Possible New Class of Antidepressants?

To give the reader some context in order to grasp the significance of the issue of a possible new class of antidepressant medications, I would offer the following points of information.

First, in spite of 30 years of hype and advertising by the pharmaceutical industry and especially the companies who have one by one introduced and advertised the so-called modern, or serotonin-based antidepressants, not much progress has been made in the actual efficacy of treating major depressive disorders with these medications. When the serotonin-based antidepressant medications started to emerge in the marketplace, the armamentarium of the psychiatrist and family physician, in the realm of novel pharmaceutical based advertising on Western television, the mode of action on a supposedly new neurotransmitter system was greatly hailed as a modern breakthrough. Serotonin actually is been known since the 1950s and the neuroscience circles in general.

Second, the only advance that was basically made was a reduction in the anticholinergic side effects of the previous generation of antidepressant medications. These the side effects are largely antihistamine. This means that they make nearly all mucous membranes and dry. This accounts for their marketed value in treating and controlling the symptoms of runny noses and watery eyes of viral colds and pollen allergies. These side effects present in the antihistamine medications and “try cyclic” antidepressant medications also cause decreased propulsion in the gastrointestinal tract, meaning the longer transit time for food and waste material through the small and large intestines. The longer that the foodstuffs and wastes stay especially in the large intestine, the more time there is for reabsorption of water from the stool. This makes for hard stool and consequently the long known constipation with all these medications. These same anticholinergic side effects can also affect heart rate and decrease blood pressure. The latter side effect is very problematic in the elderly and can cause lowered blood pressure upon standing and consequently falls in the elderly with alarming frequency and subsequent injuries such as hip fractures.

Third, the serotonin-based Prozac generation of antidepressant medications showed no better efficacy or effectiveness in treating major depressions than any of their predecessors. That is to say, at best, the second generation of antidepressant medications were effective in only up to 60% of patients with major depressions. That means that at least 40% of patients treated with any one of these medications do not respond at all or respond only incompletely.
This has spawned a secondary market for “add-on” help her medications for the Prozac generation of antidepressants. These have been the very versatile but over marketed also, and over utilized atypical antipsychotics. These medications have been utilized to add on to severe treatment-resistant depressions with varying degrees of success. These medications help especially in the restricted arena of more bipolar type depressions with psychotic components. Several of them have received FDA approval as adjunct give medications in the treatment of such bipolar like or partially psychotic depressive disorders. But as usual, there is great concern in the more ethical circles of psychiatry and in advocacy groups, with, in my opinion, good reason, about the overutilization of these medications in patients that are not benefited by their use. As usual, this is a less than well-regulated field of practice and likely will only be corrected with time and the Great American corrective mechanism of liability lawsuits for inappropriate use.

Fourth, the serotonin-based antidepressants have problems of their own. One of their more common issues which likely formed the basis of the rash of lawsuits nationally within three years after Prozac was first released was the misunderstanding of the phenomenon of Prozac induced panic disorder to episodes. Having lived through in practice through this very interesting national phenomenon, the likes of which really had not ever been seen before, and having consulted as a so-called “expert witness” on a number of cases I came to form my own views and conclusions about this time. In the novel Genesis of such an issue at the time in the early 1990s. It turned out that the expectations of Prozac and its subsequent followers Zoloft were inappropriately high in overblown especially in the public’s I and in the profession of psychiatry as well. When the rash of side effects was apprehended and misunderstood the overreaction to the emergence of a negative property of the then still incompletely understood Prozac generation of antidepressants, lawsuits abounded. Many of the claims were fueled by the notion that the many hours long, truly nearly intolerable panic states caused suicidal emotional reactions or suicidal behaviors. Within a few years, this public anti-Prozac pandemonium settled down except within the fringe anti-drug and anti-psychiatry groups, as this issue was more fully understood. It is quite paradoxical because a few of the serotonin antidepressant medications work moderately well with response rates between 38 and 60% approximately four quelling and controlling panic disorders themselves! However it remains that can a varying percentage of persons with depression, the serotonin-based antidepressants will cause the emergence of panic states and perhaps up to 30% or so of people. In addition, very very rarely, patients can experience moderately severe hypermetabolic states known as the serotonin syndrome. This is marked by fevers, muscle rigidity and some other medical metabolic abnormalities that require emergent medical treatment for a few days. I must emphasize here again that this is an extremely rare reaction and most psychiatrists have either seen a few cases in their entire practicing career or not at all. I myself see what less than one case a year even in my position as a hospitalist-based psychiatrist who regularly covers also a medical unit where patients have both serious medical disorders and active psychiatric psychopathology.

Fifth, antidepressant medications take a minimum of three to perhaps 8 to 12 weeks to reach maximum antidepressant effectiveness in the 60% of patients who respond to these medications outright. This has been a vexing issue for patients their families and psychiatrist’s ever since the late 1980s and early 1990s but almost all private insurers limited inpatient hospital stays 22 weeks or less flying in the face of psychiatric science and at least three decades of experience with antidepressant medications. Suicide rates did go up after discharge with the imposition of this length of stay restrictions nationwide. Wrongful death suits for post-discharge suicides also increased nationally. Psychiatrists and families had to monitor persons with severe depressions who were discharged prematurely from hospitals because of lack of insurance coverage. Outpatient day treatment programs were started by some larger psychiatric treatment organizations who could afford to do so. Patients were seen several times a week in such outpatient clinics to monitor their safety and continued rate of recovery or possible stalemate or relapse of depressive symptoms. Readmission for the return of depressive symptoms and suicidality went up as everyone except the insurance companies predicted. This is been an issue without resolution and continues to the present time. It is an unfortunate result of an absolute property/limitation of all antidepressant medications to date and the national cost-cutting efforts of insurance companies on such length of stay issues. This is not restricted to psychiatry alone as anyone who has undergone outpatient surgery and discharged home quickly well still needing nursing care can attest.

Recently the research regarding a completely novel medication which works on yet and another neurotransmitter system the glutamate system has been made public.

In a journal article published recently in the British journal Lancet, psychiatric investigators at the University of North Carolina at Chapel Hill school of medicine revealed that they have completed several clinical trial studies of a new medication brexanolone which is given by injection as a new antidepressant.

So far this medication is only being studied in severe postpartum depressions in women. For the curious reader, the original article in the Lancet details how the subjects were selected and what degree of postpartum depression was needed in order to qualify them for the study; this does make for interesting reading and will reassure the reader that the patient population was quite ill and makes the positive results obtained in this study all the more impressive.

Two issues make this possible future antidepressant medication of great interest.

First, it is given by injection and requires approximately 60 hours for the complete administration which apparently is a one-shot deal. This means that only one 60 hour dosage is needed for full clinical effect.

Second, the medication is given by injection and is not an oral formulation nor anywhere is there any speculation in this article and others that I’ve reviewed very recently in the online literature that suggests it will be possible to make this medication into an oral preparation later.

Is has many future repercussions that I am sure mental health policy wonks and mental health treatment personnel ranging from the physician level II entrepreneurial freestanding futures psychiatric injection clinic administrators are hungrily drooling over with great economic expectations. The previous tongue-in-cheek, somewhat sarcastic description means that I can foresee as likely far more prescient persons and I, then antidepressant freestanding brexanolone injection clinics may be springing up in strip malls everywhere in a decade or so and likely charging exorbitant fees. And of course, they will range from folding steel chairs in the waiting rooms that look like audition calls in waiting rooms in sheet B grade movie Holloway film producers offices, two high class, architectural digest levels decor driven Beverly Hills, River Oaks, Squirrel Hill, Upper East Side, Gross Pointe clinics making oodles of money for one trick pony cocaine-addicted psychiatrists (sorry I just couldn’t resist that last jab at unscrupulous psychiatrist’s).

Third, I do hope and expect that this single medication will spawn an enormous research and development effort in the coming years. Momentum for discovering a more rapidly effective antidepressant medication has been stimulated by the last several years use in an off-label fashion of nasal inhalant based ketamine and the probable coming release of an oral derivative, esketamine by Johnson & Johnson. Ketamine has long been used as a dissociative anesthetic especially for use in cataract surgery. Unfortunately, it also has been adopted by the “young and restless” generations in the last 10 years as one of the staples in the rave drug and rave club craze of indiscriminate polydrug use. Ketamine at high doses can induce euphoria but also severe dysphoria, or in the old LSD lingo, “bad trips.” Ketamine and its descendent have demonstrated that a rapid response to severe depressive states is possible and has sustained the continued off-label use by fairness number of psychiatrist nationally in the treatment of resistant major depressive disorder states.

It is easy to hope with more confidence that in future decades we will indeed have much more effective and more rapidly effective antidepressant medications given the emergence of a drug like the brexanolone injection.


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