Tricyclic antidepressants dominated psychiatric prescribing throughout the 1970s, with drugs like imipramine, amitriptyline, nortriptyline, and desipramine forming the backbone of pharmacological treatment for depression. Monoamine oxidase inhibitors, an older class that had been in use since the late 1950s, remained an important option as well, though they were already falling out of favor. The decade also saw the arrival of lithium for mood disorders in the United States, the first appearance of so-called second-generation antidepressants, and behind-the-scenes laboratory work that would eventually produce the SSRIs we know today.
Tricyclic Antidepressants Ran the Show
If you were diagnosed with depression in the 1970s, there was a strong chance your doctor would hand you a prescription for a tricyclic antidepressant, usually abbreviated as a TCA. The class gets its name from the three-ring chemical structure shared by its members. Imipramine, the first TCA, had been discovered in the late 1950s, and by the 1970s it had been joined by a stable of related compounds: amitriptyline, nortriptyline, desipramine, doxepin, clomipramine, protriptyline, trimipramine, and dothiepin (known as dosulepin in some countries). Each had a slightly different side-effect profile, but they all worked by blocking the reuptake of certain brain chemicals, primarily norepinephrine and, to varying degrees, serotonin.
These drugs were genuinely effective for many patients, which is why they held the field for so long. But they came with baggage. Common side effects included dry mouth, constipation, blurred vision, weight gain, drowsiness, and dizziness upon standing. More concerning was what happened in overdose. A safety review examining fatal toxicity across the TCA class found that desipramine appeared somewhat more likely than other TCAs to cause death in overdose, while amitriptyline, clomipramine, dothiepin, doxepin, trimipramine, and imipramine showed broadly similar toxicity levels, generally reported as less dangerous than desipramine.1PubMed Central. The cardiovascular safety of tricyclic antidepressants in overdose and in clinical use This was a real clinical worry in the 1970s: depression itself carries suicide risk, and handing a severely depressed patient a bottle of pills that could be lethal in a two-week supply created an uncomfortable paradox that doctors managed by prescribing limited quantities at a time.
The cardiovascular effects of TCAs were a particular concern even at normal doses. Some members of the class, including amitriptyline and nortriptyline, have been associated with a greater risk of cardiac complications during routine clinical use, not just in overdose.1PubMed Central. The cardiovascular safety of tricyclic antidepressants in overdose and in clinical use For older patients or anyone with pre-existing heart conditions, choosing among the available TCAs required careful weighing of risks. This limitation would eventually become one of the strongest arguments for the newer antidepressants that arrived in the following decades.
Monoamine Oxidase Inhibitors and the Cheese Problem
Before the tricyclics took center stage, monoamine oxidase inhibitors were the first antidepressants available. The key MAOIs of the era included phenelzine (Nardil), tranylcypromine (Parnate), and isocarboxazid (Marplan). These drugs work by blocking an enzyme called monoamine oxidase, which breaks down neurotransmitters like serotonin, norepinephrine, and dopamine. Block the enzyme, and you get more of those chemical messengers hanging around in the brain.
MAOIs remained in use during the 1970s, but their popularity had been declining for some time. The primary reason was the dangerous interaction between MAOIs and tyramine, an amino acid found in aged cheeses, cured meats, fermented foods, and certain wines. Eating these foods while on an MAOI could trigger a hypertensive crisis, a sudden and potentially fatal spike in blood pressure. Patients had to follow strict dietary restrictions, which made the drugs burdensome to live with and risky for anyone who slipped up. On top of the food interactions, MAOIs also had problematic drug-drug interactions that limited what other medications a patient could safely take.
Despite these drawbacks, MAOIs were not abandoned entirely. They held a niche reputation for working when other antidepressants failed, particularly in what clinicians called “atypical depression,” characterized by oversleeping, overeating, and intense sensitivity to rejection. The combination of a TCA and an MAOI was used cautiously in treatment-resistant cases by some clinicians throughout the decade, though the practice never gained wide acceptance because of safety concerns.2Psychiatric Clinics of North America. Treatment Algorithms in Treatment-Resistant Depression – Section: Development of Treatment Algorithms—Tricyclic Antidepressant (TCAs) Over the longer arc of psychiatric history, MAOIs dwindled further as tricyclics and later SSRIs offered alternatives with fewer lifestyle restrictions.3PubMed. Classics in Chemical Neuroscience: Selegiline, Isocarboxazid, Phenelzine, and Tranylcypromine
Lithium Finally Reaches the United States
One of the more striking stories of 1970s psychopharmacology involves lithium. Australian psychiatrist John Cade had described lithium’s calming effect on manic patients back in 1949, and European clinicians had been prescribing it for two decades by the time the United States approved it. In 1970, the U.S. became the fiftieth country to allow lithium on the market.4PubMed Central. The history of lithium therapy The delay was partly due to safety concerns, as lithium has a narrow therapeutic window, meaning the dose that helps is uncomfortably close to the dose that poisons.
Lithium was primarily approved for treating mania, but interest in its ability to prevent depressive episodes was growing throughout the 1970s. Clinicians noticed that patients with bipolar illness who took lithium continuously had fewer and less severe depressive episodes. This prophylactic use became widespread during the decade, even though the FDA never formally approved lithium specifically for preventing depression.4PubMed Central. The history of lithium therapy Lithium was not technically an antidepressant in the way TCAs were, but it became a crucial part of the mood-disorder toolkit during this period, and it served as an adjunct to tricyclics for patients whose depression proved stubborn.
Blood Levels and the Push Toward Precision
The 1970s marked an important shift in how clinicians thought about TCA dosing. Earlier prescribing had been largely a guessing game: start at a certain dose, wait a few weeks, and adjust based on whether the patient felt better or reported intolerable side effects. But advances in drug assay techniques made it possible to measure how much of a tricyclic was actually circulating in a patient’s blood. By the mid-1970s, measuring TCA plasma levels had become increasingly common, and researchers were beginning to correlate those levels with clinical response, side effects, and even diagnostic and prognostic outcomes.5PubMed. Therapeutic implications of tricyclic antidepressant plasma levels
This mattered because different people metabolize the same drug at very different rates. Two patients taking identical doses of nortriptyline could have blood levels that differed by a factor of ten or more. One might have levels too low to work; the other might have levels in the toxic range. By the end of the decade, guidelines for therapeutic monitoring of several TCAs were being developed, though researchers acknowledged that therapeutic ranges were well established for some drugs in the class but still unclear for others.6PubMed. Guidelines for therapeutic monitoring of tricyclic antidepressant plasma levels Nortriptyline, for instance, had one of the better-defined therapeutic windows, which partly explains why it remained a popular choice. This era laid the groundwork for what we now call therapeutic drug monitoring, a practice that is routine for lithium and still occasionally used for TCAs today.
What Happened When Standard Treatment Failed
Depression that did not respond to a first trial of a TCA was a significant problem in the 1970s, just as treatment-resistant depression remains a challenge today. Clinicians developed several strategies, some of which sound surprisingly modern and others that have mostly faded from practice.
One popular approach was thyroid hormone augmentation. Research by Arthur Prange and others in the early 1970s found that adding a small dose of the thyroid hormone T3 to imipramine could speed up and sometimes rescue an antidepressant response. In early studies, this augmentation strategy appeared effective in roughly half to as many as nine out of ten patients who had not responded to a TCA alone.2Psychiatric Clinics of North America. Treatment Algorithms in Treatment-Resistant Depression – Section: Development of Treatment Algorithms—Tricyclic Antidepressant (TCAs) The idea caught on quickly and became a standard tool in the treatment-resistant toolkit, though later research produced more mixed results. Thyroid augmentation is still occasionally used today, a direct legacy of 1970s clinical experimentation.
Other options for treatment-resistant patients included switching between different TCAs, switching from a TCA to an MAOI (with an appropriate washout period), or the riskier strategy of combining the two classes mentioned earlier. Lithium augmentation, adding lithium to an ongoing TCA regimen, also emerged during this period and would become one of the most studied augmentation strategies in the decades that followed. Electroconvulsive therapy, though often stigmatized, remained an option for the most severe and refractory cases and was considered by many psychiatrists to be the single most effective acute treatment for depression.
Second-Generation Antidepressants Start to Appear
The late 1970s brought the first hints that the TCA-and-MAOI era was not going to last forever. A group of drugs sometimes called “second-generation” or “atypical” antidepressants began to arrive, each attempting to offer antidepressant benefits with fewer of the side effects and safety hazards that plagued the existing options. Among these were maprotiline, mianserin, trazodone, and viloxazine.7PubMed Central. Metabolism of some second- and fourth-generation antidepressants: iprindole, viloxazine, bupropion, mianserin, maprotiline, trazodone, nefazodone, and venlafaxine
Maprotiline was structurally similar to the tricyclics but had a four-ring structure (making it technically a “tetracyclic”) and was somewhat more selective for norepinephrine reuptake. Mianserin, available in Europe but never approved in the U.S., worked through a different mechanism altogether, blocking certain receptors rather than inhibiting reuptake. Trazodone, which entered the U.S. market at the very end of the decade, was less cardiotoxic than the older TCAs and is still widely used today, though more often as a sleep aid than as a primary antidepressant. These drugs were imperfect in their own ways, but they signaled that the pharmaceutical industry was actively searching for alternatives to the tricyclic template.
The Serotonin Hypothesis and the Seeds of Prozac
To understand why the 1970s drug landscape looked the way it did, it helps to know what scientists believed about how depression worked at the time. The dominant biochemical framework was the monoamine hypothesis, which held that depression resulted from deficits in brain monoamines, particularly norepinephrine and serotonin. The serotonin side of this idea dates from the 1960s, when researchers first proposed that a deficit in brain serotonin, correctable by antidepressant drugs, was the root cause of the illness.8PubMed Central. The neurobiology of depression–revisiting the serotonin hypothesis. I. Cellular and molecular mechanisms
By the early 1970s, evidence for serotonin’s role had grown strong enough that researchers began asking a natural question: could you build a drug that targeted serotonin reuptake specifically, without also affecting norepinephrine, histamine, and acetylcholine receptors? Doing so might preserve the antidepressant effect while eliminating many of the side effects that made TCAs so hard to tolerate. This line of thinking led directly to the discovery and development of fluoxetine, which would eventually be marketed as Prozac.9PubMed. Case history: the discovery of fluoxetine hydrochloride (Prozac) But fluoxetine did not receive FDA approval until 1987. Throughout the 1970s, it existed only in laboratory work and clinical trials. The patients of that decade had to make do with the broader-acting, side-effect-heavy drugs on the pharmacy shelf.
This is a useful reminder that drug development timelines are long. The intellectual breakthrough that made SSRIs possible happened in the early 1970s, but patients did not benefit from it for another fifteen years. The 1970s, in a pharmacological sense, were a bridge decade: the science was pointing clearly toward more targeted drugs, but the clinical reality was still defined by drugs designed in the 1950s.
The Regulatory Landscape and Vanishing Medications
The drugs available to clinicians in the 1970s were shaped not just by scientific discovery but by an unusually active period of federal regulation. From 1967 to 1973, the FDA conducted the Drug Efficacy Study Implementation, known as DESI, a sweeping administrative review that removed nearly half of all psychiatric medications from the market.10PubMed Central. The liberal state and the rogue agency: FDA’s regulation of drugs for mood disorders, 1950s-1970s The DESI program was a response to the 1962 Kefauver-Harris Amendment, which for the first time required drug manufacturers to prove that their products actually worked, not just that they were safe. Many psychiatric drugs approved in the 1950s and early 1960s had made it to market on thin evidence, and the DESI review culled them.
For clinicians in the early 1970s, this meant that some familiar medications simply disappeared from pharmacy shelves. The upside was that the drugs that survived the review had at least some evidence of efficacy behind them. The downside was that the therapeutic arsenal shrank noticeably, concentrating prescribing even more heavily around the established TCAs and MAOIs. This regulatory bottleneck also made pharmaceutical companies more cautious about developing new psychiatric drugs, since the bar for approval had been raised.
The Bigger Psychiatric Picture
Antidepressant prescribing in the 1970s did not happen in a vacuum. The decade sat at the intersection of several large shifts in how mental illness was understood and treated. Deinstitutionalization, the movement to close large psychiatric hospitals and treat patients in the community, was well underway. The development of psychotropic medication, including antidepressants, was one of the forces that made deinstitutionalization possible: if patients could be stabilized with pills, the argument went, they did not need to live in institutions.11PubMed Central. Moving psychiatric deinstitutionalization forward: A scoping review of barriers and facilitators Whether deinstitutionalization actually served patients well is still debated, but the availability of antidepressants and other psychiatric drugs was one of its enabling conditions.
Diagnostic practice was also in flux. The 1970s fell between the DSM-II, published in 1968, and the DSM-III, which would arrive in 1980. The DSM-II’s definitions of depressive disorders were short, general, and heavily influenced by psychoanalytic theory.12The Encyclopedia of Clinical Psychology. DSM-I and DSM-II This meant that what counted as “depression” was defined more loosely and subjectively than it would be after 1980. Two clinicians evaluating the same patient might not agree on whether the person had a depressive neurosis, an involutional melancholia, or a manic-depressive reaction in its depressive phase. The lack of standardized diagnostic criteria made clinical research harder and contributed to the inconsistency in treatment outcomes that plagued the era.
The DSM-III’s eventual introduction of specific, criterion-based diagnoses would tighten things considerably. But for the patients and doctors of the 1970s, the experience of depression treatment was shaped by diagnostic fuzziness, a limited drug menu dominated by tricyclics, and a medical culture that was only beginning to think systematically about matching specific patients to specific medications.
How 1970s Antidepressants Compare to What Came Later
If you are used to hearing about SSRIs like fluoxetine (Prozac), sertraline (Zoloft), or escitalopram (Lexapro), the 1970s antidepressant landscape can feel alien. The drugs of that era were effective, sometimes powerfully so, but they were what pharmacologists call “dirty” drugs, meaning they hit many biological targets at once rather than acting selectively. A single TCA might block the reuptake of norepinephrine and serotonin, block histamine receptors (causing sedation and weight gain), block muscarinic acetylcholine receptors (causing dry mouth and constipation), and block alpha-adrenergic receptors (causing dizziness and drops in blood pressure). The therapeutic effect came from only one or two of those actions; the rest were purely unwanted.
The SSRIs that arrived in the late 1980s were not necessarily more effective at treating depression. Head-to-head comparisons have generally found that TCAs and SSRIs produce similar rates of remission. What the SSRIs offered was a dramatically better side-effect profile and much greater safety in overdose. A bottle of fluoxetine is very hard to use for a lethal overdose; a bottle of amitriptyline is not. That safety margin, more than any superiority in efficacy, is what drove the transition from the drugs of the 1970s to the ones prescribed today.
The TCAs have not vanished entirely. Amitriptyline is still prescribed, often for chronic pain or migraine prevention rather than depression. Nortriptyline sees use in smoking cessation and neuropathic pain. Clomipramine remains a first-line option for obsessive-compulsive disorder in some treatment guidelines. These drugs carved out niches beyond depression that have kept them alive well past the era that made them famous. If you find one of them on your prescription, it does not mean your doctor is practicing 1970s medicine; it means these compounds turned out to be useful for conditions their developers never anticipated.