Neurotransmitters Mechanisms and Antidepressants

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Neurotransmitters Mechanisms and Antidepressants

SP.236: Pharmacology Antidepressants Zak Fallows A note on layout: The neurotransmitters are listed from the most often targeted by antidepressant drugs (serotonin) to the least often targeted (dopamine). The mechanisms are listed in functional or “life cycle” order from the perspective of the neurotransmitter, which is first synthesized, then released, binds receptors, and ultimately is broken down. The drug classes are listed in order of historical discovery. High: Low: Serotonin SER, 5-HT Satiety Fullness, contentment Anxiety, OCD, aggression, hungry Neurotransmitters Norepinephrine NE Fight or flight Alert, concentration, memory Inattentive Dopamine DA Salience Reward, desire, learning, alert Inactive, unmotivated, hungry Example: Boosts: Used for: Increase synthesis Levodopa, 5-HTP DA and SER, respectively PD and useless, respectively Cause release Amphetamine (Adderall®) NE > DA >> SER ADHD, narcolepsy Mechanisms Receptor agonist Pramipexole DA Parkinson’s (PD) (to boost NT) Partial agonist Buspirone (BuSpar®) SER Anxiety > depression Presynaptic antagonist Mirtazapine (Remeron®) SER, NE Depression > anxiety Inhibit reuptake Fluoxetine (Prozac®) SER Depression, anxiety, OCD Inhibit breakdown Phenelzine (Nardil®) SER, NE, DA Depression > anxiety First: Notable: Mechanism: Chlorpromazine Antipsychotics* 1952 Haloperidol (Haldol®) Antagonist* (Thorazine®) Monoamine Iproniazid and Phenelzine, selegiline, Inhibit MAOIs 1953 Antidepressant oxidase inhibitors isoniazid moclobemide, harmaline breakdown Tricyclic Imipramine Amitriptyline (Elavil®), Inhibit classes TCAs 1955 antidepressants (Tofranil®) chlomipramine (Anafranil®) reuptake Fluoxetine (Prozac®), sertraline (Zoloft®), Selective serotonin paroxetine (Paxil®), citalopram (Celexa®), Inhibit SSRIs 1977 Zimelidine reuptake inhibitors escitalopram (Lexapro®), fluvoxamine reuptake (Luvox®), dapoxetine MIT OpenCourseWare http://ocw.mit.edu ES.S10 Drugs and the Brain Spring 2013 For information about citing these materials or our Terms of Use, visit: http://ocw.mit.edu/terms..

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Review: Multiple Daily Doses of Antidepressants Are Not More Effective Than Single Daily Doses
Evid Based Mental Health: first published as 10.1136/ebmh.5.2.57 on 1 May 2002. Downloaded from Review: multiple daily doses of antidepressants are not more effective than single daily doses Yildiz A, Sachs GS. Administration of antidepressants. Single versus split dosing: a meta-analysis. J Affect Disord 2001 Oct;66:199–206. QUESTIONS: In patients with depression, are multiple daily doses (MDD) of antidepressants more effective than single daily doses (SDD)? Does the pharmacokinetic half life of a drug inﬂuence the antidepressant activity of single daily doses? Data sources mean improvement from baseline was 90% for SDD Source of funding: Studies were identified by searching {PubMed}* with the and 87% for MDD. not stated. terms antidepressants, single daily dosing versus, multi- ple daily dosing, and antidepressant efficacy. Conclusions For correspondence: Dr A Yildiz, Dokuz In patients with depression, multiple daily doses of anti- Eylul Medical School, depressants are not more effective than single daily Study selection Izmir, Turkey and doses. Grouping the studies by pharmacokinetic half life Harvard Medical Studies were selected if they were randomised control- of the drug does not show an advantage for multiple School, Boston, MA, led trials (RCTs) that compared dosing schedules of the daily doses over single daily doses. USA same antidepressant (with 1 group receiving SDD) and if Agul_yildiz@hotmail. the total daily dose in the SDD and MDD groups were *Information provided by author. com the same. COMMENTARY Data extraction Single daily doses of antidepressants have always been considered inappropriate for Data were extracted on study characteristics, drug short elimination half life drugs.
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850 Physical Examination Or Selective Physical Examin Ation, and Special
850 CORRESPONDENCE mental state examination and, where indicated, a issue â€”¿wouldchanging to an SSRI be equally as physical examination or selective physical examin effective as adding one? One influential study (Nolen ation, and special investigations. This applies as eta!,1988)foundno benefitinchangingtofluvo much to people with Down's syndrome as it does to xamine for patients who were tricycic antidepressant the general population. non-responders, and is frequently cited to dismiss the We hope our papers help to establish that people strategy.However,a number ofotherauthorshave with Down's syndrome experience increased rates of found that a clinically significant proportion of tri certain psychiatric disorders, and that the pattern cyclic non-responders do respond to a subsequent of adaptive behaviour in these individuals changes SSRI given alone (Lingjaerde eta!, 1983; Delgado et with age. There is, of course, a distinction between al, 1988; Beasley et a!, 1990; White et a!, 1990). descriptive psychopathology by which a psychiatric Admittedly these have been open studies but I would diagnosis is made, and aetiological factors which argue that it is premature to dismiss changing to contribute to the described illness. Having estab another non-monoamine oxidase inhibitor anti lished different rates of psychiatric disorders, the depressant in favour of combination drug treatment next stage is to determine the relevant aetiological on current evidence. Further research is required factors. The view of Drs Prasher & Krishnan, that to determine the best â€˜¿second-step'treatmentfor sensory impairment and medical illness account for patients failing to respond to an adequate trial of a the altered rates of psychiatric disorders, is specu tricyclic antidepressant drug.
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Inhibitory Action of Antidepressants on Mouse Betaine/GABA Transporter (BGT1) Heterologously Expressed in Cell Cultures
Int. J. Mol. Sci. 2012, 13, 2578-2589; doi:10.3390/ijms13032578 OPEN ACCESS International Journal of Molecular Sciences ISSN 1422-0067 www.mdpi.com/journal/ijms Article Inhibitory Action of Antidepressants on Mouse Betaine/GABA Transporter (BGT1) Heterologously Expressed in Cell Cultures Gerile 1, Chiharu Sogawa 1, Kazumi Ohyama 2, Takashi Masuko 3, Tadashi Kusama 3, Katsuya Morita 4, Norio Sogawa 1 and Shigeo Kitayama 1,* 1 Department of Dental Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8525, Japan; E-Mails: [email protected] (G.); [email protected] (C.S.); [email protected] (N.S.) 2 RI Research Center, Okayama University Dental School, Okayama 700-8525, Japan; E-Mail: [email protected] 3 Laboratory of Physiology and Anatomy, College of Pharmacy, Nihon University, Funabashi 274-8555, Japan; E-Mails: [email protected] (T.M.); [email protected] (T.K.) 4 Department of Dental Pharmacology, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima 734-8553, Japan; E-Mail: [email protected] * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel: +81-86-235-6660; Fax: +81-86-235-6664. Received: 29 December 2011; in revised form: 28 January 2012 / Accepted: 17 February 2012 / Published: 24 February 2012 Abstract: Betaine/γ-aminobutyric acid (GABA) transporter (BGT1, SLC6A12) is a member of the Na+- and Cl−-dependent neurotransmitter transporter gene family with a homology to the GABA transporters (GATs), GAT1 (SLC6A1), GAT2 (SLC6A13) and GAT3 (SLC6A11) (HUGO nomenclature).
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Serotonin Transporter Occupancy with Tcas and Ssris: a PET Study in Patients with Major Depressive Disorder
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Serum Fluoxetine and Norfluoxetine Levels Support the Safety of Fluoxetine in Overdose Stephanie Pope* and Solomon G
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Trazodone Hydrochloride in the Treatment of Dysesthetic Pain in Traumatic Myelopathy: a Randomized, Double-Blind, Placebo-Controlled Study
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Antagonism of Nicotinic Acetylcholine Receptors by Inhibitors of Monoamine Uptake HE Lo´Pez-Valde´S and J GarcıÁ-Colunga
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Inhibition of G Protein-Activated Inwardly Rectifying K+ Channels By
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Duloxetine Increases Serotonin and Norepinephrine Availability in Healthy Subjects: a Double-Blind, Controlled Study
Neuropsychopharmacology (2003) 28, 1685–1693 & 2003 Nature Publishing Group All rights reserved 0893-133X/03 $25.00 www.neuropsychopharmacology.org Duloxetine Increases Serotonin and Norepinephrine Availability in Healthy Subjects: A Double-Blind, Controlled Study ,1 1 1 2 2 Stephan A Chalon* , Luc-Andre´ Granier , Franc¸ois R Vandenhende , Peter R Bieck , Frank P Bymaster , Melissa J Joliat2, Christine Hirth3, William Z Potter2 1 2 3 Lilly Research Laboratories, Mont-Saint-Guibert, Belgium; Lilly Research Laboratories, Indianapolis, IN, USA; Universite´ Louis Pasteur, Strasbourg, France Evidence suggests that compounds that increase the synaptic availability of more than one neurotransmitter have greater efficacy in the treatment of depression than single-acting drugs. Preclinical studies indicate that duloxetine acts to inhibit serotonin (5-HT) and norepinephrine (NE) transporters. The ability of duloxetine to alter 5-HT and NE reuptake was tested in 12 healthy male subjects. Placebo, desipramine 50 mg b.i.d., and duloxetine (80 mg q.d. or 60 mg b.i.d.) were compared in a randomized, double-blind, three- period crossover study in 12 healthy male subjects. Whole-blood 5-HT, urinary excretion of NE and major metabolites, and TYR PD30 (IV tyramine pressor dose needed to increase systolic blood pressure by 30 mmHg) were measured at steady state. Vital signs were measured periodically. Duloxetine affected 5-HT reuptake, with whole-blood 5-HT depletion vs placebo (80 mg q.d.: p ¼ 0.07; 60 mg b.i.d.: p ¼ 0.02; combined regimens: p ¼ 0.01). Cardiovascular changes reflecting increased sympathetic tone were observed with both duloxetine and desipramine, and both treatments significantly decreased whole body NE turnover (po0.01).
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