulates that the generation of neurons in the postnatal hippocampal dentate gyrus is involved in the etiology and treatment efficacy of major depressive disorder (MDD). The hypothesis was established in the 1990s but was built on a broad foundation of earlier research on the hippocampus, serotonin and MDD. It has gone through several growth phases fueled by discoveries both correlative and causative in nature. Recently, the hypothesis has also been broadened to also include potential relevance for anxiety disorders, like post-traumatic stress disorder (PTSD). As any hypothesis should be, it has been tested and challenged, sometimes vigorously. Here we review the current standing of the neurogenesis hypothesis of affective and anxiety disorders, noting in particular how a central postulate – that decreased neurogenesis results in depression or anxiety – has, in general, been rejected. We also review the controversies on whether treatments for these disorders, like antidepressants, rely on intact neurogenesis for their efficacy, and the existence of neurogenesis-dependent and -independent effects of antidepressants. In addition, we review the implications that the hypothesis has for the response to stress, PTSD, and the neurobiology of resilience, and highlight our own work showing that adult-generated neurons are functionally important for the behavioral response to social stress. We conclude by emphasizing how advancements in transgenic mouse technology, rodent behavioral analyses, and our understanding of the neurogenesis process will allow us to refine our conclusions and perform ever more specific experiments. Such scrutiny is critical, since if we “mistake the scaffolding for the building” we could overlook opportunities for translational impact in the clinic. This article is part of a special Issue entitled ‘Anxiety and Depression’.

37) Eisch, Amelia J., and David Petrik. “Depression and hippocampal neurogenesis: a road to remission?.” Science (New York, NY) 338.6103 (2012): 72.

“the neurogenic hypothesis of depression”.

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
38) Boldrini, Maura, et al. “Benzodiazepines and the potential trophic effect of antidepressants on dentate gyrus cells in mood disorders.” International Journal of Neuropsychopharmacology 17.12 (2014): 1923-1933.

39) Biol Psychiatry. 2003 Sep 1;54(5):499-503.
Depressed new neurons–adult hippocampal neurogenesis and a cellular plasticity hypothesis of major depression. Kempermann G1, Kronenberg G. 1Max Delbrück Center for Molecular Medicine Berlin-Buch, and Department of Experimental Neurology, Charité University Hospital, Humboldt University, Berlin, Germany.
In a novel theory, a failure of adult hippocampal neurogenesis has been proposed to provide the biological and cellular basis of major depression. The as yet unresolved function of the new hippocampal neurons will have to be in the center of any attempt to prove this hypothesis. Only knowledge of normal functional relevance of new neurons will allow an assessment of their potential role in disturbed hippocampal function in depression; however, major depression is not primarily a hippocampal disorder. We therefore propose that consideration of the neurogenesis hypothesis of depression be the most prominent aspect of a more general cellular plasticity hypothesis.

40) Boldrini, Maura, et al. “Hippocampal angiogenesis and progenitor cell proliferation are increased with antidepressant use in major depression.” Biological psychiatry 72.7 (2012): 562-571.
Antidepressants increase human hippocampal NPCs and angiogenesis selectively in the anterior and mid DG. These results raise the possibility of a causal relationship between angiogenesis and neurogenesis, as seen in other proliferating tissues, and support their possible role in the mechanism of action of antidepressants.

full free pdf
41) Mahar,Ian, et al. “Stress, serotonin, and hippocampal neurogenesis in relation to depression and antidepressant effects.” Neuroscience & Biobehavioral Reviews 38 (2014): 173-192.

Changes in Morphology of Serotonigeric Nerve Terminals

42) Brain Res. 2000 Mar 6;858(1):92-105.
Comparative study of fluoxetine, sibutramine, sertraline and dexfenfluramine on the morphology of serotonergic nerve terminals using serotonin immunohistochemistry.
Kalia M, O’Callaghan JP, Miller DB, Kramer M. Department of Biochemistry, Molecular Pharmacology and Anesthesiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA.

We compared the effects of treatment with high doses of fluoxetine, sibutramine, sertraline, and dexfenfluramine for 4 days on brain serotonergic nerve terminals in rats. Methylenedioxymethamphetamine (MDMA) and 5,7-dihydroxytryptamine (5,7-DHT) were used as positive controls because both compounds deplete brain serotonin. Food intake and body weight changes were also monitored and yoked, pair-fed animals were used to control for possible changes in morphology due to nutritional deficits. Fluoxetine, sibutramine, sertraline and dexfenfluramine all produced a significant reduction in body weight. Fluoxetine, sibutramine and sertraline treatment resulted in no depletion of brain serotonin but produced morphological abnormalities in the serotonergic immunoreactive nerve network. In contrast, dexfenfluramine and MDMA depleted brain serotonin and produced morphological changes in the serotonin nerve network. These results indicate that even though fluoxetine, sibutramine and sertraline do not deplete brain serotonin, they do produce morphological changes in several brain regions (as identified by serotonin immunohistochemistry). Dexfenfluramine and MDMA, on the other hand, markedly deplete brain serotonin and also produce morphological changes. Collectively, these results lend support to the concept that all compounds acting on brain serotonin systems, whether capable of producing serotonin depletion or not, could produce similar effects on the morphology of cerebral serotonin systems.

SSRI Induced Sexual Dysfunction

43) The Observer Mental health: ‘It feels like we’ve been lobotomised’: the possible sexual consequences of SSRIs
Long-term sexual dysfunction is a recognised side-effect for some patients who take these widely prescribed antidepressants, and can leave sufferers devastated. So why is there so little help available?

“I reassured myself that I would be fine as soon as I fully ceased the 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.” Rosie Tilli post-SSRI sexual dysfunction (PSSD), where both men and women who have taken various SSRIs have been left with sexual problems, persisting for years or even decades.

Midwestern Doctor

44)  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

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45) Gnanasegar, Rahavi, et al. “Does menopause hormone therapy improve symptoms of depression? Findings from a specialized menopause clinic.” Menopause 31(4)(2024):320-325

46) Herson, Megan, and Jayashri Kulkarni. “Hormonal agents for the treatment of depression associated with the menopause.” Drugs & Aging 39.8 (2022): 607-618.

free pdf
47) Gordon, Jennifer L., and Susan S. Girdler. “Hormone replacement therapy in the treatment of perimenopausal depression.” Current psychiatry reports 16 (2014): 1-7.

48) 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.

49) Halbreich, Uriel, and Linda S. Kahn. “Role of estrogen in the aetiology and treatment of mood disorders.” CNS drugs 15 (2001): 797-817.
There is growing evidence suggesting that estrogen may be efficacious as a sole antidepressant for depressed perimenopausal women.

50)) Wieland, Scott, et al. “Anxiolytic activity of the progesterone metabolite 5α-pregnan-3α-ol-20-one.” Brain research 565.2 (1991): 263-268.

51) 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.

52) Studd, John, and N. Panay. “Hormones and depression in women.” Climacteric 7.4 (2004): 338-346.

53) Walther, Andreas, Jonas Breidenstein, and Robert Miller. “Association of Testosterone Treatment With Alleviation of Depressive Symptoms in Men: A Systematic Review and Meta-analysis.” JAMA psychiatry 76.1 (2019): 31-40.

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Lithium

J Neurochem. 2000 Oct;75(4):1729-34.
Enhancement of hippocampal neurogenesis by lithium.
Chen G1, Rajkowska G, Du F, Seraji-Bozorgzad N, Manji HK.
Increasing evidence suggests that mood disorders are associated with a reduction in regional CNS volume and neuronal and glial cell atrophy or loss. Lithium, a mainstay in the treatment of mood disorders, has recently been demonstrated to robustly increase the levels of the cytoprotective B-cell lymphoma protein-2 (bcl-2) in areas of rodent brain and in cultured cells. In view of bcl-2’s antiapoptotic and neurotrophic effects, the present study was undertaken to determine if lithium affects neurogenesis in the adult rodent hippocampus. Mice were chronically treated with lithium, and 5-bromo-2-deoxyuridine (BrdU) labeling of dividing cells was conducted over 12 days. Immunohistochemical analysis was undertaken 1 day after the last injection, and three-dimensional stereological cell counting revealed that lithium produced a significant 25% increase in the BrdU-labeled cells in the dentate gyrus. Double-labeling immunofluorescence studies were undertaken to co-localize BrdU-positive cells with neuron-specific nuclear protein and showed that approximately 65% of the cells were double-labeled. These results add to the growing body of evidence suggesting that mood stabilizers and antidepressants exert neurotrophic effects and may therefore be of use in the long-term treatment of other neuropsychiatric disorders.

J Neurochem. 2004 Apr;89(2):324-36.
Lithium selectively increases neuronal differentiation of hippocampal neural progenitor cells both in vitro and in vivo.
Kim JS1, Chang MY, Yu IT, Kim JH, Lee SH, Lee YS, Son H.
Lithium has been demonstrated to increase neurogenesis in the dentate gyrus of rodent hippocampus. The present study was undertaken to investigate the effects of lithium on the proliferation and differentiation of rat neural progenitor cells in hippocampus both in vitro and in vivo. Lithium chloride (1-3 mM) produced a significant increase in the number of bromodeoxyuridine (BrdU)-positive cells in high-density cultures, but did not increase clonal size in low-density cultures. Lithium chloride at 1 mM (within the therapeutic range) also increased the number of cells double-labeled with BrdU antibody and TuJ1 (a class III beta-tubulin antibody) in high-density cultures and the number of TuJ1-positive cells in a clone of low-density cultures, whereas it decreased the number of glial fibrillary acidic protein-positive cells in both cultures. These results suggest that lithium selectively increased differentiation of neuronal progenitors. These actions of lithium appeared to enhance a neuronal subtype, calbindin(D28k)-positive cells, and involved a phosphorylated extracellular signal-regulated kinase and phosphorylated cyclic AMP response element-binding protein-dependent pathway both in vitro and in vivo. These findings suggest that lithium in therapeutic amounts may elicit its beneficial effects via facilitation of neural progenitor differentiation toward a calbindin(D28k)-positive neuronal cell type.

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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.
Recent studies have demonstrated that lithium has a neuroprotective effect against brain ischemia. Whether this effect is mediated by hippocampal neurogenesis remains unknown. The ERK (extracellular signal-regulated kinase) pathway plays an essential role in regulating neurogenesis. The present study was undertaken to investigate whether lithium regulates hippocampal neurogenesis by the ERK pathway and improves spatial learning and memory deficits in rats after ischemia. Rats were daily injected with lithium (1 mmol/kg) and 2 weeks later subjected to 15-min ischemia induced by four-vessel occlusion method. 5-bromo-2′-deoxyuridine (Brdu; 50mg/kg) was administrated twice daily at postischemic day 6, or for 3 days from postischemic day 6 to 8. We found that lithium increased the ERK1/2 activation after ischemia by western blotting analysis. There was a significant increase in Brdu-positive cells in the hippocampal dentate gyrus after lithium treatment, compared with ischemia group at postischemic days 7 and 21; furthermore, the survival rate of Brdu-positive cells was elevated by lithium. Inhibition of the ERK1/2 activation by U0126 diminished these effects of lithium. The percentages of Brdu-positive cells that expressed a neuronal marker or an astrocytic marker were not significantly influenced by lithium. Moreover, lithium improved the impaired spatial learning and memory ability in Morris water maze, and U0126 attenuated the behavioral improvement by lithium. These results suggest that lithium up-regulates the generation and survival of new-born cells in the hippocampus by the ERK pathway and improves the behavioral disorder in rats after transient global cerebral ischemia.

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

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