Psychiatry’s serotonin-imbalance theory of depression, long discarded by researchers, was finally flushed down the toilet by psychiatry and the mainstream media in 2022. And psychiatrists’ primary treatments for depression—their so-called “antidepressants”—are now circling the drain. This leads to at least two questions: (1) What model of depression actually fits the facts? (2) What approach to depression makes sense?
Before getting to those questions, a summary of the discrediting of psychiatry’s chemical-neurobiological theories of depression and of its so-called “antidepressant” drugs.
Psychiatry’s Chemical-Neurobiological Theories of Depression
More than 25 years ago, researchers disproved the serotonin-imbalance theory of depression. In Blaming the Brain (1998), Elliot Valenstein, professor emeritus of psychology and neuroscience at the University of Michigan, detailed earlier research showing that it is just as likely for people with normal serotonin levels to feel depressed as it is for people with abnormal serotonin levels, and that it is just as likely for people with abnormally high serotonin levels to feel depressed as it is for people with abnormally low serotonin levels. Valenstein concluded, “Furthermore, there is no convincing evidence that depressed people have a serotonin or norepinephrine deficiency.”
While researchers had discarded the serotonin and other chemical imbalance theories by the 1990s, the first unequivocal declaration by establishment psychiatry of the invalidity of these imbalance theories was in the Psychiatric Times in 2011, when psychiatrist Ronald Pies stated: “In truth, the ‘chemical imbalance’ notion was always a kind of urban legend—never a theory seriously propounded by well-informed psychiatrists.”
Then in 2022, psychiatrist Joanna Moncrieff and her co-researchers published a review in Molecular Psychiatry of hundreds of different types of studies attempting to detect a relationship between depression and serotonin that concluded that there is no evidence of a link between low levels of serotonin and depression; this resulted in the mainstream media finally reporting on the jettisoning of the serotonin-imbalance theory of depression.
Less publicized in 2022 was another powerful discrediting of psychiatry’s neurobiological disease model. Published in Neuron, Raymond Dolan—one of the most influential neuroscientists in the world— and his co-authors, reflecting on the more than 16,000 neuroimaging studies published during the last 30 years, concluded, “Despite three decades of intense neuroimaging research, we still lack a neurobiological account for any psychiatric condition.”
Genes and depression? An investigation, published in 2021 in the Journal of Affective Disorders, of 5,872 cases and 43,862 controls that examined 22,028 genes, reported that the study “fails to identify genes influencing the probability of developing a mood disorder” and “no gene or gene set produced a statistically significant result.”
In summary, researchers have found no serotonin nor any other neurotransmitter association with depression, no neurobiological associations, and no genetic associations.
With the fall of the serotonin-imbalance theory, there was no scientific explanation for the mechanism of antidepressants. However, psychiatry assured the general public that antidepressants are still very effective medications, and the New York Times, trusting establishment psychiatry sources, published a 2022 article titled, “Antidepressants Don’t Work the Way Many People Think,” in which it reported that “nearly 70 percent of people had become symptom-free by the fourth antidepressant.” What is the scientific reality of antidepressant effectiveness?
Antidepressant Drugs
As is the case with any treatment for depression—including bloodletting—there will always be patients who offer positive testimonials. However, in science, such testimonials are called “anecdotal reports” and are not considered sufficient evidence for effectiveness. Scientific effectiveness is assessed by comparing a treatment to a placebo control and to the natural course without any treatment. Moreover, scientific effectiveness is gaged not simply by short-term drug-company studies but by long-term outcomes, and by evaluating whether benefits outweigh adverse effects.
In 2002, the Journal of the American Medical Association (JAMA) published a study comparing depression remission outcomes of a placebo to the herb St. John’s wort and to Zoloft. The placebo worked better than both St. John’s wort and Zoloft, as a positive “full response” occurred in 32% of the placebo-treated patients, 25% of the Zoloft-treated patients, and 24% of the St. John’s wort-treated patients.
Later in 2002, a leading researcher of the placebo effect, Irving Kirsch, examined 47 drug company studies on various antidepressants. These studies included published and unpublished trials, but all had been submitted to the Food and Drug Administration (FDA), so Kirsch used the Freedom of Information Act to gain access to all data. He reported that “all antidepressants, including the well-known SSRIs . . . had no clinically significant benefit over a placebo,” describing antidepressants as “clinically negligible” with respect to depression remission.
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.”
Moreover, such drug-company antidepressant trials are dice-loaded in favor of the antidepressant (for example, using an inactive placebo rather than an active placebo which would more truly blind subjects); and drug studies submitted to the FDA are routinely short-term, usually around six to eight weeks.
In the long-term, outcomes are worse. In 2017, the journal Psychotherapy and Somatics published, “Poorer Long-Term Outcomes among Persons with Major Depressive Disorder Treated with Medication,” which found that controlling for depression severity, the outcomes of 3,294 subjects over a nine-year period showed that antidepressants may have had an immediate, short-term benefit for some people, but at the nine-year follow-up, antidepressant users had significantly more severe symptoms than those individuals not using antidepressants.
Another important question for scientists is: What is the natural course of depression without any medication? Published in 2006 was the National Institute of Mental Health (NIMH) study, “The Naturalistic Course of Major Depression in the Absence of Somatic Therapy,” which examined depressed patients who had recovered from an initial episode of depression, then relapsed but did not take any medication following their relapse. One year later, the recovery rate of these non-medicated depressed patients was 85%.
In evaluating any drug treatment, scientists also examine whether its benefits outweigh its adverse effects. In antidepressant studies, depression remission is routinely reported for 25% to 35% of the subjects. However, the journal Drug, Healthcare and Patient Safety, in a 2010 examination of several studies, reported that the percentage of sexual dysfunction for SSRI antidepressants runs from 25%–73%; and in one study of 344 patients who had a history of normal sexual function before SSRI treatments, there was an overall incidence of 58% sexual dysfunction. Furthermore, post-SSRI sexual dysfunction (PSSD), in which sexual dysfunction exists even after discontinuation of the SSRI, was first reported to regulators in 1991.
Psychiatry acknowledges that the majority of patients do not remit with a single antidepressant, but it has insisted that if patients are treated with enough different antidepressants, nearly 70% of them will achieve remission. They justify this with the 2006 reported results of the NIMH-funded “Sequenced Treatment Alternatives to Relieve Depression (STAR*D).}
In the year-long STAR*D study of 4041 patients, there were four stages. In each stage patients who did not remit with one antidepressant were prescribed a different one or augmented with another drug. STAR*D investigators claimed a 67% cumulative remission rate, however, from the very beginning this rate was published, it was challenged as being unjustified by the data.
The first challenge of STAR*D appeared as an editorial in the same 2006 issue of the American Journal of Psychiatry that the STAR*D study had been reported. In this critique, psychiatrist J. Craig Nelson notes that 67 percent remission rate did not account for relapse, noting the following: “Among those achieving remission, relapse rates were 33.5% [in Step 1], 47.4% [in Step 2], 42.9% [in Step 3], and 50.0% [in Step 4] . . . . I found a cumulative sustained recovery rate of 43% after four treatments, using a method similar to the authors but taking relapse rates into account.”
Further analyses of STAR*D data revealed even worse news. Ed Pigott and his co-researchers published an analysis in 2010 that showed of the 4041 patients who entered the study, only 108 remitted, stayed well, and remained in the study to its one-year end. Thus STAR*D could only document a get-well/stay-well rate at the end of a year of only 3%. This in contrast to the previously mentioned 2006 NIMH-funded study that documented a one-year remission rate of non-medicated depressed patients of 85%.
Despite all this, STAR*D’s “nearly 70% recovery” rate has not only been trusted and reported by the mainstream media but taught to psychiatry students, including in the 2018 textbook 50 Studies Every Psychiatrist Should Know.
Then in 2023, Ed Pigott and his co-researchers, utilizing the Restoring Invisible and Abandoned Trials initiative, conducted a reanalysis of STAR*D, which was published in BMJ. Pigott reported that among the 4041 subjects, only 3110 actually had met the depression criteria, and so 931 patients who should have been excluded from the calculation of a remission rate had not been excluded, which inflated the remission rate. STAR*D remission rate was also inflated through violating research protocol by switching the primary outcome measures, and by reversing the protocol on dropouts so that they were no longer viewed as treatment failures. And then results were further inflated by creating a “theoretical” remission rate based on the notion that if the drop-outs had stayed in the trial through all four stages of treatment, they would have remitted at the same rate as those who did stay in the trial to that end—this not justified by what is known from previous research about dropouts.
If STAR*D investigator’s original protocol been adhered to, Pigott concluded, “In contrast to the STAR*D-reported 67% cumulative remission rate after up to four antidepressant treatment trials, the rate was 35%.” Furthermore, that original protocol did not account for relapse.
Perhaps one day, a jury will decide whether the shenanigans of STAR*D investigators were merely “scientific misconduct” or rise to the level of “fraud.” However, owing to establishment psychiatry’s Psychiatric Times, standard drug treatment for depression may no longer be simply circling the drain but half-way down it. The cover of the December 2023 Psychiatric Times issue announced: “STAR*D Dethroned? Since 2006 It Stands Out As An Icon Guiding Treatment Decisions Of Major Depressive Disorders. But What If It’s Broken?” In this cover story, the editor-in-chief of the Psychiatric Times acknowledged that Pigott and his co-researchers reanalysis is “well-researched,” and he concluded: “For us in psychiatry, if the BMJ authors are correct, this is a huge setback, as all of the publications and policy decisions based on the STAR*D findings that became clinical dogma since 2006 will need to be reviewed, revisited, and possibly retracted.”
A Model of Depression That Actually Fits the Facts
To repeat, no associations have been found between depression and serotonin (nor with any other neurotransmitter), nor with any neurobiological mechanism, nor with any gene or gene set. What then is associated with depression and suicidality? The answer is overwhelming life pains. Specifically:
Financial Poverty: Personal and Family Challenges to the Successful Transition from Welfare to Work (1996) reported that Americans on public assistance have at least three times higher rate of depression. A 2013 national survey, issued by the U.S. government’s Substance Abuse and Mental Health Services Administration (SAMHSA), reported that among American adults, serious suicidal thoughts occurred in 6.6% of those with family incomes below the Federal poverty level, which is more than double the 3.1% serious suicidal thoughts of those adults with annual family incomes at 200% or more of the Federal poverty level.
Unemployment: According to that SAMHSA report, these are the following percentages for adults having a major depression episode: 9.5% for the unemployed; 7.8% for part-time employed; and 5.3% for full-time employed. The unemployed were more than twice as likely as those who were full-time employed to have serious thoughts of suicide (7% for unemployed vs. 3% employed); and the unemployed were more than four times likely to attempt suicide (1.4% for the unemployed vs. 0.3% for the employed).
Involvement with the Criminal Justice System: SAMSHA also reported that the percentage of American adults with serious suicidal thoughts was 10.7% for those on parole or a supervised release from prison in the past 12 months, and 9.2% among those who were on probation.
Childhood Trauma: Adverse childhood experiences include physical and emotional abuse, physical and emotional neglect, and family trauma (such as a parent in prison, or witnessing a parent physically abused by the other parent). A 2004 study, “Adverse Childhood Experiences and the Risk of Depressive Disorders in Adulthood,” reported that exposure to such traumatic experiences is “associated with increased risk of depressive disorders up to decades after their occurrence”; and that childhood emotional abuse increased risk 2.7 fold for lifetime depressive disorders. In multiple studies linking childhood trauma to depression, The Truth About Depression (2003) reports that depression was from 1.6 to 12.2 times more common in individuals with a history of significant childhood trauma than in controls who did not report such trauma.
Miserable Significant Relationship: The Interactional Nature of Depression (1999) reports hundreds of studies documenting the interpersonal nature of depression. In one study of unhappily married women who were diagnosed with depression, 70% of them believed that their marital discord preceded their depression, and 60% believed that their unhappy marriage was the primary cause of their depression. In another study, the best single predictor of depression relapse was found to be the response to a single item: “How critical is your spouse of you?”
Lack of Social Support: Bowling Alone (2000) reports, “Low levels of social support directly predict depression, even controlling for other risk factors.” In 2004, the British Medical Journal reported that postpartum depression occurs in 10 to 20% of women in the United Kingdom and the United States but is considered rare in Fiji and some African populations with structured social supports after childbirth.
Critical Thinking: Ironically, while a denial of painful realities can cause problems, an awareness of painful realities can fuel depression and anxiety. Several classic studies indicate that depressed people actually deceive themselves less than nondepressed people. In 1980, the Journal of Abnormal Psychology reported that depressed subjects judge other people’s attitudes toward them more accurately than nondepressed subjects; as the nondepressed perceived themselves more positively than others saw them, whereas the depressed saw themselves as they were actually seen by others. In 1979, the Journal of Experimental Psychology reported that nondepressed subjects overestimated their contribution to winning a rigged game, while depressed subjects more accurately evaluated their lack of control when losing or winning.
The pain of shame and anxiety are routinely associated with depression, and painful losses—from the loss of a loved one and the loss of physical capacities, to existential losses of meaning and purpose—are routinely associated with depression.
Association and correlation don’t necessarily mean causality, as one can argue, for example, that it’s not clear whether unemployment results in depression, or depression results in unemployment; however, studies show nondepressed individuals become depressed after unemployment. Moreover, it is farfetched to argue that childhood depression causes adverse childhood experiences rather than such trauma fueling later depression; and as noted, in the study about unhappily married depressed women, the majority of these women believed that their unhappy marriage preceded their depression.
A variety of overwhelming pains are consistently associated with depression, and a more sensible model of depression would take this into account. One such model of depression is to view this phenomenon not as a disease, disorder, or pathology, but rather as a problematic “strategy” to reduce and shut down overwhelming pain.
Consider the “symptoms” of what is commonly called “depressive disorder.” These include the diminishment of energy, pleasure, interest, sexual desire, concentration, decisiveness, and appetite, accompanied by self-reproach, worthlessness, shame, and suicidal thoughts. The strategy of shutting down overwhelming pain is problematic because it is not selective for only pain but also shuts down our energy, pleasure, and cognitive functions. This shut down can result in complete immobilization or a fear of such immobilization, both of which are psychologically painful, and this can result in the pain of self-loathing and shame. In a vicious cycle, all of this results in more overwhelming pain, resulting in greater efforts to shut down pain.
Perhaps another model could fit the data better, however, unlike psychiatry’s chemical-neurobiological medical model, at least this model has some empirical evidence and rationality.
A More Sensible Approach
Overwhelming pains—including financial and legal pains, childhood trauma, relationship pain, and a variety of losses—are clearly associated with depression, and there is significant evidence that such overwhelming pain precedes depression, though in a vicious cycle, depression and immobilization can result in further overwhelming pain.
Some overwhelming pains are the result of societal policies, and thus political activism can be a solution. And while trauma and relationship pain can also be created, in part, by societal policies, talented therapists can help individuals heal from trauma, extricate from toxic relationships, and find community. Nowadays, however, depressed people are primarily treated with drugs.
Psychoactive Drugs. Psychoactive or psychotropic drugs are drugs that affect neurotransmitters. Such drugs include antidepressants and other prescription psychiatric drugs, as well as alcohol, cannabis, cocaine, and heroin, along with psychedelics such as LSD and psilocybin, and the dissociative anesthetic ketamine. Unlike medications such as antibiotics or insulin, psychoactive drugs don’t kill the source of infection or correct biochemical deficits. Instead, psychoactive drugs can, for some individuals, reduce, shut down, or dissociate them from overwhelming pains. However, each of these psychoactive drugs comes with a set of adverse effects as well as tolerance and withdrawal problems. While there are individuals who report that psychoactive drugs have helped them function, the question is how sustainable are these drugs? As noted, Psychotherapy and Somatics reported that among subjects equally depressed, at the nine-year follow-up, antidepressant users had significantly more severe symptoms than those individuals not using antidepressants; and as Robert Whitaker documented in Anatomy of an Epidemic (2010), while short-term use of psychoactive drugs may be beneficial for some individuals, long-term use often makes matters worse, not only for depression but for other crises.
Thus, it should be uncontroversial that depressed individuals deserve a truly informed choice and dialogue about the use of psychoactive drugs. It should also be uncontroversial that a sustainable approach to depression would include (1) changing societal policies to reduce avoidable overwhelming pains; and (2) dramatically changing the selection and training of mental health professionals so there would be more talented therapists.
Activism to Change Societal Policies: At the most obvious level, this would include:
(1) Eliminating, reducing or at least mitigating the effects of financial poverty. Some examples of social policy changes: significantly subsidizing housing costs; providing a guaranteed basic income; eliminating student-loan debt; and otherwise creating greater financial justice.
(2) Eliminating, reducing or at least mitigating the effects of unemployment. This would include increasing and extending unemployment benefits; and prohibiting CEOs of giant corporations from making 400 times more than the average worker while cutting jobs to raise stock prices.
(3) Preventing unnecessary involvement with the criminal justice system; for example, abolishing societal hypocrisy by decriminalizing all psychoactive drugs.
(4) Recognizing that alienating jobs that are vulnerable to layoffs are among the many reasons why so many people experience ever-increasing anxiety, powerlessness, resentment, and rage, which creates parents who in their interactions with their children have little frustration tolerance, making traumatic adverse childhood experiences more likely.
(5) Implementing policies at every level of society that build and maintain community.
Selecting and Training More Talented Therapists: Many depressed people today are immediately prescribed an antidepressant drug (more often from a primary care physician than a psychiatrist). Along with an antidepressant, or prior to taking one, some depressed people will try psychotherapy, but only with great luck will they find a talented therapist.
In The Great Psychotherapy Debate (2001), Bruce Wampold notes that while therapists tend to believe their therapy techniques—such as cognitive-behavioral therapy (CBT)—are significant, patients believe having someone who understands them and is interested in them is most important. Wampold documents research confirming that “belief in approach,” “relationship alliance,” and “therapist personal characteristics” are more important factors than any therapy techniques.
It has long been known that the variable of therapy technique has little effect on outcome. In 2008, the Journal of Consulting and Clinical Psychology (“Psychotherapy for Depression in Adults: A Meta-Analysis of Comparative Outcome Studies”) reported seven meta-analyses on 53 studies comparing psychotherapy techniques (CBT, psychodynamic, behavioral-activation, social skills training, problem-solving, interpersonal, and nondirective), and concluded: “This study suggests that there are no large differences in efficacy between the major psychotherapies for mild to moderate depression” (interpersonal therapy was slightly more effective, and CBT had a significantly higher dropout rate). In 2024, a Journal of Clinical Psychology study, “The Equivalence of Psychodynamic Therapy (PDT) and Cognitive Behavioral Therapy (CBT) for Depressive Disorders in Adults: A Meta-Analytic Review,” reported equivalent effectiveness of PDT and CBT.
Vital for helping depressed people are therapist “personal characteristics” that produce a collaborative “relationship alliance,” which facilitates healing and energizes and motivates patients to take constructive actions. Unfortunately, such personal characteristics are difficult to quantify, making standard empirical research difficult. However, as others have pointed out (probably misattributed to Albert Einstein), not everything that can be counted counts, and not everything that counts can be counted.
My experience is that talented therapists who facilitate healing are authentic and able to be fully present. They have a gentle presence, and they are superior listeners. They are not reactive to negativity; and the overwhelming pain of another does not make them anxious, so they are less likely to try to control “symptoms,” but instead focus on the whole person. Their lack of fear of emotional pain allows them to have a special kind of humor that is extraordinarily sensitive to pain, and adept at knowing how to lighten its burden. The personal characteristics of talented therapists create conditions for healing, which enable depressed people to experience being cared about; and this results in becoming more open to caring about others and becoming less self-absorbed—opening them up to the entirety of nature beyond themselves, which results in healing.
When I was in my training around many psychiatrists while interning in hospitals and other institutional settings, it was only those rare disgruntled resident psychiatrists whose company I enjoyed; and so I found myself rephrasing Charles Bukowski, saying, “I don’t hate psychiatrists, but I feel better when they are not around.” Helpful therapy with depressed people means dealing with painful aspects of their life—such as childhood trauma and toxic relationships—and obviously, it is not a great idea for a depressed person to be pained by the personal characteristics of a therapist while dealing with their own pain.
Talented therapists not only help facilitate healing but are also energizing and motivating, which is extremely important for depressed people. Seriously depressed people routinely lack the energy for constructive behaviors such as physical exercise. In 2000, Psychosomatic Medicine reported a study that compared outcomes for patients with depression in three treatment groups: (1) Zoloft, (2) Zoloft + exercise, and (3) exercise only. At the end of four months, there were no significant differences in the remission rates of these groups; however at 10 months, exercise only had the lowest relapse rates: depression symptoms returned for 38% of the Zoloft group and for 31% of the Zoloft + exercise group, but depression symptoms returned for only 8% of the exercise only group. While there is no better antidote to depression than physical exercise, depressed people routinely need to be energized and motivated to take constructive actions.
The personal characteristics of energizing therapists are, in many ways, the opposite of the traits routinely selected for in professional training programs. Virtually all medical schools and most graduate psychology programs select future professionals based primarily on their academic achievements, much of which requires a great deal of compliance. People with a talent for energizing and motivating are authentic, spontaneous, playful, risk taking, and find a way to have fun even with people who are seriously depressed.
The socialization process in training programs for virtually all psychiatrists and most psychologists routinely results in psychiatrists and psychologists who are so terrified of being judged by their superiors as “inappropriate” that they are afraid to be authentic, spontaneous, playful, and risk taking. So, even when a program applicant has not only sufficient grades and test scores to gain entrance into a professional program but also the personal characteristics to be a talented therapist, these programs routinely extinguish these talents, and so many gifted people quit when they recognize how hard they will have to fight to retain their authenticity and integrity.
Thus, there are only a handful of professionals I have met who have the talent to help depressed people. These talented therapists are usually anti-authoritarians who have fought off their professional socializations, and they often have had backgrounds outside of academia that have nurtured rather than squashed their talents. One such talented clinical psychologist—who has received high praise from my referrals—is an anti-authoritarian with a background as a personal trainer and in improv comedy who, in her graduate training, fought to maintain her authenticity and integrity.
Psychiatry’s depression outcomes are poor because its bio-chemical-electrical treatments are based on a depression model that science has flushed down the toilet. It should be obvious that new models of depression based on facts rather than fiction need to be created. With such models, hopefully, it will become obvious that when it comes to helping depressed people, societal policies and the talent level of therapists are damn important.
