4.1 SSRIs are viewed as an alternative option to

Serotonin Selective Reuptake Inhibitors:

In light of the reactions of TCA, biochemical research,
hence, searched for more secure medications that specifically or only block
monoamine uptake sites. The particular serotonin reuptake  inhibitors (SSRIs) with high affinity to
serotonin uptake sites, low affinity to noradrenaline uptake sites, and low
affinity for neurotransmitter receptors were the outcome of these endeavors (Frazer 1997). SSRIs are hence the
first class of rationally outlined therapeutic medications in psychiatry.  After the presentation of fluvoxamine, in
Great Britain in 1983, fluoxetine turned out to be generally accessible,
trailed by paroxetine, citalopram, and sertraline (Catterson and Preskorn
1996). Based on clinical trials, SSRIs are
viewed as an alternative option to TCAs). With respect to therapeutic efficacy,
SSRIs and TCAs are practically equipotent (Bech 1988), (Rickels et al. 1990). Because of the
absence of receptor antagonism, SSRIs are practically without dangerous
symptoms, for example, cardiotoxicity and CNS toxicity. SSRIs are safe (Hotopf and Barbui 2005) and simple to deal
with (Leonard and Tollefson 1994). In a Swedish study
comprising of 1202 reports depicting adverse responses to  SSRIs, the frequently detailed occasions were
neurological  (22.4%), psychiatric
(19.4%), and gastrointestinal (18%)  side
effects (Spigset 1999). The Swedish
investigation uncovered contrasts in recurrence and kind of adverse responses
amongst male and female, old and youthful patients and between the distinctive
SSRIs. Due to the beneficial security profile of SSRIs, treatment of depression
with antidepressant medications could change from essentially hospitalized
inpatients to outpatients (Sheehan et al. 1998). Also, the utilization of SSRIs was
expanded from major depression to minor depression (Szegedi et al. 1997) and another psychiatric issue that is
suggested to be related to the dysfunctional state of the serotonin system.
This includes anxiety, obsessive-compulsive disorder (Fineberg 1996), or premenstrual
dysphoric disorders (Epperson et al. 2012),(Gunasekara et al. 1998). In
this way, the utilization of SSRIs is a rational, mechanism-based treatment. In
addition to the higher security of SSRIs, the pharmacology of the new
medications was first viewed as being less perplexing than for TCAs. The
metabolism of TCAs prompts various metabolites with pharmacological properties
that are not quite the same as that of the parent medication.  Generally, SSRI metabolites do not display
pharmacological properties that are significant in vivo. In addition, the
metabolites are likewise particularly inhibitors of the uptake of serotonin. In
this manner, after the presentation of SSRIs, little consideration was given to
their pharmacokinetics in depressed patients being treated with SSRIs. This
view has changed totally. Contrasts in the pharmacokinetics, particularly in
drug-drug interactions, are currently the significant determination criteria to
utilize a distinct SSRI (Baumann 1996), (Brosen 1996). A
few SSRIs inhibit cytochrome P450 (CYP) isoenzymes (Harvey and Preskorn 1996), (Preskorn 1996b). The drug-drug
interactions of SSRIs made another estimation of a medication’s
pharmacokinetics in general for pharmacotherapy, since it wound up plainly
clear that drug-drug interactions are an issue of SSRIs, as well as of other
drugs (Preskorn and Magnus 1994), (Harvey and Preskorn 1995), (Shader et al. 1996), (Nemeroff et al. 1996)

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Concentration: Response Relationship

  A challenging
component of the SSRIs, in light of the fixed-dose studies, is that the
response rate, generally, does not increase at doses over the “minimum
effective dose.” This element has been partly in charge of the popularity
of the SSRIs, as a result of the proposal that, unlike with other
antidepressant agents, dose titration was unnecessary and the starting dose was
also the effective dose. In double-blind, controlled studies of patients suffering
from a major depressive disorder, daily doses of 20, 40, and 60 mg of
fluoxetine delivered almost equivalent remission (Altamura et al. 1988), (Wernicke et al. 1988), (Schweizer et al. 1990).
Correspondingly, no distinction was found in the overall remission rates in
patients treated with 20, 30, or 40 mg/day of paroxetine or 50, 100, 150, or
200 mg/ day of sertraline (Dunner and Dunbar 1992), (Preskorn and Baker 1997). In
spite of this information that support a “flat dose: response” for
SSRIs, there are obviously singular patients who just advantage from a dose
other than the usually effective minimum dose. It is conceivable that the
requirement for a higher dose in a particular patient is associated to
pharmacokinetics (i.e., lower plasma concentrations of medication accomplished
at a given dosage); however efficient TDM studies have not been conducted to
investigate this issue.

The level of serotonin reuptake inhibition correlates
with SSRI concentration and henceforth, the antidepressant effect identified
with this mechanism of action must be concentration-dependent as well (Preskorn 1993). Nevertheless it is
likely that the “flat dose: response curve” of the SSRIs is because
of the fact that 70%–80% of serotonin reuptake sites is inhibited at the
“usually effective minimum dose” 
and, minimal extra uptake is inhibited as the dose is increased (Lemberger et al. 1985), (Routledge and Marsden 1987), (Preskorn 1996b). This information
recommends the likelihood of a threshold effect for the SSRIs, reminiscent of
that of the monoamine oxidase inhibitors (MAOIs), for which inhibition of
70%–80% of monoamine oxidase (MAO) activity is vital for the ideal
antidepressant effect to happen.

The “flat dose: response curve” of the SSRIs
may partly clarify why various endeavors utilizing “routine dosages”
have failed to recognize a steady connection between SSRI plasma levels and
antidepressant efficacy (Preskorn and Fast 1991), (Goodnick 1994), (Amsterdam et al. 1997). Straightforward
connection is a very limited method  for
finding a connection between drug concentration and response, particularly when
it includes complex factors, for example, enantiomeric forms of the medication
with different biological activity, deferred time to achieve steady-state  plasma/tissue drug concentration, delayed onset  of clinical response, and interpatient
changeability in pharmacokinetic parameters (Koran et al. 1996).


The five SSRIs that are presently accessible to treat
depression or another issue with a suggested dysfunctional serotonergic system
show comparable therapeutic efficacies and comparable adverse response
profiles, regardless of a moderately wide range of affinities to serotonin
uptake sites. There are only a few differences in the frequency and degree of
rare effects, for example, hyponatremia (Cotton et al. 1999), extrapyramidal
manifestations (Leo 1996), or withdrawal symptoms after drug
cessation (Haddad 1997), presumably because
of interactions with other target structures other than uptake sites (Goodnick and Goldstein
1998). As summarized in Table 1, SSRIs
primarily vary in their pharmacokinetic properties. To choose a particular
SSRI, its t1/2, linearity of kinetics, and interaction potential should be
considered. The long t1/2 of fluoxetine might be both invaluable and
disadvantageous. It is invaluable for a patient with poor compliance since drug
concentrations decrease just marginally when the patient skip a dosage. On the
other hand, at least month of a constant drug is important to achieve
steady-state levels of fluoxetine. Also, on account of fluoxetine nonresponse
long wash-out periods are recommended before changing the patient to a TCA or a
monoamine oxidase inhibitor to keep away from drug interactions or the
development of a serotonin syndrome.

Nonlinear kinetics of fluvoxamine, fluoxetine, and
paroxetine complicate dosing. Dosage escalation prompts disproportionate
increases in drug concentrations, which might be basic to the recommendation
that there may be an upper-edge old concentration in blood that decides
nonresponse. TDM might be helpful to accomplish ideal drug concentrations in an
individual patient. Therapeutically effective blood concentrations of SSRIs,
however, still need to be established.

The announcement that dose titration guided by TDM is
vital for TCAs, however not for SSRIs, is sometimes given in drug data leaflets
on SSRIs. Nevertheless, this has neither been checked nor distorted in the
literature. The proposed absence of information on a “therapeutic
window” for SSRIs, therefore, can’t be considered as an advantage of SSRIs
over TCAs, as long as valid investigations on therapeutic serum concentrations
are absent for SSRIs.

The most genuine difference between the five SSRIs is
their potential for drug-drug interactions. Paroxetine, fluoxetine, and
norfluoxetine are powerful inhibitors of CYP2D6 and fluvoxamine of CYP1A2 and
CYP2C19 (perhaps at the same time CYP3A4 and CYP2D6). Combining these SSRIs
with drugs that are substrates of the inhibited enzymes has the potential for
great toxicity unless they are perceived and appropriately prescribed.  

With an extending information base, it will be
conceivable to comprehend and anticipate drug interactions with SSRIs. Most
drug interactions of SSRIs have been identified by chance since there was no
information of CYP inhibitory properties when the medications were presented to
the market. After having presented SSRIs, we discovered that extensive
examinations on substrate and inhibitor properties of medications must be
directed in the early stages of drug development. For SSRIs, even now our
insight on substrate and inhibitor specificities of drug- metabolizing enzymes
is incomplete.

In addition, studies that have portrayed substrate and
inhibitor properties of SSRIs in vitro delivered variable information between
different studies (Brosen 1993), (Lane 1996), (von Moltke et al. 1995). Hence, the test
systems should be optimized to raise data that are substantial for clinical
utilization of the drugs

Thinking back on the most recent 10 years of intensive
SSRI use, we have discovered that the presentation of SSRIs has brought another
class of medications, as well as refocused our consideration on the
significance of pharmacokinetic properties to the action of drugs in general.
Pharmacokinetic properties of a drug must not be viewed as the essential
properties of a synthetic substance. They may contrast between and inside
people. Clinicians must know about this to provide safe and solid care to their



 Because of their wide therapeutic index, there
is no convincing motivation to screen plasma levels of any of the SSRIs as a
standard of care to anticipate toxicity. However, in view of the wide
variability in plasma SSRI concentrations accomplished at a routine dose, TDM
is valuable for individual dosage optimization (Lundmark et al. 2000). Roughly half of the patients on any single
dose of an SSRI do not accomplish an ideal response in terms of alleviation of
their depressive episode (Preskorn 1996a). For these patients,
TDM can give essential target data to preclude noncompliance and distinguish
those people who are pharmacokinetic anomalies (i.e., have especially moderate
or quick drug clearance). In the “nonresponder” on the typically
effective minimum dosage of an SSRI, a determination of drug concentration can
be utilized to coordinate treatment choices (i.e., low drug concentration and
absence of effectiveness, high drug concentration and poor tolerability)
furthermore, decrease the deferral in getting the patient on an ideal dosage.
Another unique utilization of TDM with the SSRI fluoxetine is decided whether
its metabolite, norfluoxetine, is still present after drug discontinuation.
Such plasma monitoring would help the clinician to choose when it is safe to
begin treatment with another agent and avoid a drug-drug interaction (e.g.,
when changing to