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After Prozac: Treating Depression Three Decades Later* (Part I)

By Walter Donway

September 5, 2025

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For most of recorded human history, depression, once termed melancholia, was a condition shrouded in mystery, moral judgment, and therapeutic impotence. The ancients attributed it to imbalances in black bile or divine punishment; medieval healers saw it as a spiritual affliction. By the 11th century, Persian physician Avicenna had identified melancholia as a depressive mood disorder, writing that “If melancholia is due to the brain, the patient loves solitude and darkness…avoids people, and behaves as if obsessed.” His work, The Canon of Medicine, became the standard of medical thinking in Europe along with the work of Hippocrates and Galen. But well into the 20th century, psychiatry had few answers beyond widespread institutionalization, crude shock therapies, or psychoanalysis that could be endless and bring little relief.

For most of recorded human history, depression, once termed melancholia, was a condition shrouded in mystery, moral judgment, and therapeutic impotence.

In the 1950s and ‘60s, a few breakthrough medications—like imipramine and monoamine oxidase inhibitors—became the pharmacological treatments of choice, but, because of their notoriously troubling side effects, were reserved for the severely afflicted. Psychotherapy, too, evolved, yet for many, especially those with crushing, recurrent major depression, recovery remained uncertain, slow, or out of reach. (Clinicians in the United States started using the term “major depressive disorder (MDD)” during the 1970s, and it entered the DSM-III in 1980. Today, DSM-5-TR is a primary tool in its diagnosis.)

 

Revolution and Aftermath

This was the world into which burst the “little green-and-white capsule,” Prozac (Fluoxetine) in 1987, hitting psychiatry like a French Revolution—sweeping away old regimes, upending expectations, and promising liberation from chronic despair.” Selective serotonin reuptake inhibitors (SSRIs), of which Prozac was only the first, work by blocking the reabsorption (reuptake) of serotonin in the brain, thereby increasing serotonin levels in the synaptic cleft. This enhanced serotonin signaling is believed to improve mood and alleviate symptoms of depression and anxiety. SSRIs virtually swept away the ancien régime of older antidepressants, the tricyclics and MAOIs, because Prozac was virtually without side effects, “as tolerable as vitamins.” SSRIs (and later SNRIs, affecting norepinephrine) became the first-line therapy for major depression worldwide. Medications for antidepressant treatment became more accessible because they were perceived as virtually risk-free (and so were prescribed by primary care physicians) and lifted some of the stigma of depression; it was just another treatable biochemical illness.

By 2018, 13.2% of U.S. adults were on antidepressant medications.

By 2018, 13.2% of U.S. adults were on antidepressant medications.

Early in the SSRI era, depression care centered on medications but almost always included psychotherapy; psychotherapists, after all, were the ones prescribing the medicines to their patients. SSRIs and SNRIs were often combined with cognitive-behavioral therapy. With a safer side-effect profile than older drugs, they could be used long-term, enabling millions to manage depression as a chronic condition. In time, therapists evolved strategies for when a first antidepressant failed (in the vernacular, “pooped out”). For example, they added a second agent (like bupropion or an atypical antipsychotic) or switched to another class of agents that could help some non-responders.

Acceptance and blockbuster success conferred on SSRIs the status of a panacea. But they typically required weeks to exert full effects, and many patients did only modestly better than on a placebo. About 10–30% of patients showed little or only partial improvement on these automatically-prescribed, first-line antidepressants. Even among those who did respond, full remission was far from certain; many were left with residual symptoms, and there was a high risk of relapse because depression is relentlessly cyclical. Half of patients with major depressive disorder (MDD) fail to achieve remission with treatment and psychotherapy–underscoring the limits of the panacea.

Severe depressions can produce an overwhelming sense of paralysis so that the simplest tasks, such as getting out of bed, feel insurmountable. Individuals have described this state as feeling “powerless and stuck,” with limbs that feel “leaden,” leading to numbness and apathy. This profound exhaustion can mean days spent confined to bed. This debilitating inertia is linked in many cases to “psychomotor retardation,” a slowing of mental and physical processes. At worst, it can escalate to near-paralysis, robbing individuals of control over their bodies and actions. For some, depression is a feeling of being “stuck in a heavy, aching body drained of energy,” leading to exhaustion or even paralysis.

 

My Experience with Prozac

Prozac did not “save my life,” but it did transform it. I know my own experience best; therefore, I will focus on three points: the experience of depression before Prozac, the impact of Prozac, and problems after Prozac.

My father struggled against depression all his adult life. He was productive, financially successful, mentally sharp, and not unfulfilled. His depression manifested as episodes, like what Winston Churchill called his “black dog.” But when he retired, my father’s depression took over; what has been called “workaholism” held it at bay. He never spoke of his condition, never sought treatment, and avoided alcohol because I am quite sure his father had treated his depression by drinking. Depression has a genetic element that is powerful and persistent.

I was ambitious, functional, and often happy, but at times I was in the men’s room at my workplace, weeping.

I explicitly identified my depression in my mid-20s, about the time I moved to Manhattan and entered psychotherapy. I was ambitious, functional, and often happy, but at times I was in the men’s room at my workplace, weeping.

I saw a total of four psychotherapists, reimbursed by my employer, for perhaps 10 years. I could not tell you if things got better. But the therapy sessions did provide relief. Two of the psychotherapists I saw, including a distinguished psychiatrist from a major medical center, committed suicide.

I encountered stigma. I was a program officer at The Commonwealth Fund, a prominent New York City foundation in the health field. My boss had an impressive understanding of healthcare, but my twice-a-week absences for my therapy sessions riled him. He asked: “What are you, Woody Allen?” And he characterized psychotherapy as “rolling around on the floor wondering where it all went wrong.”

At some point, my internist, a prominent physician in Manhattan, said, in effect, “You have to see a real doctor.” He referred me to a psychiatrist, who prescribed the brand-new cure, Prozac. I never again had an anxiety attack or a weeping session. For someone with long-term depression, the recommendation is lifelong medication. No side effects, no problem. I have been on SSRIs for half a century. At one point, I felt the episodes of depression returning. My psychiatrist said Prozac had “pooped out” and prescribed Effexor, which worked.

On medication, my feelings no longer drove me to psychotherapy; I felt normal. But my psychiatrist insisted on periodic visits. Otherwise, she could not keep prescribing my Effexor. I needed medication, so I went. Then, caught short when my psychiatrist was on vacation, I asked my cardiologist to renew my prescription. He did and kept renewing it. I stopped seeing my psychiatrist (who gave my cardiologist a call to complain). Now, my primary care physician routinely prescribes whatever dose of Effexor I request.

My son, rather early on, was diagnosed as depressed and is maintained on Prozac.

 

Back to the Lab

In time, these realities re-energized research on therapies for depression. But arguably, this was delayed by the pharmaceutical triumph of SSRIs. After the 1990s, the development of truly novel antidepressants stalled; for some 15–20 years, no fundamentally new medication class emerged. Drug makers often opted to “tweak” existing drugs (reformulations or me-too drugs) rather than invest in high-risk novel mechanisms. Some major companies scaled back R&D in psychiatry altogether, partly because of the scientific challenges and also the expiration of SSRI patents. From about 2000 to the late 2010s, no new mechanism for an antidepressant reached the market.

Pharmaceutical companies, after profiting immensely from SSRIs and SNRIs, saw those drugs going generic and faced repeated failures in trials of other mechanisms. This contributed to several big companies downsizing or closing neuropsychiatric research units in the 2000s. A 2017 commentary bluntly stated that antidepressant R&D was at a stalemate, firms abandoning or downgrading psychiatric drug development in response to high costs and high failure rates. The easy wins had been tweaking serotonin, norepinephrine, etc., and the tougher biological targets assumed scientific leaps many companies would not risk without clear biomarkers. Academia, meanwhile, was debating the “serotonin hypothesis” instead of boldly pursuing new treatments. Naturally, as always, dedicated researchers explored new ideas—it just took years for some to bear fruit. The emergence of ketamine, for instance, came from academic studies in the 2000s. Psychedelic therapy research came from academia and philanthropy. So, while industry investment idled for a time, scientific curiosity did not vanish.

Meanwhile, progress relied on optimizing existing treatments and trying non-traditional approaches, but the hopeful news is that the tide seems to have turned because of the evident need to address treatment-resistant depression. Thus, depression therapy has evolved since SSRIs with a focus on treating severe and resistant cases. Some of these “new” approaches are the re-emergence of older modalities like ECT; some are new twists on therapies such as ketamine, neuromodulation, psychedelics, or psychotherapy.

By the mid-2000s, large clinical trials like the “STAR*D” study affirmed that a sequence of medication adjustments could eventually achieve remission in many patients, but, as psychotherapists had worked out on their own, only through trial-and-error and often with substantial delay. Patients needed treatments that worked faster or overcame biochemical hurdles that SSRIs did not.

Psychotherapy (loosely, “talk therapy”) remained a cornerstone of treatment, especially for mild-to-moderate depression, and as an adjunct in tougher cases.

A point that should not be lost is that psychotherapy (loosely, “talk therapy”) remained a cornerstone of treatment, especially for mild-to-moderate depression, and as an adjunct in tougher cases. Such therapy, after all, is the only way to reach and interact with another mind. Forms of psychotherapy such as cognitive-behavioral therapy (CBT), interpersonal therapy, and others proved the equal of medication for many patients. Notably, research suggested that combining therapy with medication yielded better outcomes than either alone and that psychotherapy could confer more durable long-term benefits (lower relapse rates) than pharmacotherapy. One meta-analysis of 21 studies in hard-to-treat depression reported that adding psychotherapy to other treatments significantly improved outcomes in treatment-resistant cases. This gave therapy modalities such as cognitive therapy and behavioral activation a new impetus.

 

When Depression Resists Treatment

It was not enough. By the 2010s, the sizable subset of patients not helped by SSRIs or SNRIs drove new efforts such as neurostimulation techniques, fast-acting antidepressants, and other unconventional treatments. It was an acknowledgment of the new scientific understanding that depression is heterogeneous; a “one-size-fits-all” SSRI approach left other biological subtypes of depression inadequately treated. This became the catalyst for the diversification of strategies.

Since we are talking about treatment-resistant depression (TRD), I will define it as essentially a “major depression” that does not respond to at least two adequate trials of antidepressants. These cases can be severe and chronic. For example, sufferers often are bedbound, with profound impairment in daily function. TRD is common, affecting an estimated 20–30% of depression patients. They suffer disproportionately high rates of persistent disability, hospitalization, and suicide risk. Thus, TRD tended to dominate the post-SSRI era challenge to treating depression. Because it is defined by its resistance to treatment, existing medications have to be tried first using a kind of algorithm: ensure optimal use of existing medications (dose/duration or switching to a different class of anti-depressant); consider augmentation strategies, adding a medication from another class such as lithium, thyroid hormone, atypical antipsychotics, or psychostimulants; and throughout, continue psychotherapy, which evidence shows can help in TRD.

If these steps fail to bring about sufficient improvement, therapists turn to somatic (device-based) therapies, primarily electroconvulsive therapy (ECT), more recently transcranial magnetic stimulation (TMS), and less commonly vagus nerve stimulation (VNS) or experimental deep brain implants. One hurdle is that TRD does not manifest as a uniform syndrome. Patients may have never responded to any antidepressant at all; some may have had periods of responsiveness not sustained. Certain subtypes of depression (e.g., psychotic depression with delusions or hallucinations or severe bipolar depression) are notoriously medication-refractory, but at times respond to other modalities (psychotic depression responds strikingly well to ECT). One agreement seems to be that TRD often implies the need to try a different mechanism of action entirely, not more of the same. This insight has led to a renaissance of new treatments targeting novel pathways from glutamate to psychedelic effects on neuroplasticity to gamma-aminobutyric acid (GABA), a chemical messenger in the brain that slows it down by blocking certain signals and thus is known for producing a calming effect.

 

Electroconvulsive Therapy

Developed in the 1930s, ECT remains one of the most effective treatments for major depression, especially severe cases unresponsive to medications. In ECT, brief electrical currents pass through the brain under anesthesia to induce a controlled seizure, which leads to neurochemical changes that can alleviate depression. ECT’s reputation has never recovered from the misconceptions and stigma (owing mostly to its crude portrayal in early psychiatry), but modern ECT is a far safer and more refined procedure, performed with muscle relaxants and careful monitoring. It repeatedly achieves outcomes in severe depression that no drug or therapy can currently match. Response rates to ECT in melancholic or psychotic depression range from 70% to 90%, with most patients showing marked improvement.

Modern ECT is a far safer and more refined procedure, performed with muscle relaxants and careful monitoring.

A recent analysis of than 2,000 patients with moderate-to-severe depression reported an overall 73% response rate and 51% remission rate with ECT, with “response” denoting a 50% give-or-take reduction in symptoms and “remission” meaning essentially symptom-free. The numbers are dramatically higher than response rates to any single antidepressant trial, illustrating why ECT is often considered the gold-standard treatment for refractory depression. Patients with psychotic depression, frequently completely debilitated by delusions, have a particularly impressive remission rate—up to 95% remission in psychotic depression versus about 83% in nonpsychotic cases.

ECT lifts mood, but more urgently can save lives where acute suicidal depression or depression with refusal to eat are present.

ECT lifts mood, but more urgently can save lives where acute suicidal depression or depression with refusal to eat are present. As a result, depressed patients who receive ECT have significantly lower mortality rates and fewer suicide attempts in contrast to those treated with medication alone. One reason may be that ECT works faster than most treatments, with a typical ECT course of 6–12 sessions over 2–4 weeks, and severely ill patients often feel better after a few sessions. For comparison, it typically takes 4–6+ weeks for antidepressants to take full effect.

Although ECT doubtless also could help much less severely depressed people, the treatment tends to be reserved for the toughest cases, partly because it requires anesthesia and induces seizure, meaning a hospital or outpatient surgical setting is required. But partly also because of its side effects, the chief of which is memory impairment. ECT can cause acute confusion and retrograde amnesia (forgetting memories, especially around the treatment period). Again, current techniques are better, for instance, reducing cognitive side effects by using ultra-brief pulse stimuli and unilateral electrode placements. Even in patients who experience memory gaps or difficulty retaining new memories for days to weeks following treatment, the cognitive effects are transient—an acceptable trade-off for relief from years of crippling depression. Follow-up can include periodic ECT or continuation of antidepressants to prevent relapse.

The bottom line is that ECT has evolved to remain relevant and valuable in the antidepressant toolkit, a highly effective option for those essentially bedbound by depression or those who have failed multiple medications. Research may, in time, yield alternatives that rival ECT’s efficacy without its drawbacks, but for now, ECT is a beacon of hope for severe depression. And with more time, the underutilization of ECT due to stigma, the hesitation to use even “the most effective treatment in depression,” may become a thing of the past.

 

*The content of this article is for information or education only and is not medical advice or a substitute for professional medical advice, diagnosis, or treatment. Readers should consult a qualified healthcare provider for personal health questions and never delay professional medical help due to information read online.

 

This is part one of a two-part article

 

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