Hello Gt06,
I?m sure you know all anti-depressants carry some risk of side
effects. What you are seeking is the fastest acting medication, with
the fewest side effects. Escitalopram, an SSRI,(Lexapro is the brand
name in the US) is an excellent choice, as it meets those criteria.
Agomelatine (Valdoxan) looks very promising as well, but appears to
still be undergoing clinical trials.
Your doctor and you should discuss which medication is best for you
however, as s/he is familiar with your medical and mental health
history. Any information contained within this answer is intended for
information purposes only, and not intended to diagnose or treat.
?In addition, there are several "newer" medications for depression and
for attention deficit disorder that are worth mentioning. The newest
antidepressants on the American market are Lexapro, which is derived
from the drug Celexa, and Paxil CR, a longer acting form of Paxil. All
of the drugs called SSRI's (selective serotonin reuptake inhibitors)
are equally effective, compared to each other, for depression, panic
disorder, social anxiety, obsessive-compulsive disorder, and some of
the symptoms of post-traumatic-stress disorder PTSD). They are all
more effective for depression, panic disorder, and social anxiety,
than for obsessive-compulsive disorder and PTSD, which are harder to
treat. There are slight differences in side effects between these
drugs, which is how I usually choose between them. I do not think that
the newer ones offer substantial advantages over the older ones. These
drugs do not work for attention deficit disorder.?
http://www.m-a-h.net/shrinktime/issue1.htm
?Numerous double-blind, placebo-controlled trials have demonstrated
the efficacy of SSRIs in the treatment of depression. In addition,
SSRIs have been proved effective in treating anxiety disorders,
including obsessive-compulsive disorder (OCD), panic disorder, and
social phobia.4 Common side effects of SSRIs include transient nausea,
diarrhea, insomnia, somnolence, dizziness, akathisia, and long-term
orgasmic dysfunction.5 However, secondary pharmacologic actions may
account for differences in efficacy and tolerability and may assist
the prescriber in selecting a specific SSRI for an individual patient.
As with all antidepressants, care must be taken with SSRIs to screen
patients for symptoms of bipolar disorder before prescribing, to avoid
precipitating a manic episode.?
http://www.aafp.org/afp/20030201/547.html
?Selective serotonin reuptake inhibitors (SSRIs) are the first-line
treatment for panic disorder. Tri2-cyclic antidepressants (TCAs) are
equally effective, but they are less well tolerated than the SSRIs. In
treatmentresistant cases, benzodiazepines like alprazolam may be used
when the patient does not have a history of dependency and tolerance.
Due to possible serious side effects and interactions with other drugs
and food components, the irreversible monamine oxidase inhibitor
(MAOI) phenelzine should be used only when first-line drugs have
failed. In generalised anxiety disorder, venlafaxine and SSRIs can be
recommended, while buspirone and imipramine may be alternatives. For
social phobia, SSRIs are recommended for the first line, and MAOIs,
moclobemide and benzodiazepines as second line. Obsessive-compulsive
disorder is best treated with SSRIs or clomipramine.?
http://www.wfsbp.org/pdf/guides/824Anx-OCD-PTSDBandelow.pdf
?Before treatment can begin, the doctor must conduct a careful
diagnostic evaluation to determine whether your symptoms are due to an
anxiety disorder, which anxiety disorder(s) you may have, and what
coexisting conditions may be present. Anxiety disorders are not all
treated the same, and it is important to determine the specific
problem before embarking on a course of treatment. Sometimes
alcoholism or some other coexisting condition will have such an impact
that it is necessary to treat it at the same time or before treating
the anxiety disorder.
If you have been treated previously for an anxiety disorder, be
prepared to tell the doctor what treatment you tried. If it was a
medication, what was the dosage, was it gradually increased, and how
long did you take it? If you had psychotherapy, what kind was it, and
how often did you attend sessions? It often happens that people
believe they have "failed" at treatment, or that the treatment has
failed them, when in fact it was never given an adequate trial.?
http://www.mamashealth.com/mental/treatments.asp
?Patients with anxiety disorders sometimes express groundless or
exaggerated fear of side effects of psychopharmacological drugs, e.g.
addiction (even with drugs without known addiction potential).?
?In general, the frequency of adverse events is higher for TCAs than
for newer antidepressants, such as the selective serotonin reuptake
inhibitors (SSRIs) or selective serotonin/ norperinephrine reuptake
inhibitors (SSNRIs). Thus, the latter drugs should be tried first
before TCAs are used.?
?The efficacy of the antidepressant venlafaxine, a selective serotonin
noradrenaline reuptake inhibitor, in generalised anxiety disorder has
been shown in several controlled studies (see below for references).
At the beginning of treatment, side effects like nausea, restlessness
or insomnia may occur and hamper compliance with treatment. The
antianxiety effect may occur with a latency of two to four weeks, in
some cases even later.?
http://www.wfsbp.org/pdf/guides/824Anx-OCD-PTSDBandelow.pdf
Escitalopram (Lexapro) SSRI
============================
?Selective serotonin reuptake inhibitors have become the drugs of
choice in the treatment of depression, and they are also effective in
the treatment of obsessive-compulsive disorder, panic disorder, and
social phobia. New indications for selective serotonin reuptake
inhibitors include post-traumatic stress disorder, premenstrual
dysphoric disorder, and generalized anxiety disorder.?
?Selective serotonin reuptake inhibitors (SSRIs) have replaced
tricyclic antidepressants as the drugs of choice in the treatment of
depressive disorders, mainly because of their improved tolerability
and safety if taken in overdose. SSRIs block the reuptake of serotonin
(5-HT1A, 5-HT2C, and 5-HT3C) into the presynaptic nerve terminal,
thereby enhancing serotonin neurotransmission, which presumably
results in their antidepressant effects.?
http://www.aafp.org/afp/20030201/547.html
?Escitalopram is a highly selective serotonin reuptake inhibitor
(SSRI) with minimal effects on norepinephrine and dopamine neuronal
reuptake. It is the S-enantiomer of racemic citalopram, and appears to
be responsible for most or all antidepressant activity of the racemic
compound. Escitalopram is at least 100 times more potent than the
R-enantiomer as a serotonin reuptake inhibitor, and has little
affinity for other receptors including serotonergic, alpha-and
beta-adrenergic, dopamine, histamine, muscarinic, or benzodiazepine
receptors. Antagonism of muscarinic, histaminergic, and adrenergic
receptors has been associated with various anticholinergic, sedative,
and cardiovascular
side effects seen with other psychotropic drugs.?
?Escitalopram appears to be at least as effective as citalopram for
the treatment of depression and may have a faster onset of activity,
but additional study and clinical experience is needed. In addition,
escitalopram significantly increased the time to relapse in the
36-week long-term study compared with placebo.?
ADVERSE EFFECTS (1)
(Most common, 5-15%)
_ Diarrhea
_ Dizziness
_ Dry mouth
_ Ejaculation disorder
_ Fatigue
_ Influenza-like symptoms
_ Insomnia
_ Nausea
_ Rhinitis
_ Somnolence
_ Sweating increased
(Less common, 2-5%)
_ Abdominal pain
_ Anorgasmia
_ Appetite decreased
_ Constipation
_ Impotence
_ Indigestion
_ Libido decreased
_ Sinusitis
http://www.ptcommunity.com/QUIKReports/content/escitalopram.pdf
?Escitalopram is the active isomer of the racemic selective serotonin
reuptake inhibitor (SSRI) antidepressant citalopram (Celexa®).
Escitalopram is the most selective of all SSRIs.?
?Chemical studies have shown escitalopram to be over 100 times more
potent as an SSRI than Rcitalopram.Comparing the therapeutic effects,
escitalopram has been shown to improve depressive symptoms more
quickly than citalopram as well as have less potential for adverse
effects?
?Escitalopram 10-20 mg/day was found to be well tolerated and
effective in patients who have failed treatment with another SSRI due
to adverse events.
The incidence of side effects is less with escitalopram compared to
all other SSRIs.?
There is a chart on this site illustrating how Escitalopram has the
fewest adverse effects in comparison to similar SSRIs.
?A patient receiving escitalopram may find improvement in depressive
and anxiety symptoms after one week, much sooner than any other SSRI.
Patients can effectively be switched from citalopram or other SSRIs to
escitalopram.
The side effect profile of escitalopram is comparable to placebo. Drug
interactions are low as well. Another advantage of escitalopram is the
cost savings; escitalopram is less expensive than citalopram.?
There is also a chart on this page comparing side effect incidences in
comparison to Escitalopram?s closest relative ? Celexa.
http://www.cpsrx.com/mayjune03.pdf
Venlafaxine (Effexor):
=======================
?Venlafaxine (Effexor®) became the first agent in a category of
antidepressants known as the SSNRIs. It lacks the adverse effects of
TCAs while implementing the combined antagonism of 5-HT and NE. This
mechanism may lead to a more rapid onset of therapeutic effect.7
Unfortunately, venlafaxine has the potential to increase blood
pressure in a dose-dependent manner in approximately 3-13% of
patients.8 Duloxetine is a new addition to the SSNRIs, and it appears
to exhibit a greater balance in the relative reuptake inhibition of
5-HT and NE.?
http://www.clevelandclinicmeded.com/medical_info/pharmacy/septoct2004/duloxetine.htm
? ?Withdrawal syndrome - sometimes severe and prolonged. Characterised by:
o headaches
o nausea
o dizziness
o mood lability
o Gastrointestinal upset
o recurrence of depression
o bizarre dreams
o paraesthesiae
o auditory hallucinations
? Nausea
? Vomiting
? Dizziness
? Sexual dysfunction
? Hypotension
? Constipation
? Sweating
? Anxiety
? Convulsions
? Sleeplessness
? Palpitations
? Tremor
? Abdominal pain
? Rash
? Hypertension
About 40% of patients taking venlafaxine suffer nausea and vomiting;
thought to be dose related i.e. more severe with higher doses.
http://www.priory.com/sideven.htm
?Remission rates were significantly higher with venlafaxine than with an SSRI.?
?Are all antidepressants equally effective?
It is often stated that the various different classes of
antidepressant medication are equally effective (American Psychiatric
Association, 1993; Depression Guideline Panel, 1993). However, the
methods used to conduct randomised clinical trials render them
relatively insensitive to possible differences between active
antidepressants (Thase, 1999). Studies seldom compare groups larger
than 120 patients, which does not afford the statistical power to
detect modest but still clinically meaningful differences. In
addition, multi-site trials may have relatively lower statistical
power because of greater patient heterogeneity and lower reliability
of diagnoses or dependent measures (Thase, 1999). Moreover, the
composition of study groups can have a marked influence on the
apparent efficacy of a treatment (Quitkin et al, 1993; Thase et al,
1997).?
http://bjp.rcpsych.org/cgi/content/full/178/3/234
Duloxetine (Cymbalta) -SSNRI
============================
****This drug is not to be taken by patients with glaucoma.
?Duloxetine is used to treat depression.Duloxetine is also used to
treat pain and tingling caused by diabetic neuropathy (damage to
nerves that can develop in people who have diabetes). Duloxetine is in
a class of medications called selective serotonin and norepinephrine
reuptake inhibitors (SSNRIs). It works by increasing the amounts of
serotonin and norepinephrine, natural substances in the brain that
help maintain mental balance and stop the movement of pain signals in
the brain.?
?Duloxetine controls depression and relieves the pain of diabetic
neuropathy, but does not cure these conditions. It may take 1-4 weeks
or longer before you feel the full benefit of duloxetine. Continue to
take duloxetine even if you feel well. Do not stop taking duloxetine
without talking to your doctor. Your doctor will probably decrease
your dose gradually. If you suddenly stop taking duloxetine, you may
experience withdrawal symptoms such as dizziness, upset stomach,
vomiting, headache, pain, burning or tingling in hands or feet,
irritability, and nightmares. Tell your doctor if you experience any
of these symptoms when your dose of duloxetine is decreased.?
Duloxetine may cause side effects. Tell your doctor if any of these
symptoms are severe or do not go away:
? upset stomach
? vomiting
? constipation
? diarrhea
? heartburn
? decreased appetite
? dry mouth
? cough
? sweating or night sweats
? blurred vision
? dizziness
? extreme tiredness
? weakness
? muscle pain or cramps
? changes in sexual desire or ability
? runny nose
Some side effects can be serious. The following symptoms are uncommon,
but if you experience any of them, or those mentioned in the IMPORTANT
WARNING section, call your doctor immediately:
? shaking hands that you cannot control
? rash
? difficult, painful, or very frequent urination
? fever, sore throat, chills, or other signs of infection
? unusual bruising or bleeding
? pain in the upper right part of the stomach
? yellowing of the skin or eyes
? dark colored urine
? flu-like symptoms
http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a604030.html
?Duloxetine is believed to exert its antidepressant effect through
the potentiation of serotonergic and noradrenergic activity in the
central nervous system. This selective serotonin and norepinephrine
reuptake inhibitor (SSNRI) was approved on August 3, 2004, for the
treatment of major depressive disorder (MDD).
Efficacy. Duloxetine was evaluated for the treatment of depression in
4 randomized, double-blind, placebo-controlled, fixed dose studies in
adult outpatients aged 18 to 83 years (N=1059) meeting DSM-IV criteria
for major depression. Patients were randomized to duloxetine 60 mg
once daily or placebo for 9 weeks in 2 of the studies. In the third
study, patients were randomized to duloxetine 20 or 40 mg twice daily
or placebo for 8 weeks. In the fourth study, patients were randomized
to duloxetine 40 or 60 mg twice daily or placebo for 8 weeks.
Duloxetine demonstrated superior efficacy over placebo in all 4
studies as measured by improvement in the 17-item Hamilton Depression
Rating Scale (HAMD-17) total score.?
http://www.biopsychiatry.com/duloxetine/index.html
?(Cymbalta)It was approved by the Food and Drug Administration (FDA)
in August 2004 for the treatment of major depressive disorder (MDD)
and one month later received an indication for the treatment of
peripheral neuropathic pain associated with diabetic neuropathy (DN).
Major Depressive Disorder (MDD): MDD is characterized by a depressed
mood or loss of interest in activities for a minimum of 2 weeks.1,2 At
least four other symptoms must be experienced by the patient and may
include fatigue, change in sleep patterns or appetite, impaired
concentration, feelings of guilt, or periodic thoughts of death or
suicide.1 MDD may manifest as unipolar depression, referring only to
the periodic occurrence of depressive symptoms, or as bipolar
depression, where depressive symptoms alternate with manic episodes
consisting of a combination of increased psychomotor activity,
decreased need for sleep, and delusional, grandiose, paranoid, or
psychotic behavior.?
http://www.clevelandclinicmeded.com/medical_info/pharmacy/septoct2004/duloxetine.htm
Milnacipran (Ixel)
=================
?Milnacipran (Ixel) is a new antidepressant with essentially equal
potency for inhibiting the reuptake of both serotonin and
noradrenaline, with no affinity for any neurotransmitter receptor
studied. A review of the studies comparing milnacipran, placebo and
active comparator antidepressants provides clear-cut evidence of its
efficacy in both severe and moderate depression in hospitalized and
community settings. Meta-analyses of the original data of controlled
trials involving 1032 patients, comparing milnacipran with imipramine
or selective serotonin reuptake inhibitors (SSRIs), show that
milnacipran provides antidepressant efficacy similar to that of
imipramine and significantly superior to that of the SSRIs.?
http://www.biopsychiatry.com/milnacipran.htm
?What makes Milnacipran different from the Selective Serotonin
Reuptake Inhibitors (SSRIs) ? drugs like Prozac® ? and Selective
Norepinephrine Reuptake Inhibitors (SNRIs) ? drugs like Effexor ? is
that Milnacipran affects two neurotransmitters, norepinephrine and
serotonin, almost equally (a 3:1 norepinephrine to serotonin balance).
In contrast a SNRI, tends to act much more on serotonin than
norepinephrine, (Effexor has a 1:30 norepinephrine to serotonin
ratio).?
?Trials involving 1032 patients show that Milnacipran provides
antidepressant efficacy similar to that of imipramine and
significantly superior to that of the SSRIs. Analysis of over 3300
patients shows that both the general and cardiovascular tolerability
of Milnacipran are superior to those of the TCAs with fewer
cholinergic side effects. The tolerability of Milnacipran was
comparable to that of the SSRIs, with a higher incidence of dysuria
with Milnacipran, and a higher frequency of nausea and anxiety with
the SSRIs.
As a result of this, and other, research, Milnacipran is now the new
therapeutic option for depression, offering clinical efficacy in the
range of the TCAs combined with a tolerability equivalent to that of
the SSRIs. In addition, Milnacipran is a promising treatment for
chronic pain conditions like Fibromyalgia and Lupus.?
?Cases in which this medicine should NOT be used (Contra-indications)
This medicine should NOT be used in the following cases:
? Known allergy to Milnacipran or another constituent
? Association with non-selective MAO inhibitors (iproniazide,
nialamide), B selective MAO inhibitors (selegiline), digitalis
(digoxine) and anti-migraine drugs belonging to that class of
Sumatriptan (see interactions with other drugs)
This medicine should generally not be used in the following cases:
? In association with epinephrine or nor epinephrine by parenteral
route, clonidine and related compounds and A selective MAO inhibitors
(moclobemide, toloxatone), (See interactions with other drugs);
? Difficulties in urinating (prostrate adenoma);
The undesired effects observed during treatment are observed mainly
during the first two weeks of treatment.
? Dizziness, excessive sweating, anxiety, hot flushes and minction
problems (urinary complaints);
? Nausea, vomiting, dry mouth, constipation, tremors, palpitations,
agitation, headache, cutaneous eruption, erythemateous, prurit; it is
to be noted that patients with a history of cardiovascular disorder or
concomitant cardiac medication might have a higher incidence of
cardiovascular adverse events (e.g., hypertension, hypo tension,
postural hypo tension and palpitations);
? Hepatic biological disturbances
Certain symptoms can be part of your depression.?
http://arthritis.about.com/gi/dynamic/offsite.htm?zi=1/XJ&sdn=arthritis&zu=http%3A%2F%2Fwww.antiaging-systems.com%2Fa2z%2Fmilnacipran.htm
Patients taking Milnacipran comment:
http://anxietyhelp.org/treatment/medication/Milnacipran.html
Agomelatine (Valdoxan)
=====================
?Patients who are in remission from major depressive disorder
experience fewer symptoms of sexual dysfunction if they are treated
with agomelatine (Valdoxan) than with venlafaxine XR (Effexor),
according to research presented here at the 55th annual conference of
the Canadian Psychiatric Association (CPA).?
?"Both [of the drugs are] equally effective in terms of their
remission rates and drops in depression scales," Dr. Kennedy said in
an interview. "But if you look at the sexual measures, you find that
80% of the patients on the new drug versus 59% of those on venlafaxine
reported no reduction in drive or arousal."
http://www.docguide.com/news/content.nsf/news/8525697700573E18852570B6006FE4BD
?Valdoxan combines antidepressant efficacy, even in severely depressed
patients, with an extremely favourable side-effect profile and has the
additional benefit of sleep regulation in depressive patients,
according to new data presented at the 18th Congress of the European
College of Neuropsychopharmacology (ECNP) today.
The ability of Valdoxan to relieve depressive patients' sleep
disruption without affecting daytime vigilance is a key advantage for
an antidepressant medicine as sleep complaints are a very common and
disabling feature of depression.?
?Excellent side-effect profile -
Valdoxan has an innovative pharmacological profile; it is the first
melatonergic antidepressant acting as a MT1 and MT2 receptor agonist
with additional 5-HT2C receptor antagonist properties. Due to this
unique mode of action, it does not show the typical side effects found
with SSRIs and SNRIs, in particular sexual dysfunction and drug
discontinuation symptoms*, two common side-effects that patients find
particularly troubling.
A trial comparing Valdoxan with venlafaxine showed comparable
antidepressant efficacy of both treatments, but significantly less
sexual dysfunction with Valdoxan. In addition, a placebo-controlled,
double-blind study comparing Valdoxan with paroxetine showed that,
after one week of treatment discontinuation, no signs of
discontinuation symptoms were seen in the Valdoxan group compared to
significant discontinuation symptoms in the paroxetine group.?
?Valdoxan was discovered and developed by Servier. The drug is
currently in Phase III trials and a registration dossier for an
indication in major depressive disorder (MDD) was submitted to the
European Regulatory Agency (EMEA) in 2005.?
http://www.pslgroup.com/dg/254122.htm
?The drug is currently in Phase III trials and a registration dossier
for an indication in major depressive disorder (MDD) was submitted to
the European Regulatory Agency (EMEA) in 2005.
There are many issues with current therapies for these disorders,
particularly for depression. Selective Serotonin Reuptake Inhibitors
(SSRI) are the current choice.
However, there is a 3-week gap for the drug to take effect. During
this period the person becomes anxious for the drug to work and then
more depressed because they feel the drug isn't working.?
http://www.drugresearcher.com/news/ng.asp?n=63465-servier-valdoxan-mt-receptor
More on Valdoxan:
http://www.biopsychiatry.com/agomelatine/valdoxan.html
Additional Info:
================
This comparison report can be ordered for $48.99 USD
http://www.ingentaconnect.com/content/bsc/bjcp/1996/00000042/00000006/art00498
A comparison chart:
http://www.ohsu.edu/medicine/residency/handouts/pharmpearls/Psychiatry%20CNS%20Neuro/ComparisonDuloxetineOtherCommonlyUsedAntidepressants.pdf
Combining antidepressants
?Some of the newest antidepressants, however, challenge the notion
that combining mechanisms is always undesirable. Two drugs in which
multiple mechanisms reduce undesired actions rather than cause them
are nefazodone and mirtazapine. Both agents increase serotonin, as do
the SSRIs.1,2 However, the anxiety, sexual dysfunction, and sleep
disturbance associated with SSRIs and mediated by stimulating 5-HT2
receptors can be prevented by the 5-HT2 antagonists nefazodone and
mirtazapine; the nausea associated with SSRIs and mediated by
stimulating 5-HT3 receptors can also be prevented by the 5-HT3
antagonist mirtazapine.?
http://www.psychiatrist.com/pcc/brainstorm/br5808.htm
Previous answers that cover your topic, that may interest you:
http://answers.google.com/answers/threadview?id=544406
http://answers.google.com/answers/threadview?id=516381
http://answers.google.com/answers/threadview?id=561761
I hope this is the answer you were seeking. If any part of my answer
is unclear, please request an Answer Clarification, and allow me to
respond, before rating this answer. I will be glad to assist you
further, before you rate.
Regards, Crabcakes
Search Terms
=================
Lexapro efficacy + side effects
Duloxetine efficacy + side effects
Milnacipran efficacy + side effects
Agomelatine + efficacy + side effects
SSRI + SSNRI + comparison
SSRI + fewest side effects
SSRI + PTSD
Antidepressants + PTSD |
Clarification of Answer by
crabcakes-ga
on
21 Jan 2006 13:33 PST
Hello again Gt06,
I have found more scholarly articles for you (most customers want
information they easily understand), but as far as breaking down drug
interactions and comparing selected drug side effects is far beyond
the scope of your original question. In fact, they are quite different
questions. This search and post took me over 1.5 hours. It would take
me a week to compile all new information you have requested.
Your original question stated:
I am looking for a drug with:
- fast effect (possibly less than average 3 weeks)
- no side effects (heart, glaucoma, hypertension, anxiety rebound, ecc)
- strong improvement also on co-morbid "Generalized Anxiety - PTSD - DESNOS"
- strong effect of motivation
Looking on the web, I have read something interesting on:
-milnacipram
-escitalopram
-agomelatine
-duloxetine
I need quick advice supported by serious arguments.
I supplied the information you asked for, with much more than a
"medium deep search." Most of the information you are now requesting
is not available for 2005 or is available on a fee basis through
proprietary or subscription sites.
Now your question has added parameters:
I?d like to restate again my priorities:
1. To find a drug that is effective on: a) depression with b)
co-morbid GAD and heavy lack of c) motivation (sometime called
?anhedonia?), due possibly to d) PTSD (in its no-single-event form,
that is currently termed DESNOS by van der Kolk etc.)
2. With NO initial strong anxiety effect (like Paroxetine). This would
forbid a flexible use (stop and reenter when I need), if anytime I
start I have to ?pay? a bad ?1-week-worst-then-ever? price-tag.
3. With few side effects (I don?t pretend none), on: a) glaucoma, b)
hypertension c) heart
After having gone thru all the online docs, I am now in favour of 1)
Mirtazapine and 2) Venlafaxine (Agomelatine not being available).
As such, I?d like to have a better/deeper understanding of:
1. Specific activity on receptors: 5HT1-2 ?3 etc. Is it true that SSRI
acts on all of them, and insofar stimulation of the 5HT2A type is the
source of initial ANXIETY? (or is the 5HT1A; and 5HT3 is the source of
nausea? ? see later)
2. ?agonist? and/or ?antagonist? role of chemicals. What does it mean?
(not clear to me).
3. more info about mirtazapine and modafinil (NaRI).
4. more info about minaprine (cantor; sero+dopa) bupropion (zyban;
nora+dopa) amineptine (survector; dopa). Stimulating dopamine they
should act on ?motivation? or not?
Also:
1. milnacipran not adviced with clonidine? (and so many side effects?)
2. agomelatine stimulate or block 5HT2C?
3. escitalopram stimulates also 5HT2 5HT3? (anxiety+nausea)?
4. is it true that instead the 5HT1B is the relevant receptor for
depression? (confirmed by the fact that protein P11 ? ?the depression
protein? - acts on this receptor?)
5. is it true instead that (Johannes Tauscher) receptor 5HT1A is
involved with ANXIETY?
My personal comparison table: (bad formatted here!)
milnacipram (ixel);NaSSRI;acts on sero nora;5HT NA (NE??);better than
ssri; balanced 3:1= ne:se; ok pain, GAD;nok dysuria, anxiety,
palpitations, hypertension
escitalopram (lexapro);SSRI;acts on sero;5HT1A 5HT2C 5HT3C;very
selective; potent; fast;(my note: not ok if stimulates 5HT2=anxiety)
duloxetine (cymbalta);SSNRI;acts on sero nore;5HT NE;said to be
?balanced?; nok for GLAUCOMA!;slow
agomelatine (valdoxan);new class;melatonergic agonist MT1 MT2
(5HT2C??);ok for sex, sleep;NO SIDE EFFECTS;NOT YET AVAILABLE
modafinil;NaRI;alpha-1 agonist;5HT?; ok for sleep apnea
mirtazapine (remeron);NaSSA;block alpha-2, stimulate 5HT1A; block 5HT2
5HT3 = no dark mood, anxiety and nausea;no side effects
venlafaxine (effexor);SSNRI;sero, nore, (dopa?);5HT NE;unbalanced
1:30=ne:se; slow; nausea; not ok for hypertension but only high dose
?A substantial body of literature and clinical experience supports
the notion that enhancing both serotonergic and noradrenergic
neurotransmission simultaneously and specifically may provide greater
efficacy in depression treatment. Venlafaxine (Effexor) is a
nontricyclic antidepressant with dual serotonin and norepinephrine
reuptake inhibition with weak reuptake inhibition of dopamine (Gumnick
& Nemeroff, 2000) that has demonstrated efficacy in treating
depression, as well as producing fewer side effects than tricyclics
(Table 1). However, at higher doses there is the increased risk of
high blood pressure (Gumnick & Nemeroff). Another SNRI, duloxetine
hydrochloride (Cymbalta), was approved in 2004 for the treatment of
major depressive disorder. Duloxetine is a potent inhibitor of both
serotonin and norepinephrine reuptake and a less potent inhibitor of
dopamine reuptake?
?As with most drugs, there is a potential for antidepressants to
interact with other concomitantly administered medications, because
many patients with depression have comorbid medical and psychiatric
illnesses that require medication (Greenblatt, von Moltke, Harmatz, &
Shader, 1998; Gumnick & Nemeroff, 2000). Pharmacokinetic interactions
occur when one medication affects
the absorption, distribution, metabolism, or excretion of another
drug. Most antidepressants are metabolized via the hepatic cytochrome
P450 isoenzyme system in the liver. For example, administration of a
drug that inhibits a P450 enzyme responsible for the metabolism of a
specific antidepressant can lead to excess levels of that
antidepressant (Gumnick & Nemeroff). Patients should be assessed for
other illnesses and medications during the initial office visit to
determine the best antidepressant to prescribe with the patient?s
current medication regimen.?
http://www.aann.org/ce/pdf/0504c.pdf
?Cognitive and Psychomotor Effects of Antidepressants with Emphasis on
Selective Serotonin Reuptake Inhibitors?
http://www.gjpsy.uni-goettingen.de/gjp-article-lane2.pdf
?Serotonin Syndrome Induced by a Combination of Bupropion and SSRIs.?
http://www.clinicalneuropharm.com/pt/re/clnneupharm/abstract.00002826-200409000-00005.htm;jsessionid=DSea0TfUpktUJ2aWB4rLOC0Tg8BlXMs0mcuviWxHNRJc1FnRycdd!1871300765!-949856144!9001!-1
?THE BIOLOGICAL RESPONSE TO PSYCHIC TRAUMA: MECHANISMS AND TREATMENT OF
INTRUSION AND NUMBING? Old (1991) but informative
http://www.cirp.org/library/psych/vanderkolk2/
Serotonin Receptors
===================
?5-HT1A receptors play a role in anxiety and probably also in
depression. Previous studies showed that disruption of 5-HTT function
either by chronic SSRIs or by knock-out of the 5-HTT gene produces a
desensitization (decrease in physiological responses to the
stimulation of 5-HT1A receptors) of 5-HT1A receptors in the
hypothalamus and dorsal raphe nucleus (Le Poul et al., 1995 ; Li et
al., 1996 , 1997a , 1999 ; Blier et al., 1998 ). Behaviorally, 5-HTT
knock-out mice (5-HTT / mice) are more anxious relative to 5-HTT +/+
mice (as examined by the elevated zero maze and light/dark box)
(Murphy et al., 1999 ; C. Wichems, unpublished data). Interestingly,
these behavioral alterations also are observed in 5-HT1A receptor
knock-out mice (Heisler et al., 1998 ; Parks et al., 1998 ; Ramboz et
al., 1998 ; Zhuang et al., 1999 ). These results suggest that
desensitization of 5-HT1A receptors may play an important role in the
effects of 5-HTT on emotion. In fact, several clinical studies have
reported that the combined administration of 5-HT1A antagonists with
SSRIs produces an earlier therapeutic effect than SSRIs alone,
suggesting that desensitization of 5-HT1A receptors may contribute to
the therapeutic effects of SSRIs. Therefore, studying the mechanisms
underlying the desensitization of 5-HT1A receptors induced by
disruption of the function of 5-HTT should help us to understand the
effects of 5-HTT on the regulation of emotion.?
http://www.jneurosci.org/cgi/content/full/20/21/7888
?Although selective serotonin reuptake inhibitors (SSRIs) block
serotonin (5-HT) reuptake rapidly, their therapeutic action is
delayed. The increase in synaptic 5-HT activates feedback mechanisms
mediated by 5-HT1A (cell body) and 5-HT1B (terminal) autoreceptors,
which, respectively, reduce the firing in 5-HT neurons and decrease
the amount of 5-HT released per action potential resulting in
attenuated 5-HT neurotransmission. Long-term treatment desensitizes
the inhibitory 5-HT1 autoreceptors, and 5-HT neurotransmission is
enhanced. The time course of these events is similar to the delay of
clinical action. The addition of pindolol, which blocks 5-HT1A
receptors, to SSRI treatment decouples the feedback inhibition of 5-HT
neuron firing and accelerates and enhances the antidepressant
response. The neuronal circuitry of the 5-HT and norepinephrine (NE)
systems and their connections to forebrain areas believed to be
involved in depression has been dissected.?
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11444761&dopt=Abstract
?The serotonin-1A (5HT1A) receptor system has been implicated in the
pathophysiology of major depression by postmortem studies of suicide
victims and depressed subjects dying of natural causes. This
literature is in disagreement, however, regarding the brain regions
where 5HT1A receptor binding differs between depressives and controls
and the direction of such differences relative to the normal baseline,
possibly reflecting the diagnostic heterogeneity inherent within
suicide samples. PET imaging using the 5HT1A receptor radioligand,
[11C]WAY-100635, may clarify the clinical conditions under which 5HT1A
receptor binding potential (BP) is abnormal in depression.?
http://www.indyrad.iupui.edu/public/emorris/PETjournalCLub/Drevets/biol_psych_5ht1a%20in%20depression-sdarticle.pdf
?Antidepressant-Like Behavioral Effects Mediated by
5-Hydroxytryptamine2C Receptors?
http://jpet.aspetjournals.org/cgi/content/full/295/3/1120
?In the cortex of animals, serotonin (5-HT) levels increase after
several weeks of treatment with selective serotonin reuptake
inhibitors (SSRIs). Studies using an intrasubject design to examine
the effects of SSRI treatment on 5-HT2A receptors in the cortex of
drug-free depressed patients are needed. In theory, agonist
stimulation of 5-HT2A receptors could be relevant to SSRI treatment by
promoting neuronal growth and survival as well as direct elevation of
mood. The objective of this study was to evaluate the effect of 6
weeks of paroxetine treatment on 5-HT2A receptors in depressed
patients. METHOD: After a medication-free period of at least 3 months,
19 depressed patients were treated for 6 weeks with paroxetine, 20
mg/day. The authors used [18F]setoperone and positron emission
tomography to assess 5-HT2A receptor binding potential in the patients
before and after treatment and in 19 age-matched healthy subjects.?
http://ajp.psychiatryonline.org/cgi/content/full/158/1/78
?Long-Term Antidepressant Treatments Result in a Tonic Activation of
Forebrain 5-HT1A Receptors?
http://www.jneurosci.org/cgi/content/full/18/23/10150
Anxiety and the Serotonin Receptor
?THERAPEUTIC EFFECTS OF SEROTONIN1A PARTIAL AGONISTS IN ANXIETY
Bearing the preclinical correlates in mind, we review below the
therapeutic effects of the 5-HT1A partial agonists in the DSM-IIIR
anxiety disorder categories.
Generalized Anxiety Disorder
The azapirones, such as buspirone, are the first modern
pharmacotherapeutic alternative to benzodiazepines for the treatment
of generalized anxiety disorder (GAD). The 3- to 4-week delay in onset
of anxiolytic effects of the azapirones closely resembles that of
imipramine treatment of GAD (33), but benzodiazepine effects are more
rapid. Several well-controlled studies have shown that buspirone is
superior to placebo and are equivalent to a range of benzodiazepines
in the treatment of GAD. Goldberg and Finnerty (28) first reported
anxiolytic properties of buspirone. Rickels et al. (57) subsequently
reported in a placebo-controlled study that buspirone (20 to 25
mg/day) was as effective as diazepam (20 to 25 mg/day) over a 4-week
period in the treatment of 212 anxious outpatients, although diazepam
appeared slightly better than buspirone for somatic anxiety symptoms,
whereas the opposite was observed for interpersonal difficulties.
Subsequent controlled studies indicate similar efficacy for buspirone
as compared to diazepam (22) and clorazepate (13), lorazepam, and
alprazolam (14). Subsequent studies by Petracca et al. indicate
similar efficacy for buspirone and lorazepam, although abrupt
termination of treatment at 8 weeks resulted in discontinuation
symptoms only in the lorazepam group (52). Strand et al. (67) have
reported on the similar efficacy of buspirone and oxazepam treatment
of GAD in a primary care setting, where anxiety disorders are the most
frequently encountered psychiatric disorders. Rickels (58) has
suggested that buspirone, the only azapirone approved by the U.S. Food
and Drug Administration, may be particularly appropriate in those with
chronic variants of GAD, the anxious elderly, and possibly those with
mixed anxiety and depression. Buspirone, according to the authors,
appears most helpful in GAD patients who do not insist on the
immediate relief provided by the benzodiazepines. If GAD patients are
able to wait for a more gradual onset of anxiolytic effects, they
avoid the dependency-producing effects of benzodiazepines.
Anxiety with Comorbid Depression
Anxious patients frequently present with complicating depressive
symptomatology. Early clinical observation of buspirone-treated
patients suggested antidepressant properties in addition to anxiolytic
effects. Robinson and colleagues (59) report on five
placebo-controlled studies involving 382 patients with DSM-III major
depression and significant associated anxiety symptoms (i.e., Hamilton
Anxiety Rating Scales (HARS) greater than or equal to 18). Buspirone,
initiated at 15 mg/day, and increased to a maximal dose of 90 mg/day
was effective for both depressive and anxiety symptoms. In general
patients with higher HARS and HDRS scores responded better to
buspirone than did less severely ill patients. A limitation of this
analysis was the absence of separate evaluation of depressive
symptoms, raising the possibility that improvement of HDRS scores were
primarily related to improvement of overlapping anxiety-related items.
Other depression studies using azapirones are remarkable for their
high drop-out rates. Fabre (23) reports a 64% drop-out rate from a
buspirone-treated group for various reasons. Jenkins et al. (32)
reports a 71% drop-out rate from a group treated with high doses of
gepirone, whereas a 57% drop-out rate was observed for the low-dose
group. Other controlled studies have confirmed gepirone's
antidepressant properties (55). The high drop-out rates observed with
azapirone treatment combined with the lack of confirmatory data
supporting primary antidepressant efficacy suggests a limited role
where a range of other effective antidepressant treatments are
available.?
http://www.acnp.org/g4/GN401000125/CH123.html
Atagonistic/Agonistic reaction
==============================
Agonist: Biochemistry A drug or other chemical that can combine with a
receptor on a cell to produce a physiologic reaction typical of a
naturally occurring substance.?
http://www.thefreedictionary.com/agonist
Antagonist: Biochemistry A chemical substance that interferes with the
physiological action of another, especially by combining with and
blocking its nerve receptor.?
http://www.thefreedictionary.com/antagonist
Agonist: An agonist is a substance that binds to a receptor and
triggers a response in the cell. An agonist is the opposite of an
antagonist in the sense that while an antagonist also binds to the
receptor, it fails to activate the receptor and actually blocks it
from activation by agonists. A partial agonist activates a receptor
but does not cause as much of a physiological change as does a full
agonist.?
http://en.wikipedia.org/wiki/Agonist
Antagonist reaction:
?In medicine and biology, a receptor antagonist is a substance that
inhibits the normal physiological function of a receptor. Many drugs
work by blocking the action of endogenous receptor agonists such as
hormones and neurotransmitters.
There are two kinds of receptor antagnoists:
? Antagonists that compete with an agonist for a receptor are
competitive antagonists. An example is the interleukin-1 receptor
antagonist, IL-1Ra.
? Antagonists that antagonize by other means are non-competitive antagonists.
Antagonists stop agonists from acting on certain receptors by blocking them.
http://en.wikipedia.org/wiki/Receptor_antagonist
An Introduction to the biology of the serotonin receptor subtype 5-HT3
?Most targets of pharmacologically active drugs are ion channels and
receptors. The development of pharmacaphore concepts has been of
tremendous value for the identification and design of new agonists and
antagonists for these receptors. These receptors come in two classes
-- ionotropic and metabotropic. They are either ligand gated ion
channels or G-protein coupled receptors that bind ligands, but
transmitt a conformational signal across the cell membrane activating
a cytoplasmic process (metabolic control) or a secondary ion channel.
Here the ionotropic subtype of serotonin gated receptors shall be
discussed. Serotonin receptors are also found to be either GPCRs or
ligand gated ion channels. While seven GPCR types of serotoning
receptors are known, only two subtypes of the ionotropic receptor have
been described. Serotonin receptor 3A, or 5HT-3A, has been cloned and
sequenced in the 1980s and only in early 1999, has a second subtype
been identified (5HT-3B). The latter is a regulatory subunit able to
modulate the intrinsic channel activity of the 3A subtype. The abiltiy
of 5HT-3A subunits to form homooligomeric channels in oocyte
expression systems has greatly helped in understanding the structure
function relationship of this subtype, including a well documented
pharmacology.?
http://www.whatislife.com/reader/anaesthetics/anaesthetics.html
Mirtazapine
===========
?Mirtazapine is an antidepressant drug with a unique pharmacological
profile, consisting of potent antagonism of central a2-adrenergic
autoreceptors and heteroreceptors as well as an antagonism of both
5-HT2 and 5-HT3 receptors. As a result, mirtazapine seems to enhance
both the neurotransmission of serotonin and norepinephrine (NE).
So far, there are no reports of an influence of genetic variants on a
clinical response to mirtazapine. The catechol-O-methyltransferase
(COMT) plays a crucial role in the degradation of NE,10 thereby
regulating availability
of central NE and presumably consecutively affecting NE/5-HT
interactions. The COMT gene, which codes for both the membrane-bound
(MB-COMT) and soluble (SCOMT) form of the enzyme, is therefore a
candidate for a possible genetic influence on antidepressant response.
Within the gene, a transition of guanine to adenine at
codon 158 leads to a substitution of Val108 by Met108 in the S-COMT
(or the corresponding amino acids at position 158 in the MB-COMT).
This single-nucleotide polymorphism (SNP) affects the level of enzyme
activity in human tissues
with a trimodal distribution of low (COMTLL; COMTMET/MET),
intermediate (COMTHL; COMTVAL/MET) and high (COMTHH; COMTVAL/VAL)
activities with three- to fourfold differences between COMTMET/MET and
COMTVAL/VAL.10
?Mirtazapine affects the neurotransmission of NE13 and COMT plays a
crucial role in the degradation of NE.10
Therefore, COMT activity may be partly responsible for the observed
differences in treatment response. The mechanisms that lead to the
observed differences in antidepressant response are largely unknown.
Such mechanisms might be related to adaptive downregulation of central
a2-autoreceptor function following increased NE availability.14,15
Hypothetically, subjects with COMTMET/MET genotype could have a higher
central NE availability and, consecutively, a
relatively lower density of (downregulated) a2-autoreceptors compared
to subjects with the COMTVAL/VAL and COMTVAL/MET allele variants.
Treatment with mirtazapine, which exerts pharmacologic effects via
present a2-receptors, could result in a reduced responsiveness of
a2-autoreceptors and consequently in reduced antidepressive effects.?
http://www.nature.com/cgi-taf/DynaPage.taf?file=/tpj/journal/v5/n1/full/6500289a.html&filetype=pdf
?Mirtazapine-induced arthralgia? $39.00 USD
http://www.blackwell-synergy.com/doi/abs/10.1111/j.1365-2125.2005.02481.x
?Neurologic oral manifestations caused by a new formulation of mirtazapine? $20
http://neurology.org/cgi/content/citation/65/2/333
?The effectiveness of mirtazapine in the treatment of post-traumatic
stress disorder: A 24-week continuation therapy?
http://www.blackwell-synergy.com/doi/abs/10.1111/j.1440-1819.2005.01447.x
Abstract on:Effects of different antipsychotics and the antidepressant
mirtazapine on glucose transporter mRNA levels in human blood cells.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16002093&dopt=Citation
Abstract on ?Antinociceptive effects of the antidepressants
amitriptyline, duloxetine, mirtazapine and citalopram in animal models
of acute, persistent and neuropathic pain.?
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15695164&dopt=Citation
Abstract: ?Mirtazapine and venlafaxine in the management of collateral
psychopathology during alcohol detoxification.?
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15610945&dopt=Citation
Abstract: ?A systematic review of the serotonergic effects of
mirtazapine in humans: implications for its dual action status.?
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16342227&dopt=Citation
Abstract: ?Mirtazapine-Induced Serotonin Syndrome.
Clinical Neuropharmacology. 26(2):54-57, March/April 2003.
Ubogu, Eroboghene E.; Katirji, Bashar
Abstract:
Summary: An 85-year-old woman developed sudden confusion and
dysarthria progressing to mutism, orobuccal dyskinesias, generalized
tremors worse with activity, ataxia, and rigidity with cog wheeling
without high-grade fevers or dysautonomia. These findings were related
temporally to the institution of mirtazapine as monotherapy for a
major depressive illness with superimposed anxiety disorder.
Withdrawal of the agent resulted in early notable clinical resolution
with only residual hypertonia after 2 weeks. This is a rare report of
serotonin syndrome induced by mirtazapine monotherapy. The
hypothesized pathophysiologic mechanism in this case is
overstimulation of serotonin (5-hydroxytryptamine or 5-HT) type 1A
receptors (5-HT1A) in the brainstem and spinal cord in an individual
with risk factors for hyperserotoninemia resulting from reduced,
acquired endogenous serotonin metabolism.
Complete article with a paid account only.
http://www.clinicalneuropharm.com/pt/re/clnneupharm/abstract.00002826-200303000-00002.htm;jsessionid=DSdi3zhfFqJcxioPep281FOWX3atTycC5g7gO4c5JbTA6rPx1Pwf!-65114708!-949856145!9001!-1
Venlaxafine
============
Efficacy and tolerability of venlafaxine compared with selective
serotonin reuptake inhibitors and other antidepressants: a
meta-analysis.
"Background In individual studies and limited meta-analyses
venlafaxine has been reported to be more effective than comparator
antidepressants, particularly selective serotonin reuptake inhibitors
(SSRIs)."
http://bjp.rcpsych.org/cgi/content/full/180/5/396
?Venlafaxine, a serotonin norepinephrine reuptake inhibitor (SNRI),
has action on both serotonin and norepinephrine. It has been shown to
produce higher remission rates than SSRIs.25 It is well absorbed and
well tolerated, and the extended-release (XR) formulation has a
half-life of about 24 hours, allowing for once-daily administration. A
recent meta-analysis found it to be more effective than SSRIs and
superior to imipramine.26 Venlafaxine is associated with a
dose-dependent increase in diastolic blood pressure, and like SSRIs,
it carries the risk of serotonin syndrome and sexual dysfunction.?
http://www.pharmacists.ca/content/cpjpdfs/feb05/Clinical-Chang.pdf
Abstract : ?A Double-Blind, Placebo-Controlled Study of a Flexible
Dose of Venlafaxine ER in Adult Outpatients With Generalized Social
Anxiety Disorder.?
http://www.psychopharmacology.com/pt/re/jclnpsychopharm/abstract.00004714-200410000-00004.htm;jsessionid=DSeknd0AaE5FvVMIWMQ57JbfJTI6SbaVSoDiVCIrqIuZymFfxS0n!-65114708!-949856145!9001!-1
Abstract: ?The Effect of One-Week Treatment with Venlafaxine on 35%
CO2 Hyperreactivity in Patients with Panic Disorder: An Open Study.?
http://www.psychopharmacology.com/pt/re/jclnpsychopharm/abstract.00004714-200302000-00020.htm;jsessionid=DSffWVQUIHOulUB50eWACHf0YElNu10UdwGwPG5CK297AgLLYmxi!-65114708!-949856145!9001!-1
I hope the additional information is useful. You may consider posting
a new question for your additional answers.
Sincerely, Crabcakes
Search Terms using Google Scholar
DESNOS + antidepressants + neurotransmitters + 2005
DESNOS + antidepressants + neurotransmitters
|
Clarification of Answer by
crabcakes-ga
on
21 Jan 2006 15:20 PST
Hello again! Here is some additional information for you:
?Depression seems to be characterized by a dysregulation of the
noradrenergic system (4), which has a key role in maintenance of blood
pressure. In persons with depression, the efficacy of the
alpha2-adrenergic receptor may be compromised by either decreased
responsiveness of the receptor (5) or reduced adrenergic activity in
the central nervous system (CNS)?
?Most persons with hypertension are evaluated and treated by primary
care physicians, who need to be vigilant about identifying and
aggressively treating hypertension in patients who have concomitant
depression. This vigilance about the coexistence of depression and
hypertension is particularly important in groups at high risk of
depression, such as elderly persons, women, separated or divorced
persons, and those with a family history of depression.?
?Overall, venlafaxine has a low incidence of clinically significant
increases in blood pressure with doses less than 200 mg per day and
should not be precluded from being used when indicated.
Mirtazapine (Remeron) blocks histaminic and specific serotonin and
alpha2-adrenergic receptors, resulting in increased availability of
serotonin and norepinephrine in the CNS. Case reports have linked use
of mirtazapine with hypertension, particularly in patients taking
concurrent therapy with low-dose amitriptyline (31). As in cases with
other medications that may increase blood pressure, physicians need to
monitor blood pressure in patients taking antidepressants.?
?SSRIs interact with the P-450 system to varying degrees. Fluoxetine
hydrochloride (Prozac) and paroxetine hydrochloride (Paxil) are potent
inhibitors of the isoenzyme CYP2D6, and fluvoxamine maleate (Luvox)
inhibits almost all P-450 enzymes. Significant elevation of serum
levels of drugs metabolized by the CYP2D6 isoenzyme, such as
beta-blockers, TCAs, mexiletine hydrochloride (Mexitil), and
propafenone hydrochloride (Rythmol), can occur when they are
prescribed with these SSRIs. Sertraline hydrochloride (Zoloft) and
citalopram hydrobromide (Celexa) are weak inhibitors of the P-450
system and hence are suitable for use in patients who take medications
metabolized by the hepatic microsomal system.
Bupropion is primarily a norepinephrine reuptake inhibitor, and one of
its metabolites is a potent inhibitor of CYP2D6. The SSRI nefazodone
hydrochloride (Serzone) is a strong inhibitor of CYP3A4 and can cause
an increase in serum levels of calcium channel blockers, such as
amlodipine (Norvasc), felodipine (Plendil), and verapamil (Calan,
Isoptin, Verelan).?
http://www.postgradmed.com/issues/2002/06_02/shrivastava.htm
Hypertension
http://connections.lww.com/Products/koda-kimble/documents/PDFs/Ch21.pdf
Mirtazapine(Remeron)
?Pharmacokinetic properties
After oral administration of Remeron tablets, the active constituent
mirtazapine is rapidly and well-absorbed (bioavailability ~50%),
reaching peak plasma levels after about 2 hours. Binding of
mirtazapine to plasma proteins is approx. 85%. The mean half-life of
elimination is 20-40 hours; (26 hours in males, 37 hours in females);
longer half-lives, up to 65 hours, have occasionally been recorded and
shorter half-lives have been seen in young men. The half-life of
elimination is sufficient to justify once-a-day dosing. Steady state
is reached in about 5 days with 50% accumulation, after which there is
no further accumulation. Mirtazapine displays linear pharmacokinetics
within the recommended dose range.
Mirtazapine is extensively metabolised and eliminated via the urine
and faeces within four days. Major pathways of biotransformation are
demethylation and oxidation followed by conjugation. The demethyl
metabolite is pharmacologically active and appears to have the same
pharmacokinetic profile as the parent compound.
In vitro data from human liver microsomes indicate that cytochrome
P450 enzymes CYP 2D6 and CYP 1A2 are involved in the formation of the
8-hydroxymetabolite of mirtazapine, whereas CYP 3A4 is considered to
be responsible for the formation of the N-demethyl and N-oxide
metabolites.
The presentation of mirtazapine is as a racemate. It is not known
whether first pass extraction of the drug is stereoselective, but it
is known that the clearance of the two enantiomers is by different
metabolic processes. It is not known whether food affects the
bioavailability of the two enantiomers.
Population subgroups
Liver Disease - Following a single 15 mg oral dose of mirtazapine, the
oral clearance of mirtazapine was decreased by approximately 30% in
hepatically impaired patients compared to subjects with normal hepatic
function. Caution is indicated in administering Remeron (mirtazapine)
to patients with compromised hepatic function (see ?Dosage and
directions for use?.)
Renal Disease - Following a single 15 mg oral dose of mirtazapine,
patients with moderate [glomerular filtration rate (GFR) = 11-39
mL/min/1,73 m²] and severe [GFR <10 mL/min/1,73 m²] renal impairment
had reductions in mean oral clearance of mirtazapine of about 30% and
50% respectively, compared to normal subjects. Caution is indicated in
administering Remeron to patients with compromised renal function (see
?Dosage and directions for use?.)
Elderly Patients - Following oral administration of mirtazapine 20
mg/day for 7 days to subjects of varying ages (range, 25-74), oral
clearance of mirtazapine was reduced in the elderly compared to the
younger subjects. The differences were most striking in males, with a
40% lower clearance in elderly males compared to younger males, while
the clearance in elderly females was only 10% lower compared to
younger females. Caution is indicated in administering Remeron to
elderly patients (see ?Dosage and directions for use?).?
SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Side effects that occurred during clinical trials with Remeron ,
categorised by body system, are as follows:
Common side-effects
Body as a whole:
Increase in appetite and weight gain, asthenia, flu syndrome, increased sweating.
Metabolic and nutritional disorders:
Oedema, peripheral oedema.
Neurological:
Somnolence/ drowsiness, sedation, dizziness, abnormal dreams,
paresthesia, tremor, vertigo.
Digestive system:
Dry mouth, increased appetite, constipation, nausea.
Less common:
Liver: elevations of serum transaminase activities.
Uncommon:
Blood: Granulocytopenia, agranulocytosis. See ?Warnings?.
Circulation: Orthostatic hypotension.
CNS: Epileptic seizures, tremor, mania, convulsions (insults), myoclonus.
Skin: Exanthema.
Other side-effects noted in clinical studies are:
Digestive system:
Vomiting, anorexia, dyspepsia.
Metabolic and nutritional disorders
Thirst, bitter taste.
Neurological
Thinking abnormal, tremor, confusion, hyperesthesia, apathy, amnesia,
abnormal accommodation, agitation, impaired concentration.
Skin and appendages
Rash.
Uncommon side-effects, of which a causal relationship has not been
established, include:
Increased (nonfasting) cholesterol and triglycerides, hypertension,
vasodilatation.
Myalgia, myasthenia, arthralgia.
Dyspnoea, cough increased, sinusitis.
Urinary frequency, urinary tract infection.
Face oedema, photosensitivity reaction, abdomen enlarged, angina
pectoris, myocardial infarction, bradycardia, ventricular
extrasystoles, syncope, migraine, hypotension, eructation, ataxia,
delirium, delusions, depersonalisation, dyskinesia, extrapyramidal
syndrome, libido increased, co-ordination abnormal, dysarthria,
hallucination, manic reaction, neurosis, dystonia, hostility, reflexes
increased, emotional lability, euphoria, paranoid reaction, eye pain,
abnormality of accommodation, conjunctivitis, deafness,
keratoconjunctivitis, lacrimation disorder, glaucoma, hyperacusis, ear
pain, kidney calculus, cystitis, dysuria, urinary incontinence,
urinary retention, impotence.
http://home.intekom.com/pharm/donmed/remeron.html
Page 2 describes the action of Mirtazapine.
http://www.wisconsinmedicalsociety.org/uploads/wmj/kochar.pdf
?Many standard antidepressants take two to four weeks, and sometimes
up to 12 weeks, before they are fully effective. People who take them
may also experience a temporary period of increased anxiety.
Consequently, about a third of patients stop taking antidepressants
for anxiety disorders before completing the initial phase of therapy.
A combination of a benzodiazepine and an antidepressant is sometimes
used to avoid the initial anxiety symptoms and to hasten control of
panic symptoms. The benzodiazepine can then be withdrawn and the
antidepressant, with its negligible chance for long-term abuse, is
continued.
No one should become disheartened if one drug treatment fails. Another
may prove to be very effective, even it is a drug of a similar type.
Drug combinations should be tried if a single drug and
cognitive-behavior therapy has failed. Because many anxiety disorders
are chronic, drug therapy sometimes is needed for prolonged periods,
even years.?
http://www.umm.edu/patiented/articles/what_medications_used_anxiety_disorders_000028_7.htm
?Mirtazapine (Remeron) may be an effective treatment for panic
disorder, generalized anxiety disorder, obsessive-compulsive disorder,
and even posttraumatic stress disorder. In addition to taking it
orally, mirtazapine is now available as a tablet that dissolves on the
tongue. It may be more rapidly effective than other SSRIs and has
stronger early actions against anxiety in patients who also suffer
depression. It may cause less sexual dysfunction than some other
antidepressants. It interacts with histamine, a chemical involved in
allergic responses; these actions can cause drowsiness, which may make
it a useful drug for patients who suffer from insomnia. The drug also
causes blurred vision. The drug has been associated with weight gain,
although in one study it was not significant. It does not appear to
have the adverse acute effects on the heart that other newer
antidepressants have, although it may elevate cholesterol and
triglyceride levels slightly.?
http://www.umm.edu/patiented/articles/what_medications_used_anxiety_disorders_000028_7.htm
?Like with other antidepressants care should be taken in patients with:
? micturation disturbances like prostate hypertrophy (although
problems are not to be expected because REMERON possesses only very
weak anticholinergic activity)
? acute narrow-angle glaucoma and increased intra-ocular pressure
(also here little chance of problems with REMERON because of its very
weak anticholinergic activity)
? diabetes mellitus
http://www.medsafe.govt.nz/Profs/Datasheet/r/Remerontab.htm
Venlafaxine
?Venlafaxine (Effexor) is now approved for generalized anxiety
disorder. In studies of patients with GAD, venlafaxine significantly
reduced anxiety and improved overall well-being compared with placebo.
It may have some benefits for social anxiety. As with the SSRIs, and
unlike other newer antidepressants, venlafaxine impairs sexual
function. Of concern are reports of changes in blood pressure and
heart conduction abnormalities, which may cause serious problems in
elderly patients. Some patients report severe withdrawal symptoms,
including dizziness and nausea.?
http://www.umm.edu/patiented/articles/what_medications_used_anxiety_disorders_000028_7.htm
?TO THE EDITOR: We report a case of bilateral acute angle closure
glaucoma associated with venlafaxine.? Page 1
https://mja.com.au/public/issues/176_05_040302/ng_letter_fm.pdf
Ocular Side Effects of Drugs
http://www.optometry.co.uk/files/e5e5328ee4772fe94f2d6f229de5c48a_patel20030418.pdf
Antiglaucoma medication and clinical depression
http://www.blackwell-synergy.com/links/doi/10.1046/j.1440-1614.2001.00929.x
Sincerely, Crabcakes
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