DOCSLIB.ORG

Development of New Antidepressants Eleni Palazidou

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Development of New Antidepressants Eleni Palazidou Advances in Psychiatric Treatment (1997), vol. 3, pp. 46-51 Development of new antidepressants Eleni Palazidou The development of the first effective antidepressants noradrenergic system, led to the introduction of the in the late 1950s marked a turning point in the 'ßreceptor down-regulation hypothesis' proposed by treatment of depressive illness. In 1957 the mono- Sulser (1978), which challenged the hitherto univer amine oxidase inhibitor (MAOI) iproniazid was sally accepted 'monoamine hypothesis' of depression. discovered by chance, while searching for new The latter assumed a reduction in brain noradren- antituberculous drugs. One year later the tricyclic aline and serotonin (5-hydroxytryptamine; 5-HT) antidepressant (TCA) imipramine was introduced, concentrations as the cause of depression, therefore having been developed originally as an antipsychotic. requiring an increase in the availability of these A number of other drugs were subsequently added monoamines at the synaptic level to correct the deficit. to these two groups of antidepressants, which The ßreceptor down-regulation hypothesis proposed dominated the field for the next three decades. that a pathological 'supersensitivity' of the brain ß- In the 1970s and 1980s some new antidepressant adrenergic receptors was responsible for depressed drugs such as mianserin, zimeldine, nomifensine, mood state, and that this abnormality is corrected by maprotiline and trazodone were introduced. How antidepressant drug treatment, which leads to down- ever, it was the antidepressants developed in the late regulation (reduction in density) of ßreceptors. 1980s and the 1990s, more specifically the selective Subsequent research findings, however, show that serotonin reuptake inhibitors (SSRIs),which seriously the picture is much more complex. Changes in the threatened the position of the TCAs as the first-choice density and functional responsiveness of adrenergic drugs in the treatment of depression. receptors (the post-synaptic a, and pre-synaptic a, autoreceptors) as well as changes in the sensitivity of receptors within the serotoninergic (5-HT,and 5-HT,A Neurotransmitter function in receptor subtypes) and other central neurotransmitter systems have been demonstrated after chronic depression (>2 weeks) treatment with antidepressant drugs (Leonard, 1993), irrespective of their presumed pharmacological actions. The antidepressant drugs' The first-generation antidepressants served not ability to increase the availability of the neurotrans only as effective treatments for depression, but also mitter (noradrenaline or 5-HT) in the synaptic cleft, as investigative tools in the study of the bio by means of either inhibition of reuptake into the chemical basis of depression. A considerable body neuronal terminal (TCAs and SSRIs) or prevention of knowledge has been accumulated over the years of its breakdown (MAOIs), is only the beginning of a from both animal and clinical research, which used cascade of events involving changes in the sensitivity increasingly sophisticated methods such as of receptors at somatodendritic sites (5-HT1A receptor ligand technology and neuroimaging. receptors) and at the pre- and post-synaptic levels, as The introduction of receptor ligand technology in well as changes in neuronal signal transduction the 1970s allowed the examination of neuro- beyond the receptor. transmitter receptor status. Significant changes in the It is significant that the central neurotransmitter density of the receptors and in second messenger systems are functionally interdependent. The receptor production were demonstrated in animal exper changes described above are not limited to the iments on long-term antidepressant drug treatment. neurotransmitter system targeted by the particular The early experiments, limited to receptors within the antidepressant (the serotoninergic system for SSRIs Eleni Palazidou, MRCPsych, is Consultant Psychiatrist at the Royal London Hospital (St Clement's), 2A Bow Road, London E3 4LL, and Honorary Senior Lecturer at the Institute of Psychiatry, MRC Psychopharmacology Unit. She is particularly interested in the treatment of affective disorders. Development of antidepressants APT (1997), vol. 3, p. 47 or both the serotoninergic and adrenergic systems for receptors were identified and the production of TCAs and MAOIs). The close anatomical and selective receptor agonists/antagonists allowed physiological relationship between the neurotrans- examination of these receptors. The introduction of mitter systems militates against the notion of the the SSRIswas a turning point in the pharmacotherapy presence of two distinct biochemical depressive of depression, and the serotoninergic neurotransmit subtypes. Clinical studies provide further evidence ter system became the focus of study. More recently against the view that there may be separate noradren- the SSRIs have been joined by other types of ergic and serotoninergic depressive groups, with antidepressants such as the reversible monoamine preferential response to adrenergic or serotoninergic oxidase inhibitors (RIMAs), the serotonin/noradren- agents, respectively (Montgomery, 1982;Emrichef al, aline reuptake inhibitor (SNRI) venlafaxine, and other 1987). Nevertheless, there are subgroups of patients novel drugs. The new-generation antidepressants with specific clinical features who appear to respond differ from the older drugs in that they have a better to particular antidepressant drug groups. narrower pharmacological profile, increasing noradrenergic or serotoninergic activity, or both (Table 1), without significant direct effects on other central neurotransmitter systems. The main aims in the Development of new drugs development of the new antidepressants (which, so far, have only partly been achieved) were: (1) greater efficacy; The major progress made in our understanding of (2) absence of side-effects; the psychopharmacology of antidepressant drugs (3) lack of toxicity in overdose; and and the function of central neurotransmitter systems (4) earlier onset of action. in relation to mood state, guided the production of new antidepressants. The first antidepressants were discovered by serendipity, but subsequent antidepres Efficacy sant drug development has been to a great extent by design, with the noradrenergic and/or serotoninergic None of the antidepressants presently available has neurotransmitter systems as the primary targets. shown significantly superior efficacy in the In the 1970s and early 1980s the focus was on the treatment of depression in randomised controlled noradrenergic neurotransmitter system, partly trials or meta-analyses (see Anderson, 1997, this because of the greater understanding of its issue), although the possible superior efficacy in pharmacology, particularly in relation to receptor suicidality and the safety in overdose offer an function and the impact of the ßreceptor down- advantage to the SSRIs over TCAs in patients who regulation hypothesis of depression. The late 1980s present suicidal risk. In general, between 50 and 70% and the 1990s saw a rapid growth in the pharmacol of patients respond to the first antidepressant, ogy of the serotoninergic system. Several serotonin irrespective of its pharmacological profile. Tnble 1. Pharmacological actions of antidepressants Antidepressant Presumed mechanism of action Undesirable pharmacological actions TCAs Noradrenaline and 5-HT Anticholinergic; antihistaminic; c^-adrenoceptor reuptake inhibition antagonism; direct membrane stabilisation SSRIs 5-HT reuptake inhibition MAOIs Irreversible inhibition of MAO-A Interaction with tyramine and sympathomimetics; and MAO-B irreversible and non-selective MAO inhibition RIMA: moclobemide Reversible inhibition of MAO-A (Manerix) SNRI: venlafaxine 5-HT and noradrenaline reuptake (Effexor) inhibition Nefazodone 5-HT reuptake inhibition and 5-HT2 (Dutonin) receptor antagonism 5-HT, serotonin; MAO, monoamine oxidase; SSRIs - fluvoxamine (Faverin), fluoxetine (Prozac), paroxetine (Seroxat), sertraline (Lustral), citalopram (Cipromin); MAOIs - phenelzine (Nardil), isocarboxazid (Marplan), tranylcypromine (Parstelin); RIMA, reversible MAO inhibitor; SNRI, 5-HT/noradrenaline reuptake inhibitor. APT (1997), vol. 3, p. 48 Palazidott Side-effects and safety in overdose Box 2. Side-effect profile of SSRIs The older antidepressants are associated with a range of side-effects, which may affect compliance and Nausea/vomiting render them potentially dangerous. The TCAs have Abdominal pain a spectrum of pharmacological actions, many of Dry mouth which are seen as non-therapeutic and are responsible Constipation/diarrhoea for their fairly extensive side-effect profile (Box 1). Headache Because of their selectivity for the serotoninergic Asthenia system, the SSRIsare largely devoid of other clinically Dizziness significant pharmacological effects. However, they do Insomnia/somnolence have side-effects due to the effects of the SSRIs on the Sweating serotoninergic system and particular 5-HT receptors Anorexia (Box 2); for example, nausea and vomiting are Weight loss probably due to enhanced 5-HT., receptor activity. Nervousness/agitation Meta-analyses comparing the tolerability of the side- Tremor effects of the TCAs with those of the SSRIs (see Convulsions Anderson, 1997), and the adverse effects of newer Dystönie reactions (paroxetine) and older antidepressants, and their interactions Sexual dysfunction (reduced libido, (Henry, 1997) are discussed elsewhere in this issue. anorgasmia) Costs The
Load more

Recommended publications
  • Still the Leading Antidepressant After 40
    BRITISH JOURNAL OF PSYCHIATRY "2001), 178, 129^144 REVIEW ARTICLE Amitriptyline vv.therest:stilltheleading METHOD Inclusion criteria antidepressant after 40 years of randomised All RCTs comparing amitriptyline with any y other tricyclic,heterocyclic or SSRI were in- controlled trials cluded. Crossover studies were excluded. Studies adopting any criteria to define CORRADO BARBUI and MATTHEW HOTOPF patients suffering from depression were included; a concurrent diagnosis of another psychiatric disorder was not considered an exclusion criterion. Trials in patients with depression with a concomitant medical ill- Background Tricyclic antidepressants Amitriptyline is one of the first `reference' ness were not included in this review. have similar efficacy and slightly lower tricyclic antidepressants TCAs). Over the past 40 years a number of newer tricyclics, tolerability than selective serotonin Search strategy heterocyclics and selective serotonin re- Relevant studies were located by searching reuptakeinhibitorsreuptake inhibitors SSRIs).However, uptake inhibitors SSRIs) have been intro- the Cochrane Collaboration Depression, there are no systematic reviews assessing duced Garattini et aletal,1998). Despite Anxiety and Neurosis Controlled Trials several large systematic reviews comparing amitriptyline, the reference tricyclic drug, Register CCDANCTR). This specialised tricyclics and SSRIs there is no clear agree- vv. other tricyclics and SSRIs directly. register is regularly updated by electronic ment over first-line treatment of depression Medline,Embase,PsycINFO,LILACS, SongSong et aletal,1993; Anderson & Tomenson, Aims ToreviewTo review the tolerability and Psyndex,CINAHL,SIGLE) and non-electro- 1995; Montgomery & Kasper,1995; efficacy of amitriptyline inthe nicnicliterature searches. The register was HotopfHotopf et aletal,1996; Canadian Coordinating management of depression. searched using the following terms: Office for Health Technology Assessment, AMITRIPTYLIN**AMITRIPTYLIN oror AMITRILAMITRIL oror ELA-ELA- 19971997aa).
    [Show full text]
  • Still the Leading Antidepressant After 40 Years of Randomised Controlle
    BRITISH JOURNAL OF PSYCHIATRY "2001), 178, 129^144 REVIEW ARTICLE Amitriptyline vv.therest:stilltheleading METHOD Inclusion criteria antidepressant after 40 years of randomised All RCTs comparing amitriptyline with any y other tricyclic,heterocyclic or SSRI were in- controlled trials cluded. Crossover studies were excluded. Studies adopting any criteria to define CORRADO BARBUI and MATTHEW HOTOPF patients suffering from depression were included; a concurrent diagnosis of another psychiatric disorder was not considered an exclusion criterion. Trials in patients with depression with a concomitant medical ill- Background Tricyclic antidepressants Amitriptyline is one of the first `reference' ness were not included in this review. have similar efficacy and slightly lower tricyclic antidepressants TCAs). Over the past 40 years a number of newer tricyclics, tolerability than selective serotonin Search strategy heterocyclics and selective serotonin re- Relevant studies were located by searching reuptakeinhibitorsreuptake inhibitors SSRIs).However, uptake inhibitors SSRIs) have been intro- the Cochrane Collaboration Depression, there are no systematic reviews assessing duced Garattini et aletal,1998). Despite Anxiety and Neurosis Controlled Trials several large systematic reviews comparing amitriptyline, the reference tricyclic drug, Register CCDANCTR). This specialised tricyclics and SSRIs there is no clear agree- vv. other tricyclics and SSRIs directly. register is regularly updated by electronic ment over first-line treatment of depression Medline,Embase,PsycINFO,LILACS, SongSong et aletal,1993; Anderson & Tomenson, Aims ToreviewTo review the tolerability and Psyndex,CINAHL,SIGLE) and non-electro- 1995; Montgomery & Kasper,1995; efficacy of amitriptyline inthe nicnicliterature searches. The register was HotopfHotopf et aletal,1996; Canadian Coordinating management of depression. searched using the following terms: Office for Health Technology Assessment, AMITRIPTYLIN**AMITRIPTYLIN oror AMITRILAMITRIL oror ELA-ELA- 19971997aa).
    [Show full text]
  • Tcas Versus Placebo - New Studies in the Guideline Update
    TCAs versus placebo - new studies in the guideline update Comparisons Included in this Clinical Question Amitriptyline vs placebo Clomipramine vs placebo Dosulepin (dothiepin) vs placebo AMSTERDAM2003A LARSEN1989 FERGUSON1994B BAKISH1992B PECKNOLD1976B ITIL1993 BAKISH1992C RAMPELLO1991 MINDHAM1991 BREMNER1995 THOMPSON2001B CLAGHORN1983 CLAGHORN1983B FEIGHNER1979 GELENBERG1990 GEORGOTAS1982A GOLDBERG1980 HICKS1988 HOLLYMAN1988 HORMAZABAL1985 HOSCHL1989 KLIESER1988 LAAKMAN1995 LAPIERRE1991 LYDIARD1997 MYNORSWALLIS1995 MYNORSWALLIS1997 REIMHERR1990 RICKELS1982D RICKELS1985 RICKELS1991 ROFFMAN1982 ROWAN1982 SMITH1990 SPRING1992 STASSEN1993 WILCOX1994 16 Imipramine vs placebo BARGESCHAAPVELD2002 BEASLEY1991B BOYER1996A BYERLEY1988 CASSANO1986 CASSANO1996 CLAGHORN1996A COHN1984 COHN1985 COHN1990A COHN1992 COHN1996 DOMINGUEZ1981 DOMINGUEZ1985 DUNBAR1991 ELKIN1989 ENTSUAH1994 ESCOBAR1980 FABRE1980 FABRE1992 FABRE1996 FEIGER1996A FEIGHNER1980 FEIGHNER1982 FEIGHNER1983A FEIGHNER1983B FEIGHNER1989 FEIGHNER1989A FEIGHNER1989B FEIGHNER1989C FEIGHNER1992B FEIGHNER1993 FONTAINE1994 GELENBERG2002 GERNER1980B HAYES1983 ITIL1983A KASPER1995B KELLAMS1979 LAIRD1993 LAPIERRE1987 LECRUBIER1997B LIPMAN1986 LYDIARD1989 MARCH1990 17 MARKOWITZ1985 MENDELS1986 MERIDETH1983 Nortriptyline vs placebo NANDI1976 GEORGOTAS1986A NORTON1984 KATZ1990 PEDERSEN2002 NAIR1995 PESELOW1989 WHITE1984A PESELOW1989B PHILIPP1999 QUITKIN1989 RICKELS1981 RICKELS1982A RICKELS1987 SCHWEIZER1994 SCHWEIZER1998 SHRIVASTAVA1992 SILVERSTONE1994 SMALL1981 UCHA1990 VERSIANI1989 VERSIANI1990
    [Show full text]
  • Resume of Scientific Contributions to Psychopharmacology And
    RESUME OF SCIENTIFIC CONTRIBUTIONS TO PSYCHOPHARMACOLOGY AND BIOLOGICAL PSYCHIATRY While Fridolin Sulser was a visiting scientist from Switzerland in the Laboratory of Chemical Pharmacology at the National Institutes of Health in Bethesda, Maryland, he and B.B. Brodie utilized the reserpine-like syndrome as a "model depression" and in due course discovered the secondary amine desmethyl-imipramine (DM1) formed in vivo by oxidative N-demethylation of imipramine (1,2).DMI turned out to be the first selective inhibitor of the high affinity uptake of norepinephrine and triggered the development of many secondary amines of tricyclic antidepressants as therapeutic agents (e.g. desipramine, nortriptyline, protriptyline maprotiline, oxaprotiline, and more recently reboxetine). These drugs provided more selective pharmacologic tools to dissect the role of central noradrenergic mechanisms (3). During the early 1970s, Fridolin Sulser and his associates discovered that treatment with antidepressants on a clinically relevant time basis (including tricyclics, 4- Fridolin Sulser, M.D. Curriculum Vitae MAO inhibitors, some atypical antidepressants and electroconvulsive treatment) reduces selectively the responsiveness of the norepinephrine (NE) beta adrenoceptor coupled adenylate cyclase system in limbic and cortical structures of the rat brain (4,5). This deamplification of the central beta adrenoceptor system is often linked to a down- regulation of the Brnax value of beta adrenoceptors, without changes in the KD. These findings shifted the research emphasis on the mode of action of antidepressant treatments and on the pathophysiology of affective disorders from acute presynaptic to delayed post-synaptic receptor - second messenger mediated events and emphasized the role of adaptive processes at the level of signal transduction and opened the gateway for subsequent studies on changes of programs of gene expression.
    [Show full text]
  • Pjp2'2002.Vp:Corelventura
    Copyright © 2002 by Institute of Pharmacology Polish Journal of Pharmacology Polish Academy of Sciences Pol. J. Pharmacol., 2002, 54, 8993 ISSN 1230-6002 EFFECT OF IMIPRAMINE ON BRAIN D-1 AND 5-HT-2A RECEPTORS IN A CHRONIC UNPREDICTABLE STRESS MODEL IN RATS Gra¿yna Ossowska1,#, Gabriel Nowak2,3, Bo¿ena Klenk-Majewska1, Zofia Danilczuk1, Iwona ¯ebrowska-£upina1 Department of Clinical Pharmacology, Medical University School, Jaczewskiego 8, PL 20-090 Lublin, Poland, Institute of Pharmacology, Polish Academy of Sciences, Smêtna 12, PL 31-343 Kraków, Poland, !Department of Pharmacobiology, Collegium Medicum, Jagiellonian University, Medyczna 9, PL 30-688 Kraków, Poland Effect of imipramine on brain D-1 and 5-HT-2A receptors in chronic un- predictable stress model in rats. G. OSSOWSKA, G. NOWAK, B. KLENK- -MAJEWSKA, Z. DANILCZUK, I. ¯EBROWSKA-£UPINA. Pol. J. Phar- macol., 2002, 54, 89–93. Chronic unpredictable stress (CUS) model of depression is one of the well validated animal models of depression. In this paper, we report the re- sults of investigations into dopaminergic D-1 and serotonergic 5-HT-2A re- ceptors in the brain of rats subjected to CUS procedure and treated chroni- cally with imipramine. We have examined the dopaminergic D-1 ([!H-SCH 23390) in the limbic area and serotonergic 5-HT-2A ([!H-ketanserin) recep- tors in the cerebral cortex by a saturation radioligand binding method in rats subjected to CUS paradigm, imipramine, both CUS and imipramine and control animals. CUS procedure resulted in a significant 36% increase in the D-1 receptor density in the limbic system, which was attenuated by chronic imipramine treatment.
    [Show full text]
  • Centre for Reviews and Dissemination
    Selective serotonin reuptake inhibitors (SSRIs) for major depression. Part 1: evaluation of the clinical literature Trindade E, Menon D Authors' objectives To review the efficacy and safety of selective serotonin re-uptake inhibitors (SSRIs) when used to treat major depression. Searching MEDLINE, EMBASE, PsycINFO, International Pharmaceutical Abstracts, Pascal, Health Planning and Administration database, Mental Health Abstracts, and PharmacoEconomics and Outcomes News, were searched from 1980 to 1996. Details of the search terms used were provided. In addition, Current Contents was scanned during the course of the project, and journals received by the Canadian Coordinating Office for Health Technology Assessment library were handsearched. The bibliographies from retrieved papers, those provided by other researchers, and those from earlier publications on the subject were examined (see Other Publications of Related Interest nos.1-2). Study selection Study designs of evaluations included in the review Double-blind randomised controlled trials (RCTs), including 2- and 3-arm trials, were eligible for inclusion. Specific interventions included in the review Antidepressant therapy of 4 to 12 weeks' duration, using SSRIs including fluoxetine, fluvoxamine, paroxetine and sertraline. The comparator regimens included placebo, an alternative SSRI, or other types of antidepressants. The latter included tricyclic antidepressants (TCAs) (amitriptyline, imipramine, clomipramine, dothiepin, doxepin, maprotiline, oxaprotiline, lofepramine, desipramine,
    [Show full text]
  • Maois in the Contemporary Treatment of Depression Michael E
    ELSEVIER REVIEW MAOis in the Contemporary Treatment of Depression Michael E. Thase, M.D., Madhukar H. Trivedi, M.D., and A. John Rush, M.D. We review the literature on the effectiveness of the comparator tricyclics for inpatients, whereas monoamine oxidase inhibitors (MAOis) and present tranylcypromine has not been adequately studied. Both metaanalyses of controlled trials comparing the FDA­ phenelzine and tranylcypromine appear to be more approved MAOis with both placebo and comparator effective than tricyclics in depressed outpatients with tricyclic antidepressants. For outpatients, metaanalyses atypical features. Monoamine oxidase inhibitors are also with intent-to-treat samples revealed generally comparable effective treatments for outpatients who have failed to overall efficacy for phenelzine, isocarboxazid, and respond to tricyclic antidepressants. Our review also tranylcypromine. Drug-placebo differences were 29. 5% suggests (1) the FDA-approved MAO!s treat a somewhat (± 11.1%) (phenelzine; nine studies), 41.3% (±18.0%) different group of patients than tricyclics; (2) more (isocarboxazid; three studies), and 22.1 % ( ± 25.4%) severely depressed inpatients may not respond as well to (tranylcypromine; three studies). For inpatients, MAO Is as to tricyclics; and (3) because of preferential phenelzine was 22.3% ( ± 30. 7%) (five studies) more MAO! responsivity, atypical or anergic depressions may effective than placebo, whereas the isocarboxazid-placebo be biologically different than classical depressions. difference was lower (15.3%) ( ± 12.6%). Both phenelzine [Neuropsychopharmacology 12:185-219, 1995] and isocarboxazid were significantly less effective than KEY WORDS: Phenelzine; Tranylcypromine; 1991) for reasons of both efficacy and safety. In this re­ Isocarboxazid; MAOis; Depression; Antidepressant port, we review the literature on the MAOls currently efficacy; Metaanalysis approved for the treatment of depression in the United Monoamine oxidase inhibitor (MAOI) antidepressants States by the Food and Drug Administration (FDA).
    [Show full text]
  • Supplemental Digital Content 1 Search Strategy (First Conducted on January 17, 2014; Second Retrieval on November 5, 2014)
    Supplemental Digital Content 1 Search strategy (first conducted on January 17, 2014; second retrieval on November 5, 2014) Cochrane Central Register of Controlled Trials and MEDLINE via OVID 1. exp chronic pain/ 2. Pain Management/ 3. Pain Measurement/ 4. pain*.mp. 5. 1 or 2 or 3 or 4 11. exp neoplasms/ 12. (neoplas* or cancer* or tumor* or tumour* or carcinoma* or malignan* or oncolog* or metasta* or sarcoma* or adenocarcinoma* or choriocarcinoma* or leukemia* or leukaemia*).mp. 13. 11 or 12 14. exp Anticonvulsants/ or exp Antidepressive Agents/ 15. (anticonvulsant* or antiepilept* or antidepressant* or anti-convulsant* or anti-epilept* or anti-depressant*).mp. 16. (acetazolamide or carbamazepine or clonazepam or divalproex or ethosuximide or ethotoin or felbamate or fosphenytoin or gabapentin or lacosamide or lamotrigine or levetiracetam or methsuximide or oxcarbazepine or phenobarbital or phenobarbitone or phenytoin or pregabalin or primidone or tiagabine or topiramate or trimethadione or valproate or valproic or vigabatrin or zonisamide).mp. 17. (agomelatine or amesergide or amineptine or amitriptyline or amoxapine or aripiprazole or benactyzine or brofaromine or bupropion or butriptyline or chlorimipramine or cianopramine or citalopram or clomipramine or clorgyline or clovoxamine or demexiptiline or desipramine or desvenlafaxine or dibenzepin or dimetacrine tartrate or dosulepin or dothiepin or doxepin or duloxetine or escitalopram or etoperidone or femoxetine or fezolamine fumarate or fluoxetine or fluvoxamine or ifoxetine or imipramine
    [Show full text]
  • United States Patent (10) Patent No.: US 9,572.814 B2 Casseday Et Al
    USOO9572814B2 (12) United States Patent (10) Patent No.: US 9,572.814 B2 Casseday et al. (45) Date of Patent: *Feb. 21, 2017 (54) METHODS OF IMPROVING THE 5,116,852 A 5/1992 Gammans PHARMACOKINETCS OF DOXEPN 5,332,661 A 7, 1994 Adamczyk et al. 5,502,047 B1 3/1996 Kavey (71) Applicant: Prix Sleep, Inc., Morristown, NJ 5,643,8975,585,115 A 12/19967/1997 SherwoodKavey et al. ( ) 5,725,883 A 3, 1998 Staniforth et al. 5,725,884 A 3, 1998 Sh d et al. (72) Inventors: Cara Baron Casseday, San Diego, CA 5,733,578 A 3, 1998 NE al (US); Elizabeth Ludington, San Diego, 5,741,524. A 4, 1998 Staniforth et al. CA (US); Michael Skinner, San Diego, 5,858.412 A 1/1999 Staniforth et al. CA (US); Susan E. Dubé, Carlsbad, 5,866,166 A 2f1999 Staniforth et al. CA (US); Roberta L. Rogowski 5.948,438 A 9, 1999 Staniforth et al. S. St.s i. y PhilipDi 6,103,2195,965,166 A 10/19998/2000 SherwoodHunter et al.et al. ochelson San Diego, CA (US); 6,106,865 A 8, 2000 Staniforth et al. Robert Mansbach, San Diego, CA 6,211,229 B1 4, 2001 Kavey (US) 6,217,907 B1 4/2001 Hunter et al. 6,217.909 B1 4/2001 Sherwood et al. (73) Assignee: Pernix Sleep, Inc., Morristown, NJ 6,219,674 B1 4/2001 Classen (US) 6,344,487 B1 2/2002 Kavey 6,358,533 B2 3/2002 Sherwood et al.
    [Show full text]
  • Comparative Efficacy and Acceptability of Antimanic Drugs in Acute Mania: a Multiple-Treatments Meta-Analysis
    COMPARATIVE EFFICACY AND ACCEPTABILITY OF PHARMACOLOGICAL TREATMENTS IN THE ACUTE PHASE TREATMENT OF BIPOLAR DEPRESSION: A MULTIPLE TREATMENT META-ANALYSIS [PROTOCOL] Tomofumi Miura, Toshi A. Furukawa, Hisashi Noma, Shiro Tanaka, Keisuke Motomura, Hiroshi Mitsuyasu, Satomi Katsuki, Andrea Cipriani, Sarah Stockton, John Geddes, Georgia Salanti, Shigenobu Kanba Background Description of the condition In late 19th century, Emil Kraepelin classified the major endogenous psychoses into two psychotic illnesses, manic-depressive illness and dementia praecox (Kraepelin’s dichotomy) (Trede et al. , 2005). His concept of manic-depressive illness had covered all of the major clinical forms of severe, moderate and mild melancholia. In 1957, Leonhard proposed to distinguish Kraepelin’s manic-depressive illness into bipolar illness, in which patients had histories of both depression and mania, and monopolar illness, in which patients only had histories of depression (Leonhard, 1979). This basic idea of the bipolar-unipolar distinction was supported by Angst and by Perris in 1966 (Angst, 1966, Perris, 1966), and it continues in the recent diagnostic classification system of mood disorders in DSM-IV(American Psychiatric Association, 1994) and ICD-10 (WHO, 1993). Bipolar disorder is a complex disorder, which is characterized by recurrent episodes of depression and mania (bipolar I disorder) or hypomania (bipolar II disorder)(American Psychiatric Association, 1994). The lifetime prevalence of any bipolar disorders, bipolar I and II disorders have been estimated at 1.1%, 0.7% and 0.5% respectively using the World Mental Health Survey version of the WHO Composite International Diagnostic Interview (Suppes et al. , 2001). The mean age at onset of bipolar disorder is reported to be in the early 20s, but its complex clinical features make its diagnosis difficult and there is a difference of about 8 years between age at onset and age at first treatment (Suppes, Leverich, 2001).
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 7,915,307 B2 Casseday Et Al
    USOO7915307B2 (12) United States Patent (10) Patent No.: US 7,915,307 B2 Casseday et al. (45) Date of Patent: Mar. 29, 2011 (54) METHODS OF IMPROVING THE 2003/0235617 A1 12/2003 Martino et al. PHARMACOKINETCS OF DOXEPIN 2005, 0123609 A1 6/2005 Hirsh et al. 2005/0239838 A1 10/2005 Edgar et al. (75) Inventors: Cara Baron Casseday, San Diego, CA FOREIGN PATENT DOCUMENTS (US); Elizabeth Ludington, San Diego, WO WO99/40898 8, 1999 CA (US); Michael Skinner, San Diego, OTHER PUBLICATIONS CA (US); Susan Dubé, Carlsbad, CA http://apma-nc.com/PatientEducation/INSOMNIA.HTM. 2000, (US); Roberta L. Rogowski, Rancho 1-4. Santa Fe, CA (US); Philip Jochelson, Prescription Drugs, http://www.grandtimes.com/Answer Drugs. San Diego, CA (US); Robert html, 1999, 1-3.* Mansbach, San Diego, CA (US) Adapin, http://www.depression-guide.com/adapin.htm, 2005, 1-3.* Somaxon's SILENORTM Demonstrates Positive Results in Long Term Phase 3 Clinical Trial in Elderly Patients with Insomnia, (73) Assignee: Somaxon Pharmaceuticals, Inc., San Somaxon Pharmaceuticals, p. 1-7, (Dec. 18, 2006). Diego, CA (US) Somaxon Pharmaceuticals Announces Positive Results in a Phase II Dose-Finding Study of Low-dose Doxepin in Adults with Primary (*) Notice: Subject to any disclaimer, the term of this Sleep Maintenance Insomnia, Somaxon Pharmaceuticals, p. 1-2, patent is extended or adjusted under 35 (Jan. 6, 2005). Somaxon Pharmaceuticals Announces Positive Results in a Phase II U.S.C. 154(b) by 35 days. Dose-Finding Study of Low-Dose Doxepin in Elderly Patients with Primary Sleep Maintenance Insomnia, Somaxon Pharmaceuticals, p.
    [Show full text]
  • Pharmacogenetics of Antidepressants and Antipsychotics
    Molecular Psychiatry (2004) 9, 442–473 & 2004 Nature Publishing Group All rights reserved 1359-4184/04 $25.00 www.nature.com/mp FEATURE REVIEW Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response J Kirchheiner1, K Nickchen1, M Bauer2, M-L Wong3, J Licinio3, I Roots1 and J Brockmo¨ller4 1Institute of Clinical Pharmacology, Campus Charite´ Mitte, University Medicine Berlin, Berlin, Germany; 2Department of Psychiatry and Psychotherapy, Campus Charite´ Mitte, University Medicine Berlin, Berlin, Germany; 3Center for Pharmacogenomics and Interdepartmental Clinical Pharmacology Center, Neuropsychiatric Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; 4Department of Clinical Pharmacology, Georg August University, Go¨ttingen, Germany Genetic factors contribute to the phenotype of drug response. We systematically analyzed all available pharmacogenetic data from Medline databases (1970–2003) on the impact that genetic polymorphisms have on positive and adverse reactions to antidepressants and antipsychotics. Additionally, dose adjustments that would compensate for genetically caused differences in blood concentrations were calculated. To study pharmacokinetic effects, data for 36 antidepressants were screened. We found that for 20 of those, data on polymorphic CYP2D6 or CYP2C19 were found and that in 14 drugs such genetic variation would require at least doubling of the dose in extensive metabolizers in comparison to poor metabolizers. Data for 38 antipsychotics were examined: for 13 of those CYP2D6 and CYP2C19 genotype was of relevance. To study the effects of genetic variability on pharmacodynamic pathways, we reviewed 80 clinical studies on polymorphisms in candidate genes, but those did not for the most part reveal significant associations between neurotransmitter receptor and transporter genotypes and therapy response or adverse drug reactions.
    [Show full text]