Psychopharmacology revolution

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The psychopharmacology revolution covers the introduction of various psychiatric drugs into clinical practice as well as their continued development. Although not exclusively limited to the 1950s period, the literature tends to suggest that this decade was a particularly fruitful time for CNS drug discovery and it has been referred to as a "golden era".

Contents

Chlorpromazine

The history of chlorpromazine can be traced back to the work of BASF who were creating dyes at around the turn of the 20th century (c.f. methylene blue). It was found that attaching basic side chains to the tricyclic phenothiazine residue resulted in compounds that functioned as reliable antihistamines.

Henri Laborit was first using chlorpromazine to treat the anxiety of patients prior to surgery. He noted the so-called "indifference" that this agent causes and suggested that it be used on agitated psychotic patients. [1] [2]

Chlorpromazine has H1, M1, and α1 receptor antagonist activity. This causes sedation, anticholinergic effects, as well as orthostatic hypotension. It also functions as a blocker of D2 receptors, although it is much weaker and less selective than haloperidol in this respect. Blockade of the D2 receptors is thought to underlie the antipsychotic effect of the typical antipsychotics. However, in the case of atypicals such as clozapine and risperidone, blockade of 5HT2A receptors are thought to also account for an important part of their pharmacology.

Minor chemical manipulations in the chemical structure of chlorpromazine was used to create novel antipsychotic agents such as thioridazine and fluoperazine.

Imipramine

Minor chemical manipulations in the structure of chlorpromazine led to the first tricyclic antidepressant (TCA), imipramine (Tofranil), whose structure is iminodibenzyl (dibenzazepine) based. [3]

Imipramine was first used on agitated psychotic patients, but it was shown that in the majority of cases their condition did not improve and actually worsened slightly. However, it was noted that a few of the patients who were depressed became more animated so its use in the treatment of depression became apparent.

Due to the chemical similarity of imipramine to chlorpromazine, this agent also functions as a H1, M1, and α1 receptor antagonist. Imipramine is also known to function as a fast sodium channel blocker, which is said to account for the cardiotoxicity of this agent. The collective effect of imipramine on these receptors is not thought to contribute to its therapeutic activity in the treatment of depression, although it is believed to account for mostly all of its side effects.

The usefulness of the TCAs in treating depression is thought to stem from their ability to inhibit the uptake of the neurotransmitters serotonin (5-HT) and noradrenaline (NA). It was proposed that designing agents that were more selective for 5-HT and/or NA would lower the incidence of side effects. This in turn has led to the development/discovery of the SSRIs and SNRIs.

Iproniazid

The so-called golden era also covers the discovery of the first monoamine oxidase inhibitor, iproniazid (Marsilid), which is hydrazine based. Like imipramine, this also was used in the treatment of depression. [3]

Iproniazid was the result of a failed medicinal chemistry attempt to improve on the anti-tubercular activity of isoniazid. It was first given to patients with tuberculosis where a surprising but wholly unexpected improvement in mood was noticed. Nathan Kline coined the term "psychic energizer" to account for this effect and posited that they be used in the treatment of depression.

Iproniazid is no longer used because it caused an unacceptable incidence in jaundice. Nevertheless, related agents such as phenelzine and isocarboxazid are still on the market.

In addition, tranylcypromine is a non-hydrazine containing irreversible inhibitor of MAO which is also available.[ citation needed ]

A limitation of these agents is their potential to cause hypertension so their safety is not guaranteed. However, it seems that the selective inhibitor of the B isoform of MAO, selegiline, is much less likely to cause hypertension.

Theory of mood disorders

The investigations into the mechanism of activity of these agents that followed their discovery led to the proposal of the "chemical imbalance" of neurotransmitters theory of mood disorders, which is supposed to account for the pathophysiology and/or pathogenesis of these states. It follows that these so-called "imbalances" can be corrected by the judicious application of appropriately selected psychotropic medication(s).

An excess of dopamine is cited as the cause of schizophrenia, [4] whereas a deficiency of noradrenaline and serotonin were cited as the cause for depression.

The discovery of reserpine was also of great significance to the development of the monoamine amine theory of depression.

Prior to the 1950s

Prior to the introduction of these agents, the management of mental disorders in America relied mainly on "psychoanalytic" methods said to be deriving from a "Freudian" understanding of the subject area. [3] [5] Apparently, there was great resistance to the use of medicine in the treatment of mental disorders prior to the 1950s. It is, however, known that various other agents including amphetamine and opium have documented use in the history of treating depression, [6] [7] and that barbiturates, lithium salts, bromide salts, various anticholinergic alkaloids, as well as opium, were all used in the history of the treatment of schizophrenia. [8] [9]

Related Research Articles

<span class="mw-page-title-main">Antipsychotic</span> Class of medications

Antipsychotics, also known as neuroleptics, are a class of psychotropic medication primarily used to manage psychosis, principally in schizophrenia but also in a range of other psychotic disorders. They are also the mainstay together with mood stabilizers in the treatment of bipolar disorder.

<span class="mw-page-title-main">Tricyclic antidepressant</span> Class of medications

Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants, which is important for the management of depression. They are second-line drugs next to SSRIs. TCAs were discovered in the early 1950s and were marketed later in the decade. They are named after their chemical structure, which contains three rings of atoms. Tetracyclic antidepressants (TeCAs), which contain four rings of atoms, are a closely related group of antidepressant compounds.

<span class="mw-page-title-main">Chlorpromazine</span> Antipsychotic medication

Chlorpromazine (CPZ), marketed under the brand names Thorazine and Largactil among others, is an antipsychotic medication. It is primarily used to treat psychotic disorders such as schizophrenia. Other uses include the treatment of bipolar disorder, severe behavioral problems in children including those with attention deficit hyperactivity disorder, nausea and vomiting, anxiety before surgery, and hiccups that do not improve following other measures. It can be given orally, by intramuscular injection, or intravenously.

<span class="mw-page-title-main">Haloperidol</span> Typical antipsychotic medication

Haloperidol, sold under the brand name Haldol among others, is a typical antipsychotic medication. Haloperidol is used in the treatment of schizophrenia, tics in Tourette syndrome, mania in bipolar disorder, delirium, agitation, acute psychosis, and hallucinations from alcohol withdrawal. It may be used by mouth or injection into a muscle or a vein. Haloperidol typically works within 30 to 60 minutes. A long-acting formulation may be used as an injection every four weeks by people with schizophrenia or related illnesses, who either forget or refuse to take the medication by mouth.

<span class="mw-page-title-main">Typical antipsychotic</span> Class of drugs

Typical antipsychotics are a class of antipsychotic drugs first developed in the 1950s and used to treat psychosis. Typical antipsychotics may also be used for the treatment of acute mania, agitation, and other conditions. The first typical antipsychotics to come into medical use were the phenothiazines, namely chlorpromazine which was discovered serendipitously. Another prominent grouping of antipsychotics are the butyrophenones, an example of which is haloperidol. The newer, second-generation antipsychotics, also known as atypical antipsychotics, have largely supplanted the use of typical antipsychotics as first-line agents due to the higher risk of movement disorders in the latter.

<span class="mw-page-title-main">Atypical antipsychotic</span> Class of pharmaceutical drugs

The atypical antipsychotics (AAP), also known as second generation antipsychotics (SGAs) and serotonin–dopamine antagonists (SDAs), are a group of antipsychotic drugs largely introduced after the 1970s and used to treat psychiatric conditions. Some atypical antipsychotics have received regulatory approval for schizophrenia, bipolar disorder, irritability in autism, and as an adjunct in major depressive disorder.

<span class="mw-page-title-main">Ziprasidone</span> Antipsychotic medication

Ziprasidone, sold under the brand name Geodon among others, is an atypical antipsychotic used to treat schizophrenia and bipolar disorder. It may be used by mouth and by injection into a muscle (IM). The IM form may be used for acute agitation in people with schizophrenia.

<span class="mw-page-title-main">Akathisia</span> Movement disorder involving a feeling of inner restlessness

Akathisia is a movement disorder characterized by a subjective feeling of inner restlessness accompanied by mental distress and an inability to sit still. Usually, the legs are most prominently affected. Those affected may fidget, rock back and forth, or pace, while some may just have an uneasy feeling in their body. The most severe cases may result in aggression, violence, and/or suicidal thoughts. Akathisia is also associated with threatening behaviour and physical aggression that is greatest in patients with mild akathisia, and diminishing with increasing severity of akathisia.

<span class="mw-page-title-main">Maprotiline</span> Antidepressant

Maprotiline, sold under the brand name Ludiomil among others, is a tetracyclic antidepressant (TeCA) that is used in the treatment of depression. It may alternatively be classified as a tricyclic antidepressant (TCA), specifically a secondary amine. In terms of its chemistry and pharmacology, maprotiline is closely related to other secondary amine TCAs like nortriptyline and protriptyline, and has similar effects to them.

<span class="mw-page-title-main">Azapirone</span> Drug class of psycotropic drugs

Azapirones are a class of drugs used as anxiolytics, antidepressants, and antipsychotics. They are commonly used as add-ons to other antidepressants, such as selective serotonin reuptake inhibitors (SSRIs).

<span class="mw-page-title-main">Imipramine</span> Antidepressant

Imipramine, sold under the brand name Tofranil, among others, is a tricyclic antidepressant (TCA) mainly used in the treatment of depression. It is also effective in treating anxiety and panic disorder. Imipramine may also be used off-label for nocturnal enuresis and chronic pain. Imipramine is taken by mouth.

Biological psychiatry or biopsychiatry is an approach to psychiatry that aims to understand mental disorder in terms of the biological function of the nervous system. It is interdisciplinary in its approach and draws on sciences such as neuroscience, psychopharmacology, biochemistry, genetics, epigenetics and physiology to investigate the biological bases of behavior and psychopathology. Biopsychiatry is the branch of medicine which deals with the study of the biological function of the nervous system in mental disorders.

<span class="mw-page-title-main">Trimipramine</span> Antidepressant

Trimipramine, sold under the brand name Surmontil among others, is a tricyclic antidepressant (TCA) which is used to treat depression. It has also been used for its sedative, anxiolytic, and weak antipsychotic effects in the treatment of insomnia, anxiety disorders, and psychosis, respectively. The drug is described as an atypical or "second-generation" TCA because, unlike other TCAs, it seems to be a fairly weak monoamine reuptake inhibitor. Similarly to other TCAs however, trimipramine does have antihistamine, antiserotonergic, antiadrenergic, antidopaminergic, and anticholinergic activities.

<span class="mw-page-title-main">Chlorprothixene</span> Chemical compound

Chlorprothixene, sold under the brand name Truxal among others, is a typical antipsychotic of the thioxanthene group.

<span class="mw-page-title-main">Amisulpride</span> Atypical antipsychotic and antiemetic medication

Amisulpride is an antiemetic and antipsychotic medication used at lower doses intravenously to prevent and treat postoperative nausea and vomiting; and at higher doses by mouth to treat schizophrenia and acute psychotic episodes. It is sold under the brand names Barhemsys and Solian, Socian, Deniban and others. At very low doses it is also used to treat dysthymia.

<span class="mw-page-title-main">Dibenzepin</span> Chemical compound

Dibenzepin, sold under the brand name Noveril among others, is a tricyclic antidepressant (TCA) used widely throughout Europe for the treatment of depression. It has similar efficacy and effects relative to other TCAs like imipramine but with fewer side effects.

<span class="mw-page-title-main">Sulpiride</span> Atypical antipsychotic

Sulpiride, sold under the brand name Dogmatil among others, is an atypical antipsychotic medication of the benzamide class which is used mainly in the treatment of psychosis associated with schizophrenia and major depressive disorder, and sometimes used in low dosage to treat anxiety and mild depression. Sulpiride is commonly used in Asia, Central America, Europe, South Africa and South America. Levosulpiride is its purified levo-isomer and is sold in India for similar purpose. It is not approved in the United States, Canada, or Australia. The drug is chemically and clinically similar to amisulpride.

<span class="mw-page-title-main">Opipramol</span> Drug used to treat depressive and anxiety disorders

Opipramol, sold under the brand name Insidon among others, is an anxiolytic and tricyclic antidepressant that is used throughout Europe. Despite chemically being a tricyclic dibenzazepine (iminostilbene) derivative similar to imipramine, opipramol is not a monoamine reuptake inhibitor like most other tricyclic antidepressants, and instead, uniquely among antidepressants, acts primarily as a SIGMAR1 agonist. It was developed by Schindler and Blattner in 1961.

<span class="mw-page-title-main">Medifoxamine</span> Chemical compound

Medifoxamine, previously sold under the brand names Clédial and Gerdaxyl, is an atypical antidepressant with additional anxiolytic properties acting via dopaminergic and serotonergic mechanisms which was formerly marketed in France and Spain, as well as Morocco. The drug was first introduced in France sometime around 1990. It was withdrawn from the market in 1999 (Morocco) and 2000 (France) following incidences of hepatotoxicity.

<span class="mw-page-title-main">Cariprazine</span> Atypical antipsychotic medicine

Cariprazine, sold under the brand names Vraylar and Reagila among others, is an atypical antipsychotic originated by Gedeon Richter, which is used in the treatment of schizophrenia, bipolar mania, bipolar depression, and major depressive disorder. It acts primarily as a D3 and D2 receptor partial agonist, with a preference for the D3 receptor. Cariprazine is also a partial agonist at the serotonin 5-HT1A receptor and acts as an antagonist at 5-HT2B and 5-HT2A receptors, with high selectivity for the D3 receptor. It is taken by mouth.

References

  1. ↑ Rosenbloom, M (2002). "Chlorpromazine and the psychopharmacologic revolution". JAMA: The Journal of the American Medical Association. 287 (14): 1860–1. doi:10.1001/jama.287.14.1860. PMID   11939878.
  2. ↑ Ban, TA (2007). "Fifty years chlorpromazine: a historical perspective". Neuropsychiatric Disease and Treatment. 3 (4): 495–500. PMC   2655089 . PMID   19300578.
  3. 1 2 3 López-Muñoz, F.; Alamo, C. (2009). "Monoaminergic neurotransmission: the history of the discovery of antidepressants from 1950s until today". Current Pharmaceutical Design. 15 (14): 1563–1586. doi:10.2174/138161209788168001. PMID   19442174.
  4. ↑ Baumeister, A. A.; Francis, J. L. (2002). "Historical development of the dopamine hypothesis of schizophrenia". Journal of the History of the Neurosciences. 11 (3): 265–277. doi:10.1076/jhin.11.3.265.10391. PMID   12481477. S2CID   25572061.
  5. ↑ Baumeister, Alan; Hawkins, Mike (2005). "Continuity and Discontinuity in the Historical Development of Modern Psychopharmacology". Journal of the History of the Neurosciences. 14 (3): 199–209. doi:10.1080/096470490512562. PMID   16188699. S2CID   22697604.
  6. ↑ Ban, T. A. (2001). "Pharmacotherapy of depression: a historical analysis". Journal of Neural Transmission. 108 (6): 707–716. doi:10.1007/s007020170047. PMID   11478422. S2CID   19966517.
  7. ↑ Tenore, P. L. (2008). "Psychotherapeutic Benefits of Opioid Agonist Therapy". Journal of Addictive Diseases. 27 (3): 49–65. doi:10.1080/10550880802122646. PMID   18956529. S2CID   25882791.
  8. ↑ López-Muñoz, F; Ucha-Udabe, R; Alamo, C (2005). "The history of barbiturates a century after their clinical introduction". Neuropsychiatric Disease and Treatment. 1 (4): 329–43. PMC   2424120 . PMID   18568113.
  9. ↑ Ban, TA (2001). "Pharmacotherapy of mental illness--a historical analysis". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 25 (4): 709–27. doi:10.1016/s0278-5846(01)00160-9. PMID   11383974. S2CID   20630716.
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