Are the Underlying Mechanisms of Depression Completely Understood? Part II

July 27, 2026

Michelle Wyrick, Author and Clinical & Consulting Hypnotist

Tim Lineaweaver, Subject Matter Expert

If the science of depression is more complicated than commonly portrayed, the same may be said of the medications used to treat it. Public discussions of antidepressants often become polarized. One side portrays them as lifesaving medications that have transformed millions of lives. The other side portrays them as ineffective or harmful drugs that should never have been prescribed in the first place. Neither position adequately captures reality. 

Read Michelle Wyrick's Part 1: Are the Underlying Mechanisms of Depression Completely Understood? Part I

Antidepressants

Antidepressants have undoubtedly benefited many patients. To deny this would be intellectually dishonest. Yet it is equally difficult to ignore the substantial number of individuals who fail to achieve remission, experience only partial improvement, or discontinue treatment due to adverse effects. Even under the most favorable interpretations of the research literature, treatment-resistant depression remains common. For a disorder that contributes enormously to disability, lost productivity, human suffering, and suicide, such outcomes should inspire humility rather than certainty. 

If substantial numbers of patients remain symptomatic despite treatment, the logical conclusion is not that depression has been solved. Rather, it suggests that current treatment models remain incomplete. 

Psychiatric Medication Falls Short

Perhaps the most overlooked issue in contemporary psychiatric practice is not the medication itself but the quality of informed consent surrounding its use. In many areas of medicine, patients receive detailed explanations of expected benefits, potential complications, alternatives, and long-term considerations. Psychiatric prescribing often falls short of that ideal. 

Many patients report receiving little more than a diagnosis and a prescription. They are told that the medication may take several weeks to take effect. Still, they are often given far less information about what treatment may actually feel like, how improvement should be measured, which side effects commonly occur during initiation, which warning signs warrant immediate attention, what alternatives exist, or what difficulties may arise if the medication must eventually be discontinued. 

This lack of education is particularly concerning because psychiatric medications are often prescribed during periods of emotional vulnerability. Individuals struggling with depression, anxiety, grief, or suicidal thinking are not always in the best position to independently research complex pharmacological issues. The responsibility, therefore, falls to clinicians to provide thorough, clear, and balanced information.

Patients deserve to understand that all antidepressants carry boxed warnings issued by the Food and Drug Administration (FDA) regarding suicidal thoughts and behaviors in certain populations. A boxed warning, commonly referred to as a black-box warning, is the agency's strongest safety warning short of removing a medication from the market entirely. Whether to take an antidepressant is a personal decision, but a clear understanding of both potential benefits and risks should inform that decision. 

Addiction and Physiological Dependence 

Equally important is the issue of discontinuation. Although antidepressants are not generally classified as addictive in the traditional sense of compulsive drug-seeking behavior, many patients experience substantial physiological dependence and significant withdrawal symptoms when discontinuing them. Anxiety, insomnia, dizziness, sensory disturbances, mood instability, gastrointestinal symptoms, and cognitive difficulties have all been reported. Yet many patients learn about these possibilities only after treatment has already begun. 

The distinction between addiction and physiological dependence is important, but from the patient's perspective, the practical reality is often similar: stopping the medication may prove far more difficult than anticipated. Informed consent should include not only how to begin treatment but also what may be involved in ending it. 

Questions about antidepressants become even more interesting when one examines how some medications are developed and marketed. A frequently cited example involves citalopram and escitalopram. Citalopram, marketed as Celexa, consists of two mirror-image molecular forms, known as enantiomers. Escitalopram, marketed as Lexapro, contains only one of those enantiomers, specifically the form believed to be primarily responsible for the drug's antidepressant effects. 

From a pharmacological perspective, the distinction is genuine. From a commercial perspective, however, critics argue that such "chiral switches" blur the line between true innovation and product refinement. Regardless of where one stands in that debate, patients deserve to understand that medications marketed as distinct products may be closely related at the molecular level. Transparency should not be viewed as a threat to medicine. It should be viewed as a prerequisite for informed decision-making. 

Questions about generic medications deserve similar consideration. Generic drugs must demonstrate bioequivalence to their brand-name counterparts and, for most patients, perform comparably. Nevertheless, bioequivalence is a regulatory standard, not a guarantee that every individual will respond to every formulation the same way. Differences in inactive ingredients, manufacturing processes, release characteristics, and individual patient sensitivity may influence clinical response. While such concerns are sometimes dismissed, they underscore that regulatory equivalence and patient experience are not always the same.

Neuroscience

Perhaps the most intriguing challenge to conventional thinking, however, comes from neuroscience itself. For decades, public discussions of depression have focused primarily on serotonin, dopamine, and norepinephrine. Yet the brain contains numerous interconnected systems involved in emotion, motivation, attachment, reward, stress regulation, resilience, and suffering. Among these is the endogenous opioid system. 

The endogenous opioid system is involved in reward, attachment, social bonding, emotional regulation, stress responses, and the perception of both physical and emotional pain. Research increasingly suggests that emotional suffering is not merely analogous to physical pain but may involve overlapping neural circuitry. The anguish associated with grief, abandonment, humiliation, rejection, and despair is not an abstract concept. It is genuinely felt as pain. 

This observation may ultimately prove significant because severe depression often presents less as sadness than as suffering itself. Patients frequently describe emotional agony, psychological pain, and an overwhelming desire for relief. These descriptions are strikingly consistent across diagnoses, cultures, and backgrounds. 

Future generations may conclude that depression is not a single disorder arising from a single neurotransmitter imbalance but a collection of related conditions involving multiple biological, genetic, and biopsychosocial systems that shape how people experience pain, stress, attachment, reward, and meaning. Such a perspective would not invalidate current treatments. Rather, it would acknowledge that current treatments represent only one chapter in a much larger story. 

The history of medicine repeatedly shows that certainty often precedes revision. Diseases once thought simple later proved extraordinarily complex. Treatments once considered revolutionary were eventually recognized as incomplete. There is little reason to assume that depression will be an exception. 

The challenge facing psychiatry is not to abandon biology but to pursue it with greater curiosity, rigor, and humility. Patients deserve nothing less.

Suicide and Depression, Trauma, Grief, et al.

Suicide is frequently discussed as though it were a philosophical decision or a symptom to be managed. Yet for many individuals, suicidal thinking arises not from a desire for death but from a desire for relief. This distinction is crucial. The person contemplating suicide is often attempting to escape suffering rather than life itself. Whether that suffering arises from depression, trauma, grief, chronic pain, illness, social isolation, financial catastrophe, or some combination thereof, the suffering is real. Any serious discussion of depression must begin by acknowledging this fact. 

Researchers estimate that about 60% to 80% of individuals who die by suicide suffer from a mood disorder, such as clinical depression or bipolar disorder. While clinical depression is the psychiatric condition most strongly linked to suicide, most people with depression do not attempt it. 

Suicide is a very real tragedy, but clinical theories surrounding it may be incomplete. In recent years, researchers and ethicists have increasingly challenged the assumption that suicidal ideation is solely a symptom of mental illness. Instead, many experts view it as a response to profound, compounding suffering and a desire to escape unendurable pain. 

Are Traditional Risk Factors Accurate?

Historically, clinical models have relied heavily on identifying specific mental health conditions to predict and prevent suicide. However, empirical evidence suggests this approach is incomplete:

Broader Causation: Many individuals who die by suicide do not have a known or diagnosed mental health condition at the time of death. Risk is closely tied to profound life stressors, social isolation, and systemic or cultural pressures.

The Clinical Burden: As researchers highlight in the National Center for Biotechnology Information, the assumption that mental health professionals can perfectly predict who will attempt suicide places an unfair and often impossible burden on the medical system.

Thought-to-Action Shift: Second-generation psychological models—such as the Three-Step Theory (3ST)—propose that the factors causing suicidal thoughts (pain and hopelessness) are entirely different from those that confer the capability to act. 

Rethinking How We Help

As our theoretical frameworks evolve, how society and medicine approach intervention must also shift. The primary goal is relief. Experts at the Samaritans explain that most people experiencing suicidal crises do not want to die; they simply want their current situation or emotional anguish to end.

Focusing on Connection: Newer frameworks, such as the Interpersonal Psychological Theory, emphasize reversing the feeling of being a "burden" and strengthening deep, meaningful connections. If you or someone you know is experiencing suicidal thoughts, please seek immediate help. You do not have to face these challenges alone.

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