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Psychotropic Use during Pregnancy
Published in “Bert” Bertis Britt Little, Drugs and Pregnancy, 2022
Animal teratology studies of monoamine oxidase inhibitors are not consistent. Some investigations have reported no increased frequency of birth defects with tranylcypromine (Poulson and Robson, 1963), but others studies reported an increase in mortality and stillbirth rates in the isocarboxazid group (Werboff et al., 1961). Placental infarcts were more frequent in pregnant rats treated with iproniazid during gestation (Poulson et al., 1960). No animal teratology studies are published regarding phenelzine.
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Published in Anton Sebastian, A Dictionary of the History of Medicine, 2018
Antidepressants [Greek: anti, against + deprimere, to press down or to lower] Lithium was recommended as treatment for gout by Alfred Baring Garrod (1819–1907) of King’s College, London in 1859 and became an over-the-counter treatment around 1867.As periodic depression was suspected to be due to uric acid diathesis, Alexander Haig in London tried lithium for depression in 1892. When the drug Iproniazid was used for the treatment of tuberculosis it was noted to produce an elevation of mood. This observation led to the search for similar compounds to treat depression – called ‘psychic energizers’ prior to use of the term ‘antidepressants’. Iproniazid was noted to have monoamine oxidase inhibiting properties in 1952 and further research led to the discovery of other tricyclic and monoamine drugs as treatment for depression. Imipramine, the first tricyclic compound with antidepressant properties, was developed by Ronald Kuhn in 1956. However, its parent substance iminobenzyl was synthesized by Thiele and Holzinger in 1898. See melancholy, lithium.
The Psychopharmacological Revolution
Published in Petteri Pietikainen, Madness, 2015
The new drugs were quickly taken into use at tuberculosis sanatoria. Soon there were reports of the energizing effects of these drugs. In 1952, Time magazine described how tuberculosis patients were dancing with joy, which prompted physicians to ponder on the usefulness of these drugs in the treatment of depression. Several groups began to test isoniazid and iproniazid on psychiatric patients, but the results were disappointing, and their use was curtailed in sanatoria (Whitaker 2010, 53). One might have thought that this would have been the end of iproniazid, but the psychiatrist Nathan Kline rescued the compound in 1957 with his clinical report, in which he claimed that if the depressed patients were kept on medication long enough – at least five weeks – then the drug was, after all, effective. Of the 16 patients in Kline’s trial, 14 were relieved of their symptoms, and some of them were totally symptom free. These figures impressed the psychiatric community. Most importantly, Kline’s observation was accurate: it took several weeks before iproniazid began to have an antidepressant effect. Kline, who some years earlier had told Frank Berger to call mebrobamate a ‘tranquillizer’, termed the new drug a ‘psychic energizer’. As a result of Kline’s report, iproniazid, brand-named Marsilid, was released in 1958 as an energizer. The new drug appeared to elicit a ‘Mona Lisa smile’ in depressed patients (Shorter 2009, 55; Valenstein 2001, 37–8).
Where do we go next in antidepressant drug discovery? A new generation of antidepressants: a pivotal role of AMPA receptor potentiation and mGlu2/3 receptor antagonism
Published in Expert Opinion on Drug Discovery, 2022
Andrzej Pilc, Agata Machaczka, Paweł Kawalec, Jodi L. Smith, Jeffrey M. Witkin
Multiple structurally and mechanistically distinct antidepressant drugs (ADDs) have been approved for use. A timeline of the introduction of antidepressant medications into the marketplace is shown in Figure 1 (see [4] for a detailed overview). The serendipitous discovery of the antidepressant effects of imipramine [5] and of iproniazid [6] helped to develop the monoaminergic hypothesis of depression [7,8] which posits that depression is caused by deficiencies in central monoamines such as norepinephrine and serotonin (5-HT) and that enhancing the availability of these monoamines can have antidepressant effects. Imipramine is an example of the first generation of ADDs. The second generation includes selective serotonin reuptake inhibitors (SSRIs) – fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, and escitalopram; selective noradrenergic reuptake inhibitors (SNRIs) – reboxetine; and dual serotonin/norepinephrine reuptake inhibitors – duloxetine, venlafaxine and milnacipran. Multimodal-acting ADDs are exemplified by vortioxetine that, in addition to acting as an SSRI also has agonist actions at serotonin receptors (5-HT1A and 5HT1B) and antagonist actions at other pre- and postsynaptic serotonin receptors (5-HT3 and 5-HT7) [9]. Some advantages of this compound, such as effects on depression-associated cognitive impairment, have been shown in clinical trial [10].
Modeling approaches for reducing safety-related attrition in drug discovery and development: a review on myelotoxicity, immunotoxicity, cardiovascular toxicity, and liver toxicity
Published in Expert Opinion on Drug Discovery, 2021
Elena M. Tosca, Roberta Bartolucci, Paolo Magni, Italo Poggesi
Hy’s law is a simple rule for predicting the potential mortality associated with DILI: in the most widely accepted version it indicates that alanine aminotransferase (ALT) (or aspartate aminotransferase, (AST)) increase >3-fold higher than ULN accompanied with clinical jaundice (e.g. with bilirubin levels >2-fold higher than ULN) without elevated alkaline phosphatase or Gilbert’s syndrome are associated with potential mortality [141]. This rule was considered valid and of general utility so that it was adopted by FDA to refuse to file some compounds (ibufenac, perhexiline, dilevalol, and tasosartan) [142,143] or for withdrawing drugs from the market (iproniazid, ticrynafen, benoxaprofen, trovofloxacin, bromfenac, and troglitazone) [143]. It is interesting to notice that this composite endpoint was not formally used as the outcome measurement for concluding whether a compound is leading to DILI or not. More recently, some very interesting activities have been undertaken in the field of system pharmacology (DILI-sym), the outcome of which was also used to interpret Hy’s rule cases [16].
MAO inhibitors and their wider applications: a patent review
Published in Expert Opinion on Therapeutic Patents, 2018
Simone Carradori, Daniela Secci, Jacques P. Petzer
The first indication for MAO inhibitors was for the treatment of depression, and iproniazid was the first such drug to be used in the clinic. Since serotonin and norepinephrine, the neurotransmitters implicated in depressive illness, are metabolized by MAO-A in the brain, specific inhibitors of the MAO-A isoform are used as antidepressants [23,24]. Although MAO-A inhibitors have fallen out of favor due to the risks associated with tyramine-induced hypertension, some irreversibly acting compounds such as tranylcypromine are still considered appropriate and highly effective, and with the appropriate dietary restrictions, safe for the treatment of major depression [25]. In fact, most drugs used to treat depression elevate neurotransmitter amine levels and thereby oxidative stress and neurotoxic aldehydes due to the increase metabolic turnover of these amines. It has thus been suggested that, in neurodegenerative disorders, antidepressant therapy should be initiated first with MAO inhibitors only, an approach aimed at reducing further neurodegeneration [26]. MAO-B inhibitors are used in the treatment of Parkinson’s disease and act by conserving the supply of central dopamine and, when co-administered with l-dopa, further enhance the levels of dopamine ‘artificially’ derived from l-dopa [27,28]. MAO-B inhibitors are thus established therapy in Parkinson’s disease and as monotherapy in early Parkinson’s disease may delay the need for l-dopa [29]. As discussed earlier, MAO-B inhibitors may also possess a neuroprotective role in Parkinson’s disease. In this respect, MAO-B inhibitors are advocated as treatment for other neurodegenerative disorders such as Alzheimer’s disease and Huntington’s disease, where central MAO-B activity and iron levels have been found to be increased [30]. As mentioned before, MAO-A specific inhibitors may find future as protectants against cardiac cellular degeneration [31]. Interestingly, MAO-A inhibitors may have a role in cancer treatment since MAO-A levels are found to be elevated in certain types of cancer tissue such as prostate cancer, and MAO-A inhibition may, in synergism with surviving suppressants, inhibit cancer cell growth, migration, and invasion [32,33]. Finally, MAO-B inhibitors have been investigated as aids to smoking cessation, possibly acting by increasing synaptic monoamine levels and thereby mimicking the effects of smoking [34,35].