The idea of recommendation and prescription of second generation of antipsychotics in the treatment of depression (major unipolar depression, bipolar depression, depression in schizophrenia and even a milder depressive condition such as dysthymia) started in early 2000’s. First the experts recommended these agents that are originally synthesized to treat psychotic disorders such as schizophrenia, as augmentation to anti-depressants in the treatment of refractory depressions. (1-3) Soon such studies that are mostly sponsored by pharmaceutical corporations, suggested the use of antipsychotics not as an adjunct, or for the treatment of depression in psychotic disorders, or even bipolar disorder that could be accompanied by psychotic features, but for the treatment of pure unipolar major depression and as the first line treatment. (4) Nowadays it is not uncommon that even primary care physicians, psychiatrists and family physicians prescribe antipsychotics in the treatment of a patient who suffers from a simple depression. The pharmaceutical companies synthesize and market such antipsychotics (e.g. Quetiapine, Aripiprazole, Lorasidone, etc.) (these are these generic names that in different markets are sold under different brand names) have also been able to acquire indication for the treatment of depression for their products. The market sales continue to rise and the treatment indications of these antipsychotics are expanding beyond depression to other psychiatric disorders such as anxiety disorders, PTSD (Post-Traumatic Stress Disorder) and beyond. (5-6)
A curious and cautious consumer may wonder why he or she should be prescribed an antipsychotic while having no psychotic disorder (delusions, hallucinations, etc.) but a simple depression! This article attempts to explore this wonder and show throughout the history of psychiatry, that the use of antipsychotics have not been limited to the recent time and the second-generation antipsychotics, but such attempt in the past failed over time. The experts might respond to this critic that the new antipsychotics possess such chemical structure that work on the neurotransmitters involved in depression (mainly serotonin and norepinephrine). But our lay patient could respond back that what about the impact of the antipsychotic component of these medications?! If the depressed patient is not psychotic and does not have any imbalance or over-sensitively in his or her dopamine neurotransmission (involved in psychosis) what would be the consequences of taking an antipsychotic that affect this neurotransmission. For example would he or she develop side-effects such as EPS (Extra-pyramidal symptoms) or simply abnormal movement disorders such as tremors and akathisia (restlessness and feet fidgeting, etc?! What about dampening the lay patient’s dopamine system in the brain that he or she needs it for all his or her cognitive faculties, etc.?! Since the poor lay patient could not keep this dialogue long enough against the experts who are masters of twisting the facts around to prove their points of intentions per pharmaceutical giants’ order, this article will strive to do so on the behalf such lay depressed patient and million others across the globe.
Digging the grave of antipsychotics:
The first antipsychotic that was synthesized in the early 1950’s was Chlorpromazine that was marketed under different brand names of Thorazine and Largactil and truly treated relatively well the psychotic symptoms of delusions and hallucinations or positive symptoms of psychotic patients such as schizophrenia. Soon in the expansion of its market this antipsychotic was suggested in the treatment of depression and anxiety as well only a few years after its inception. (7-10) Soon other old antipsychotics after Chlorpromazine or as they are labeled first-generations, such as Trifluperazine and Haloperidol were called “major tranquilizers” for their calming effects in comparison with the “minor tranquilizers” i.e. Benzodiazepines such as Lorazepam and Diazepam. (11) In the 50-60’s when dynamic psychotherapy was still in fashion, the use of the old antipsychotics were also suggested to facilitate therapy in depressed patients, published even one such article in the most prestigious journal of psychiatry, Archives of General Psychiatry(10, 12) Another article in this distinguished journal compared the differential effects of these antipsychotics in black vs. white patients and concluded that they work better on the blacks than the whites! (13)
Never forget the past:
But the experts and the pharmaceutical corporations did or thought that the people did and their first line customers who are physicians do not review the past and they have forgotten the lessons learned yesterday. So in the new era the experts sponsored by pharmaceuticals started suggesting the treatment of depression in schizophrenia. But they did not separate depression from negative symptoms in their schizophrenic sample and posed the hostility in such patients as a sign of depression, and forgot to explain that suicidality in schizophrenia could be due to other mechanisms and causes than depression such as secondary to their delusions and hallucinations and hearing voices commanding them to kill themselves(14) While in the past first-generation antipsychotics recommended and used briefly in depression and anxiety and were labeled as major tranquilizers, with no pathophysiological or pharmacodynamics explanations, in modern era, the experts are smarter and they have such justifications.
The old or first –generation antipsychotics which were potent anti-dopaminergic agents to control and dampen positive psychotic symptoms of delusions and hallucinations that are the most bothersome to the schizophrenic patients, the family and others. The new or second-generation antipsychotics that are synthesized in late 80’s with Clozapine, in an attempt to improve the old antipsychotics so they would not cause movement disorders, were created with a different mechanism of action. In general the new antipsychotics were not only anti-dopaminergic, but serotonergic agonists as well to also improve the negative symptoms of psychosis such as schizophrenia. But while these antipsychotics improved partially the negative symptoms, they were never, none as effective as the old generations in the treatment of the bothersome and troublesome positive symptoms of delusions and hallucinations. The experts while failed in creating the ultimate antipsychotics, they totally forgot reporting on the poor effects of the second-generation antipsychotics on the positive symptoms and instead they kept pushing on the anti-negative symptomatic effects.
Soon this anti-negative symptomatic effect due to effect on the serotonergic receptors of the brain became the target for anti-depressant and anti-anxiety business mission of the pharmaceutical corporations. First came aripiprazole as “a potent, partial agonist at the human 5-HT1A receptor”, so it was recommended then approved by FDA for the treatment of major unipolar depression. (15) But the experts while admitting that this antipsychotic possesses “partial agonist activity at dopamine D2 receptors” for its anti-psychotic property, forgot or deliberately did not explain what would happen to a depressed patient without psychosis, i.e. not needing any “agonist activity at dopamine D2 receptors” when taking this medication in short and long-terms. They heroically concluded “aripiprazole is the first dopamine-serotonin system stabilizer”, but is there any instability of “dopamine-serotonin system” in depression?!
Interestingly such imbalance of two neuro-transmissions all of a sudden was posed for not depression, but ironically for anxiety and anxiety disorders as well. Soon “agonist activity at the 5-HT1A receptor” was discussed similarly for anxiety disorders as well as it had been discussed earlier for depression. (16) Thus far no one has dared or had the knowledge to ask how come three major psychiatric disorders, i.e. psychosis such as schizophrenia; depressive and anxiety disorders all share the same pathophysiology and could be treated with the same medications! If so, why on the surface their symptoms and presentations are different even to the lay eyes?! And if so while not vice versa, i.e. using antidepressants for psychotic disorders such as schizophrenia. Perhaps this kind of argument has not yet crossed the mind of antidepressant making companies! The claim of Aripiprazole in being the only new antipsychotic to have antidepressants effect has recently been challenged by a new kid on the block, Lurasidone to have a similar antidepressant efficacy but through a different mechanism. This novel antipsychotic is posed to ensue its antidepressant effect through i5-HT₇ receptor (another serotonin receptor) antagonist. (17) The same argument goes against Lurasidone or any other antipsychotic that claim to have antidepressant effect while having antipsychotic efficacy as went on in the case of Aripiprazole.
Widening the use of antipsychotic medications to the treatment of other non-psychotic conditions such as depressive illnesses for the sake of profit seeking of pharmaceutical companies, despite their useless efforts through their own made up research conducted by their own hired and paid researchers, is conceptually and ethically wrong.
Psychiatry that always from its date of inception has been an underdog of medicine and many among the profession and the public may not consider it as a medicine discipline has not over a century able to redeem itself as a companion to medicine for its own long-run wrong doings! For the most half part of the 20th century, psychiatry fell into psychoanalysis and other forms of psychotherapy and Freud as one of its prominent father, helped it more to evolve into psychology than psychiatry as a branch of medicine. For the most part of the last century, psychiatry struggles with a descent and acceptable classification of mental illnesses and the effort of DSM-III and thereafter editions, including the last DSM5 of 2013, is still lacking etiological classifications, but only symptomatic ones.
Sadly after more than a century, while psychiatry claims to be very biological and many mental illnesses are considered as functional diseases of the brain, DSM classifications lack behind such claim in totality. The term Psychiatry itself is a misnomer as by word definition and origin, it refers to a discipline of “psyche” and not “brain” and does not differentiate itself from psychology. The medications in psychiatry are also all misnomers, as antidepressants are not used only for the treatment of depression, but anxiety and its disorders, PTSD, personality disorders and so on. Antipsychotics are not also only used in the treatment of psychotic illnesses, but nowadays for depression, anxiety and its disorders, PTSD and even personality disorders. The novel antipsychotics are not even more efficacious than the old generations in the alleviation of positive symptoms of psychoses such as delusions and hallucinations.
While the field by claim invented the novel antipsychotics to prevent the first generation of antipsychotics’ extrapyramidal and Tardive Dyskinesia side-effects, they are doomed by their metabolic side-effects. So the third generation of antipsychotics have been created to improve the side-effects profile of these class of medications, but this new class, such as Aripiprazole and Lurasidone have both the old and the new side-effects altogether, though each perhaps in lesser degrees. Among many known side-effects of the novel antipsychotics, metabolic and extrapyramidal, it has also been shown that they can cause even negative symptoms instead of improving them and also tumors such as of pituitary gland and perhaps more to come as they are used more and their indications are expanded unnecessarily! (18-19)
- Adson DE, Kushner MG, Eiben KM, Schulz SC. Preliminary experience with adjunctive quetiapine in patients receiving selective serotonin reuptake inhibitors. Depress Anxiety. 2004;19(2):121-6.
- Barbee JG, Conrad EJ, Jamhour NJ. The effectiveness of olanzapine, risperidone, quetiapine, and ziprasidone as augmentation agents in treatment-resistant major depressive disorder. J Clin Psychiatry. 2004 Jul;65(7):975-81.
- Barbee JG, Conrad EJ, Jamhour NJ. Aripiprazole augmentation in treatment-resistant depression. Ann Clin Psychiatry. 2004 Oct-Dec;16(4):189-94.
- Han C, Wang SM, Kato M, Lee SJ, Patkar AA, Masand PS, Pae CU. Second-generation antipsychotics in the treatment of major depressive disorder: current evidence. Expert Rev Neurother. 2013 Jul;13(7):851-70.
- Depping AM, Komossa K, Kissling W, Leucht S. Second-generation antipsychotics for anxiety disorders. Cochrane Database Syst Rev. 2010 Dec 8;(12):CD008120.
- Hamner MB, Deitsch SE, Brodrick PS, Ulmer HG, Lorberbaum JP. Quetiapine treatment in patients with posttraumatic stress disorder: an open trial of adjunctive therapy. J Clin Psychopharmacol. 2003 Feb;23(1):15-20.
- REES WL, LAMBERT C. The value and limitations of chlorpromazine in the treatment of anxiety states. J Ment Sci. 1955 Oct;101(425):834-40.
- ROSNER H, LEVINE S, HESS H, KAYE H. A comparative study of the effect on anxiety of chlorpromazine, reserpine, phenobarbital, and a placebo. J Nerv Ment Dis. 1955 Dec;122(6):505-12.
- BARSA JA, KLINE NS. Depression treated with chlorpromazine and promethazine. Am J Psychiatry. 1957 Feb;113(8):744-5.
- FLACH FF. The use of chlorpromazine to facilitate intensive dynamic psychotherapy in depression. Psychiatr Neurol (Basel). 1957 Nov;134(5):289-97.
- DAVIDOFF E. Effect of combined chlorpromazine and dextro-amphetamine on severely depressed patients. Dis Nerv Syst. 1958 Jun;19(6):249-52.
- LORR M, MCNAIR DM, WEINSTEIN GJ, MICHAUX WW, RASKIN A.Meprobamate and chlorpromazine in psychotherapy. Some effects on anxiety and hostility of outpatients. Arch Gen Psychiatry. 1961 Apr;4:381-9.
- Raskin A, Crook TH. Antidepressants in black and white inpatients. Differential response to a controlled trial of chlorpromazine and imipramine. Arch Gen Psychiatry. 1975 May;32(5):643-9.
- Keck PE Jr, Strakowski SM, McElroy SL The efficacy of atypical antipsychotics in the treatment of depressive symptoms, hostility, and suicidality in patients with schizophrenia. J Clin Psychiatry. 2000;61 Suppl 3:4-9.
- Jordan S, Koprivica V, Chen R, Tottori K, Kikuchi T, Altar CA. The antipsychotic aripiprazole is a potent, partial agonist at the human 5-HT1A receptor. Eur J Pharmacol. 2002 Apr 26;441(3):137-40.
- Carson WH, Kitagawa H. Drug development for anxiety disorders: new roles for atypical antipsychotics. Psychopharmacol Bull. 2004 Winter;38(1):38-45.
- Cates LN, Roberts AJ, Huitron-Resendiz S, Hedlund PB. Effects of lurasidone in behavioral models of depression. Role of the 5-HT₇ receptor subtype. Neuropharmacology. 2013 Jul;70:211-7.
- Artaloytia JF et al. Negative symptoms caused by antipsychotic medications. Am J Psychiatry 2006 Mar; 163:488-93.
- Szarfman A et al. Pituitary tumors associated with antipsychotic use. Pharmacotherapy 2006 Jun; 26:748-58.