|
Outpatient Management of Depression
8 - Evaluating the Various Antidepressants |
|
|
|
This chapter will review each of the eight mechanistically
defined classes of antidepressants and summarize their safety,
tolerability, efficacy, payment and simplicity (STEPS) characteristics
specifying which are an advantage and disadvantages for that
class. When there are clinically meaningful differences between
members of a class, those differences will be highlighted.
The goal is to present a synopsis of the clinically relevant
pharmacology of these drugs to aid the practitioner in making
the best choice for a specific clinically depressed patient,
including the usual patient and
also particular subtypes of patients.
TABLE
8.1 — Percentage of New Prescriptions Written for Specific
Antidepressants During October, 1998 |
Antidepressant |
Prescription (%) |
Mixed
Uptake and Neuroreceptor Blockers (17.9) |
Amitriptyline |
12.2 |
Doxepin |
2.8 |
Imipramine |
2.9 |
Norepinephrine
Selective Reuptake Inhibitors (4.4) |
Desipramine |
0.8 |
Nortriptyline |
3.6 |
Serotonin
Selective Reuptake Inhibitors (50.5) |
Citalopram |
1.1 |
Fluoxetine |
17.5 |
Fluvoxamine |
1.2 |
Paroxetine |
14.5 |
Sertraline |
16.2 |
Serotonin
and Norepinephrine Reuptake Inhibitors (5.0) |
Venlafaxine-XR |
3.1 |
Venlafaxine-IR |
1.9 |
Serotonin-2A
Blockers* (12.0) |
Nefazodone |
3.5 |
Trazodone |
8.5 |
Specific
Serotonin and Adrenergic Receptor Blocker†
(1.9) |
Mirtazapine |
1.9 |
Dopamine
and Norepinephrine Reuptake Inhibitor (7.9) |
Bupropion-SR |
6.3 |
Bupropion-IR |
1.6 |
Monoamine
Oxidase Inhibitors (< 0.1) |
Abbreviations: TCA,
tricyclic antidepressant; XR, extended release; IR, immediate
release; SR, sustained release. |
* Also weakly inhibits
the serotonin uptake pump. † Most potent action is histamine
receptor blockade. |
This approach and information should aid
the busy primary-care practitioner in medication selection,
particularly considering only 7 minutes are often allocated
for a patient visit. Current prescribing data indicates that
the serotonin selective reuptake inhibitors (SSRIs) as a class
are the antidepressants of first choice for most practitioners,
with over 50% of all antidepressant prescriptions being for
one of the five SSRIs (Table 8.1). While
a review of STEPS is consistent with that general prescribing
pattern, a review of the available data does not support the
share of the market commanded by fluoxetine and paroxetine.
Their numbers suggest that many prescribers do not understand
the significant problems posed by the fact that these SSRIs
are prone to cause clinically significant drug-drug interactions
as a result of their inhibition of specific cytochrome P450
(CYP) enzymes and have no offsetting advantage when compared
to SSRIs (ie, citalopram and sertraline) which do not have
this disadvantage. Another interesting fact that emerges from
the prescribing data is that tertiary amine tricyclic antidepressants
(TATCAs) are the second most commonly prescribed class of
antidepressants, representing 20% of antidepressant prescriptions.
However, a number of the prescriptions for TATCAs may be for
indications other than clinical depression (eg, chronic pain,
migraine headache).
Nevertheless, the prescribing data indicates that SSRIs
and TATCAs account for seven out of ten prescriptions for
antidepressants in the United States. Thus, the other six
classes account for only 30% of antidepressant prescriptions,
suggesting that some clinicians may not be taking full advantage
of all the antidepressant options available. The goal of this
chapter is to summarize the clinically relevant pharmacology
of each class (and individual members within each class as
appropriate) to aid the busy practitioner in selecting the
best option for a patient whether the patient:
- Has classic clinical depression or a special subtype of
clinical depression (eg, atypical or bipolar depression)
- Is a first-time patient or whose depression has proven
to be refractory to the first antidepressant selected
- Is medically healthy
- Is on multiple other medications due to intercurrent
medical illness.
Mixed Reuptake Inhibitors and
Neuroreceptor Blockers
- Tertiary Amine Tricyclic Antidepressants
The chance discovery of the antidepressant properties of
TATCAs and the monoamine oxidase inhibitors (MAOIs) began
the modern era of antidepressant pharmacology almost 50 years
ago.
Advantages
- Efficacy: No single class of antidepressants works in
more patients than TATCAs.103
Several studies have reported higher response rates
in hospitalized, depressed patients treated with the TATCA,
clomipramine, than with the SSRIs, citalopram or paroxetine.55,56
Clinical trials have also shown that TATCAs are effective
in patients who have not benefited from a trial of an SSRI.245
- TATCAs are also useful in a variety of conditions other
than clinical depression including:
- Chronic pain
- Migraine headaches
- Insomnia.
For these indications, practitioners often prescribe considerably
lower doses which minimize both the adverse effects of these
drugs and their overdose risk.
- Payment: Cost can be an advantage of these antidepressants
when the choice is between being able to treat or not. That
can occur when the patient's insurance does not cover the
cost of medication and the patient has limited personal
financial resources (Table
7.10).
- Simplicity of dosing: All of the TATCAs can be taken
once a day.103
Since therapeutic ranges have been established for these
antidepressants, therapeutic drug monitoring (TDM) can be
used to rationally guide dose adjustments to ensure the
attainment of levels which produce the greatest likelihood
of antidepressant response with minimal risk of adverse
effect.191
Disadvantages
- Safety: TATCAs have a narrow therapeutic index. Even a
moderate overdose (ie, taking a 1-to-2-week supply at once)
can cause life-threatening cardiotoxicity.194
This toxicity risk alone is sufficient reason to rule out
members of this class as the preferred agent for most patients.
- The multiple actions of TATCAs also mean that these antidepressants
can interact pharmacodynamically with a number of other
types of drugs including:
- Sedative hypnotics and alcohol
- Antihypertensives
- Antiarrhythmics
- Anticholinergics.
- Tolerability: By virtue of their effects on various sites
of action, these agents cause many different types of adverse
effects. Also, the percentage of patients who report adverse
effects on these antidepressants is considerably higher
than on any other type of antidepressant (Table
6.7). Adverse effects can affect the patient's functioning
at work and home. The sedation and orthostatic hypotension
have been linked to the increased incidence of falls resulting
in hip fractures and automobile accidents in patients taking
TATCAs.132,239
They can also cause or aggravate other medical conditions.
For example, patients on chronic treatment with TATCAs also
have an increased likelihood of developing periodontal disease
as a result of the loss of the bacteriostatic effects of
saliva.4
- Simplicity of dosing: Their multiple mechanisms of action
also mean that most patients cannot be started on the usually
effective antidepressant dose of these drugs. Instead, the
dose must be gradually titrated up as the patient develops
tolerance to the acute adverse effects of the TATCAs. This
approach builds in a delay in terms of relief of the patient's
depressive episode. Even with a gradual titration, adverse
effects generally persist to some degree and can include
a trio of adverse effects including:
- Sedation due to histamine-1 blockade
- Dry mouth, constipation, urinary retention, and memory
impairment due to cholinergic receptor blockade
- Orthostatic hypotension or dizziness due to alpha-1-adrenergic
receptor blockade (Table 6.7).
Summary
Tertiary amine TCAs are not recommended as the antidepressant
of first choice for the general patient. However, they can
be quite helpful for specific patients but require careful
dose adjustment. TDM is a standard of care issue when prescribing
these antidepressants due to their narrow therapeutic index
and the wide interindividual variability in patients' metabolism.191
However, TDM generally is needed only once early in treatment
to determine whether the patient is a usual, slow or rapid
TCA metabolizer. The dose can then be adjusted to ensure the
attainment of safe and effective drug concentrations. After
that, TDM is only done for cause such as a significant change
in the patient's health status, the addition or discontinuation
of a drug (eg, fluoxetine) that could affect drug metabolism,
or to confirm that the patient is being compliant with the
prescription.
The principal reasons to use a TATCA are:
- Low acquisition cost (Table
7.10)
- Treatment refractory clinical depression
- Presence of a comorbid medical condition (eg, chronic
pain) which is responsive to these medications.
In such instances, imipramine is the generally
preferred TATCA for several reasons. First, it is one of the
least expensive antidepressants in terms of acquisition cost
(Table 7.10). Second, imipramine
is converted in the body to the secondary amine TCA (SATCA),
desipramine.188
In the usual patient on imipramine, 50% of the total circulating
TCA level will be desipramine. That percentage can be as high
as 90% in rapid demethylators. This conversion is an advantage
because desipramine has the best tolerability profile of all
of the SATCAs due to its selective action on the norepinephrine
uptake pump (Figure 6.1).
The tolerability profile of desipramine is generally comparable
to most newer antidepressants.
Nevertheless, 50% of patients will have over half of their
circulating TCA level be imipramine rather than desipramine.188
These patients will have the adverse effect profile associated
with imipramine rather than desipramine (Tables 6.5
and 6.7). The practitioner
can use TDM to establish whether the patient achieves predominantly
high levels of desipramine or imipramine. In the case of slow
demethylators who accumulate high levels of imipramine relative
to desipramine, the clinician may decide to switch to desipramine
if there are significant tolerability problems with imipramine.
Unfortunately, the cost of desipramine is not appreciably
less than many of the newer antidepressants (Table
7.10).
Norepinephrine Selective Reuptake
Inhibitors
- Secondary Amine Tricyclic Antidepressants
The SATCAs are structural analogues of
the TATCAs. While they were not rationally developed in the
same way as the SSRIs, they were developed because they had
less antihistaminergic and less anticholinergic effects in
animal models than did their TATCA forerunners (Figure
6.1). They also do not potently block alpha-1-adrenergic
receptors. At usual therapeutic concentrations, these antidepressants
only block the norepinephrine uptake pump which is the presumed
mechanism mediating their antidepressant efficacy (Table
6.2). Their clinical advantages and disadvantages stem
directly from their pharmacology.
Advantages
- Safety: In comparison to TATCAs, these antidepressants
have less potential for causing pharmacodynamic drug-drug
interactions being limited to those mediated by norepinephrine
uptake inhibition (eg, hypertensive crisis when combined
with other norepinephrine agonists, particularly MAOIs).
- Tolerability: The discontinuation rate because of adverse
effects on SATCAs is comparable to that of newer antidepressants,
including SSRIs. Given their different mechanism of action,
the adverse effects produced by these antidepressants are
different from SSRIs. For that reason, they are an option
for the patient who does not tolerate the adverse effects
produced by SSRIs (Tables 6.4
and 6.6). The most common
adverse effects on SATCAs are those expected for drugs that
are indirect noradrenergic agonists, including:
- Mild increase in blood pressure
- Increased diaphoresis
- Tachycardia
- Tremors
- Anxiety.88
- Efficacy: They are as effective as any other class of
antidepressants, and double-blind, crossover studies have
shown them to be effective in 50% of patients who do not
benefit from treatment with an SSRI.245
They can also be added to SSRIs to augment partial response
or to speed response when clinically necessary (ie, hospitalized
patient). This strategy produces dual serotonin and norepinephrine
uptake inhibition as occurs with high-dose venlafaxine.177
The difference is that the use of an SSRI and a norepinephrine
selective reuptake inhibitor (NSRI) together allows the
dose (and hence the degree of uptake inhibition) of either
one to be adjusted independently of the other. In contrast,
a dual reuptake inhibitor like venlafaxine is analogous
to a fixed combination of an SSRI and an NSRI and, thus,
the relative ratio of the uptake inhibition of serotonin
and norepineprhine is also fixed.
- Simplicity of dosing: All of the SATCAs can be taken
once a day. Since therapeutic ranges have been established
for these antidepressants, TDM can be used to rationally
guide dose adjustment to ensure the attainment of plasma
drug levels associated with the greatest likelihood of antidepressant
response and the smallest risk of adverse effects.191
TDM should be repeated when these drugs are being used to
augment the effect of fluoxetine and paroxetine because
of the substantial inhibition of CYP 2D6 caused by these
two SSRIs (Table 6.11).
When a TCA is added to a patient on fluoxetine, TDM of the
TCA should be repeated every 1 to 2 weeks for at least 6
to 8 weeks. The reason for this recommendation is the long
half-life of fluoxetine and its active metabolite, norfluoxetine.
As their levels build, the functional activity of CYP 2D6
declines resulting in a gradual increase in the levels of
the SATCAs.186
The long half-life of norfluoxetine must also be considered
when switching from fluoxetine to an SATCA or other drugs
which are substrates of CYP enzymes moderately to substantially
inhibited by norfluoxetine (Table
6.10). For a further discussion of this topic, refer
to Chapter 10.
Disadvantages
Safety: While SATCAs avoid many of the actions which plague
the use of TATCAs, they do inhibit Na+ fast channels at only
10 times their usually effective concentrations.194
For this reason, these antidepressants can be as lethal as
the TATCAs following even a modest overdose.
Payment: Unlike the TATCAs, the cost of the generic versions
of the SATCAs are not appreciably less than the newer antidepressants
which do not have the same overdose lethality risk (Table
7.10).
Summary
The recommendation is to reserve SATCAs for refractory cases
as either monodrug therapy or as a copharmacy strategy (Chapter
11).
When selecting an SATCA, some clinicians prefer nortriptyline
because its optimal therapeutic plasma level range has been
arguably better established. Others prefer desipramine because
its adverse effect profile is arguably somewhat better.
Serotonin Selective Reuptake Inhibitors
This class of antidepressants has become
the first choice for most prescribers (Table
8.1). SSRIs were the first class of antidepressant to
be successfully developed using the approach of molecular
targeting.170 The goal was
to produce antidepressants which both potently and selectively
inhibited the serotonin uptake pump (Figure
6.1). That goal of selectivity was achieved for all members
of this class in terms of neural mechanisms of action (Figure
6.3) but not in terms of CYP enzymes (Figure
6.2). Figure 6.3 explains
why members of this class are so similar in terms of their
efficacy and adverse effect profile. Figure
6.2 explains why they are so different in terms of their
risk of causing pharmacokinetic drug-drug interactions. The
advantages and disadvantages of this class in general and
specific members in particular are summarized below.
- Good safety in the event of overdose due to a wide therapeutic
index.
- Good safety in terms of pharmacodynamically mediated
drug-drug interactions which are limited to those mediated
by serotonin reuptake inhibition (eg, serotonin syndrome
when combined with other serotonin agonists like MAOIs).20,25,32,51,66,74,87,104,138,143,144,154,158,200,204,228,232,233
- Good tolerability profile with virtually all of the adverse
effects being consistent with excessive serotonin agonism:
- Nausea
- Loose stools
- Sexual dysfunction (Table
6.6).
- Efficacy in outpatients with clinical depression which
is comparable to any other type of antidepressant.103
- Efficacy in several anxiety disorders as well as clinical
depression (Table 8.2).103
- Simplicity in terms of optimal dosing because of their
flat dose-antidepressant response curve (ie, in fixed-dose
clinical trials, there is not an average increase in response
rate at doses above the usually effective, minimum dose).
In the case of fluoxetine, paroxetine, and sertraline, the
patient can be started at an effective dose without the
need for titration. In the case of citalopram
and fluvoxamine, the recommended starting dose in their
package insert was not found to be an effective dose in
their clinical trials and thus an upward titration is recommended
(Table 7.11). Also, all
of the SSRIs (with the exception of fluvoxamine) are
recommended to be taken once a day.
TABLE
8.2 — Indications Formally Labeled By the FDA for Specific
Serotonin Selective Reuptake Inhibitors* |
SSRI |
Bulimia Nervosa |
Depression |
OCD |
Panic Disorder |
PTSD |
Citalopram |
No |
Yes |
No |
No |
No |
Fluvoxamine |
No |
No |
Yes |
No |
No |
Fluoxetine |
Yes |
Yes |
Yes |
No |
No |
Paroxetine |
No |
Yes |
Yes |
Yes |
No |
Sertraline |
No |
Yes |
Yes |
Yes |
Yes |
Abbreviations: FDA,
Food and Drug Administration; SSRI, serotonin selective
reuptake inhibitor; OCD, obsessive-compulsive disorder;
PTSD, posttraumatic stress disorder. |
* All other antidepressants
are solely labeled for the treatment of depression with
the exception of bupropion which is marketed under the
brand name Zyban as an aid for smoking cessation. Venlafaxine
is indicated for the treatment of patients with generalized
anxiety disorder. Paroxetine is indicated for the treatment
of patients with social anxiety disorder. Trials with
sertraline are being reviewed by the FDA for the possible
labeling as indicated for the treatment of patients with
double depression and dysthymia. |
Disadvantages of SSRIs can be broken down into two types:
- Those shared by the SSRIs as a group
- Those which are limited to only certain SSRIs.
Although SSRIs have a good tolerability profile, their adverse
effects can be rate-limiting for some patients. That is particularly
true for the sexual dysfunction caused by these drugs.145,147
Some patients will discontinue SSRIs during the maintenance
phase because of this adverse effect, putting themselves at
risk for a recurrent episode. Approaches that have been tried
to minimize this adverse effect are further discussed in Chapter
11.
Like any antidepressant class, SSRIs
do not treat all patients with clinical depression. They produce
a full remission in approximately 50% of patients. Although
it is a popular strategy to try a second SSRI in a patient
who has not benefited from a trial of a first SSRI, there
is no compelling scientific data to support this practice
(Chapter 11). Moreover, the pharmacology
of these drugs suggest that this strategy should only work
in those patients who do not develop adequate plasma levels
of the first SSRI.170 Since
the SSRIs do not share the same pharmacokinetics (ie, metabolic
pathways) (Table 6.9), there
is a percentage of the population who will respond to a second
SSRI, but the percentage is likely to be small. A switch to
a different mechanism of action or an augmentation strategy
would seem the more prudent course of action in such cases
(Chapter 11).
As discussed in Chapter 6, a serotonin
withdrawal syndrome (Table 6.13)
can occur following the discontinuation of any SSRI. However,
the likelihood and the severity is inversely related to the
half-life of the SSRI, being most common on fluvoxamine and
paroxetine, less on citalopram and sertraline, and the least
on fluoxetine. Generally, this problem can be avoided or minimized
by slowly tapering fluvoxamine or paroxetine. When this tactic
does not work, the patient can be switched to fluoxetine,
which can then be stopped in this manner. This strategy is
analogous to using clonazepam to taper patients off of alprazolam
(ie, using a long-lived drug to taper patients of a short-lived
drug with the same pharmacodynamics).
While the above disadvantages are shared by all SSRIs, there
are others which are not. The most important of these non-shared
disadvantages is the fact that three SSRIs inhibit one or
more drug-metabolizing CYP enzyme(s) to a substantial degree
and thus have the potential for causing clinically important
pharmacokinetic drug-drug interactions (Figure
6.2 and Table 6.10).
These three SSRIs are:
- Fluoxetine
- Fluvoxamine
- Paroxetine.
Substantial inhibition means coadministration
of these SSRIs causes a several-fold increase in the levels
of the coprescribed "victim" drugs which are dependent
on the inhibited CYP enzyme for their clearance. The increased
accumulation of the "victim" drug can result in
dose-dependent adverse effects that present in a myriad of
ways. Given the importance of this topic for medicine in general,
it is further discussed in Chapter
10 with case examples of how such drug-drug interactions
can present clinically. Briefly, this issue is important for
multiple reasons:
- The majority of patients taking an antidepressant are
likely to be also on at least one other systemically taken,
prescription medication in addition to their antidepressant.
Such patients are at risk for a drug-drug interaction.
- Cytochrome P450 enzyme-mediated drug-drug interactions
are the most common types of clinically important pharmacokinetic
drug-drug interactions.
- The consequence of such interactions may be erroneously
attributed to either a sensitivity problem on the part of
the patient or even to a worsening of the patient's underlying
health problems.
- The inhibition of CYP enzymes conveys no known therapeutic
advantage to outweigh the problems posed.
This difference among SSRIs stems from the fact that when
they were developed, drug-development scientists were not
able to screen for effects on CYP enzymes which mediate the
bulk of oxidative drug metabolism.223
That is unfortunate because these effects on CYP enzymes unnecessarily
complicate the use of fluoxetine, fluvoxamine, and paroxetine
in the patient on other medications.
Given these facts, it is somewhat surprising
that fluoxetine and paroxetine are still prescribed as frequently
as they are (Table 8.1). That is particularly
true for fluoxetine since it inhibits multiple CYP enzymes
and this inhibition can persist for weeks after it has been
discontinued due to the long half-life of the parent drug
and its active metabolite, norfluoxetine.186
Clinicians need to be mindful of this issue when prescribing
another drug to a patient who has been on fluoxetine, even
weeks after it has been stopped.
Fortunately, the practitioner has two SSRI options which
do not carry substantial liability in terms of CYP enzyme
inhibition:
These two SSRIs have all the advantages of this class without
the disadvantage of CYP enzyme inhibition (Figure
6.2 and Table 6.10).
Summary
The SSRIs for many clinicians have become the treatment
of first choice for the majoritiy of their patients with clinical
depression due to their safety, tolerability and simplicity
when used alone (Table 8.1). All of
the members of this class share these advantages.
Members of this class differ substantially with regard to
their safety, tolerability and simplicity when used in a patient
on other medications (Chapter 10).
Three of the SSRIs (fluoxetine, fluvoxamine and paroxetine)
produce substantial inhibition of drug metabolizing CYP enzymes.
While citalopram and sertraline share many of the same advantages
over the other SSRIs, sertraline:
- Has been much more extensively studied in terms of drug-drug
interactions172,223
- Has Food and Drug Administration (FDA)- approval as indicated
for the treatment of several types of anxiety disorders
as well as clinical depression (Table
8.2)
- Has a recommended starting dose which is usually effective
(Table 7.11).
Serotonin and
Norepinephrine Reuptake Inhibitors
Venlafaxine is the only member of this class available in
the United States (Table 6.2).
Several other drugs in this class are or have been in clinical
trials in the United States and other countries. Venlafaxine
has dose-dependent, sequential effects on the uptake pumps
for serotonin and then norepinephrine (Figure
6.4). At 75 mg/day, venlafaxine is predominantly a serotonin
reuptake inhibitor (SRI) like the SSRIs. At 375 mg/day, it
produces comparable norepinephrine uptake inhibition to an
NSRI such as desipramine. This pharmacology is consistent
with the advantages and disadvantages of this antidepressant.
- Good safety in the event of overdose due to a wide therapeutic
index.73,103
- Good safety in terms of pharmacodynamically mediated
drug-drug interactions. At lower doses, these are limited
to those mediated by serotonin reuptake inhibition (eg,
serotonin syndrome when combined with other serotonin agonists
like MAOIs). At higher doses, it is also susceptible to
the same potential interactions as an NSRI (eg, hypertensive
crisis when combined with other norepinephrine agonists,
particularly MAOIs).73,151
- Good safety in terms of pharmacokinetically mediated
drug-drug interactions. Like citalopram and sertraline-but
in contrast to fluoxetine, fluvoxamine, nefazodone, and
paroxetine-venlafaxine does not produce substantial inhibition
of any drug metabolizing CYP enzyme at its usually effective,
minimum antidepressant dose (Table
6.10).
- Good tolerability profile. At low
doses, its adverse effects profile is similar to that of
an SSRI:
- Nausea
- Loose stools
- Sexual dysfunction (Tables 6.5
and 6.7).
- At higher doses, it can also produce the same adverse
effects as an NSRI:
- Mild increase in blood pressure
- Increased diaphoresis
- Tachycardia
- Tremors
- Anxiety (Tables 6.5 and
6.7).151,171
- Efficacy at 75 mg/day is comparable to any other type
of antidepressant in outpatients with clinical depression.169
- Better efficacy at higher doses. Venlafaxine has an ascending
dose-response curve in terms of antidepressant efficacy
in contrast to the SSRIs. That is consistent with its sequential
effects on serotonin and norepinephrine uptake inhibition
(Figure 6.4 and Table
6.2). In essence, a dose increase with venlafaxine is
pharmacologically and clinically a built-in augmentation
strategy comparable to adding an NSRI such as desipramine
to an SSRI such as sertraline.177
At doses of 225 mg/day, venlafaxine was superior to 40 mg/day
of fluoxetine in treating hospitalized patients with clinical
depression.48 In
another study, a dose increase of venlafaxine converted
more nonresponders to responders than did a comparable dose
increase of fluoxetine.52
- Simplicity in terms of optimal dosing because of the
ability to prescribe a usually effective dose (ie, 75 mg/day)
from the beginning without the need for dose titration.
As a result of the development of the
extended release version, venlafaxine can be taken once
a day.
- Disadvantages
- A somewhat higher incidence of gastrointestinal adverse
effects compared to SSRIs (Table
6.7 versus Table 6.5).
In particular, nausea appears to be more common when taking
venlafaxine than most of the SSRIs.
- Has the same liability for causing sexual dysfunction
as the SSRIs.103
- Has adrenergically mediated adverse effects at higher
doses.151,171
- Due to its relatively short half-life, venlafaxine has
a risk of causing the serotonin withdrawal syndrome (Table
6.13) comparable to that of fluvoxamine and paroxetine.219
The incidence and the severity of the serotonin withdrawal
syndrome is in part a function of the half-life of the SRI.
The half-life of venlafaxine, including that of its active
metabolite O-desmethylvenlafaxine, is approximately 12 hours.119
The extended-release formulation of venlafaxine does not
change the half-life of venlafaxine and thus does not change
the risk of the serotonin withdrawal syndrome following
abrupt venlafaxine discontinuation. While this withdrawal
state is not as medically serious as the sedative-hypnotic
withdrawal syndrome, it is not innocuous and can be quite
unpleasant. Some patients may mistake the withdrawal symptoms
for a relapse of their depressive illness and can become
so dysphoric or agitated that they can experience suicidal
ideations.209,210
It can also mimic mania which may lead to a misdiagnosis
and inappropriate treatment.125
- Ironically, dosing with venlafaxine can be viewed as
either an advantage or a disadvantage.
It is an advantage in that the patient can be started on
an effective dose (as with SSRIs) at the beginning of treatment.
Moreover, there is more compelling evidence to try a higher
dose of venlafaxine in a patient who has not benefited from
the usual starting dose than is the case with the SSRIs.
Nevertheless, the ability to titrate the dose of venlafaxine
means that the practitioner may feel less certain about
what constitutes an optimal trial of this antidepressant.
Venlafaxine is a dual action drug that predominantly acts
like an SSRI at low doses and adds the effect of an NSRI at
high doses (Table 6.2 and
Figure 6.1). Like citalopram
and sertraline and in contrast to fluoxetine, fluvoxamine,
nefazodone, and paroxetine, it has minimal effects on CYP
enzymes (Table 6.10).
Serotonin 2A Receptor Blockade
and Weak Serotonin Reuptake Inhibition
This class includes both nefazodone and
its precursor, trazodone. More prescriptions are written for
trazodone than nefazodone (Table 8.1),
most likely reflecting the extensive use of trazodone as a
nonhabit-forming sleep aid rather than as an antidepressant.
Nefazodone is a structural analogue of trazodone and was designed
with the goal of producing a better antidepressant than trazodone.271
Specifically, nefazodone is a less potent antihistamine than
trazodone. The antihistaminergic properties of trazodone are
in part responsible for its popularity as a sleep aid, but
cause significant problems with daytime sedation when it is
used as an antidepressant. Nefazodone is also a more potent
SRI than trazodone. Nevertheless, nefazodone is a much weaker
SRI than the SSRIs and venlafaxine.31,77
Nefazodone likely only produces serotonin (5-HT)-2A inhibition
at doses £ 300 mg/day and even at doses of 500 mg/day
does not appear to produce the same degree of the serotonin
reuptake inhibition as occurs with the SSRIs and venlafaxine
at their starting doses.150
This pharmacology is consistent with the clinical advantages
and disadvantages of nefazodone.
- Good safety in overdose due to a wide therapeutic index.208
- It does not disturb sleep physiology and improves the
subjective quality of sleep.10,82
- It appears to cause minimal sexual dysfunction.103
- Efficacy in patients with clinical depression and prominent
anxiety.71
- Risk of pharmacokinetically mediated drug-drug interactions.
Due to the inhibition of the drug metabolizing CYP 3A3/4
enzyme, nefazodone has the potential to cause CYP enzyme-mediated
drug-drug interactions like fluoxetine, fluvoxamine, and
paroxetine (Table 6.10).
Nefazodone-induced inhibition of CYP 3A3/4 can elevate levels
of coprescribed drugs dependent on this CYP enzyme for their
oxidative metabolism (Table
6.9) and that, in turn, can cause untoward consequences.223
- Tolerability problems limit the starting dose of nefazodone.171
The incidence and severity of the following adverse effects
increase as a function of the starting dose of nefazodone:
- Dizziness/lightheadedness
- Confusion
- Sedation
- Gastrointestinal adverse effects (Table
6.7).
Stepwise dose titration allows the patient to develop some
tolerance for these effects. The package insert advises
starting nefazodone at 100 mg twice a day for 1 week before
increasing in increments of 100 to 200 mg/day at intervals
no less than 1 week (Table
7.11). Using this strategy, the dose of nefazodone can
be increased as needed to a maximum of 600 mg/day in equally
divided doses administered 2 or 3 times per day. Such a
titration schedule means more clinician time, more patient
education, and more chances that the patient will call back
with issues or questions.
- Antidepressant efficacy at its initial starting dose
is less robust than with other antidepressants.103,177
There is no compelling evidence that nefazodone has antidepressant
efficacy at a dose of 200 mg/day. In fact, doses of 400
to 500 mg/day are required to produce the same degree of
antidepressant efficacy as the SSRIs and venlafaxine at
their starting doses as measured by the drop in the Hamilton
Depression Rating Scale scores in clinical trials.103,177
That suggests that blockade of the 5-HT2A alone is not a
robust mechanism for antidepressant efficacy (Table
6.2). As the dose of nefazodone increases, serotonin
reuptake inhibition is added to its overall effect. Thus,
dose titration is needed when prescribing nefazodone both
to improve its tolerability and increase its antidepressant
efficacy.
- Simplicity of dosing and difficulty
establishing the optimal dose. While the tolerability and
efficacy issues described above account for much of the
problem in dosing nefazodone, its pharmacokinetics, including
its effects on the drug metabolizing CYP 3A, are also important
as follows:
- Nefazodone has nonlinear pharmacokinetics (ie, its plasma
levels increase disproportionately to dose increases).109
A four-fold increase in dose can produce a 14-fold increase
in the plasma concentrations of the parent drug.
- Nefazodone at low doses has low bioavailability (ie, approximately
20% of the dose reaches the systemic circulation) due to
high first pass metabolism via the CYP 3A enzyme.103
- Since nefazodone inhibits CYP 3A, it inhibits its own
first pass metabolism. For that reason, its bioavailability
(ie, the fraction of the dose reaching the systemic circulation)
increases as its dose increases. Since the acute adverse
effects of nefazodone (as with many drugs) are dose dependent,
its nonlinear pharmacokinetics contribute to the higher
frequency and severity of adverse effects at higher starting
doses.
- The metabolism of nefazodone is also complicated in that
the parent drug has a relatively short half-life of approximately
4 hours and is converted into three pharmacologically active
metabolites:
- Hydroxynefazodone
- Triazoledione
- Meta-chlorophenylpiperazine (mCPP).139
Hydroxynefazodone has the same in
vitro pharmacology as the parent drug and, thus, is
believed to have the same clinical pharmacology.237
The in vitro pharmacology of the other two metabolites
differs substantially from that of the parent drug. The
triazoledione metabolite is a relatively pure 5-HT2A antagonist
and hence its contribution to the antidepressant activity
of nefazodone is uncertain.237
The mCPP metabolite is a 5-HT2C agonist and, when given
alone, causes anxiety and restlessness.42,107
Unusually high accumulation of this metabolite occurs in
approximately 7% of Caucasians because its clearance is
dependent on the genetically polymorphic CYP 2D6 enzyme.
- The role of CYP 2D6 in the clearance of mCPP takes on
additional significance if the patient is being switched
from fluoxetine or paroxetine to nefazodone because these
two SSRIs substantially inhibit this drug metabolizing CYP
enzyme at their usually effective antidepressant dose (Table
6.11). In fact, fluoxetine at a dose of 20 mg/day has
been shown to produce approximately an 800% increase in
mCPP levels (Table 6.11).
Although not formally studied, paroxetine at 20 mg/day would
be expected to produce comparable increases in mCPP levels
based on studies with other CYP 2D6 substrates (Table
6.11). This action on CYP 2D6-mediated metabolism of
mCPP likely accounts for the paradoxical reactions that
can occur when switching patients from either fluoxetine
or paroxetine to nefazodone.
- Nefazodone typically improves sleep and decreases anxiety;
yet, mCPP given alone does the opposite.42,107
In most patients, mCPP levels are not sufficiently high
to offset the effects of the parent drug, but these levels
can be high enough in patients who are either genetically
deficient in CYP 2D6 or who have been made functionally
deficient in CYP 2D6 as a result of treatment with either
fluoxetine or paroxetine (Table
6.11). The greater accumulation of this metabolite leads
to greater 5-HT2C agonism which can in
turn interact pharmacodynamically with persistent serotonin
reuptake inhibition produced by fluoxetine's long-lived
active metabolite, norfluoxetine.197
All of the above factors cause an apparently greater degree
of interpatient variability in terms of response to nefazodone
than is true for many of the other new antidepressants. Nevertheless,
nefazodone can be a useful antidepressant option for the primary-care
practitioner for selected patients such as those who do not
tolerate the adverse effects caused by serotonin reuptake
inhibition.
Specific Serotonin and Adrenergic
Receptor Blockers
Mirtazapine is the only member of this
class available in the United States, although its predecessor,
mianserin, is available in other countries. The mechanism
of action of mirtazapine is unique.58,59,77
It does not block the uptake pump for any of the biogenic
amine neurotransmitters (ie, serotonin, norepinephrine, and
dopamine). Instead, mirtazapine blocks histamine-1 receptors
(its most potent action) and specific serotonin and adrenergic
receptors: the 5-HT2A, 5-HT2C, 5-HT3 and alpha-2-adrenergic
receptors (Figure 6.4).58,59,77
These actions are believed to mediate its antidepressant activity
by increasing the release of serotonin and norepinephrine
and hence their availability to their respective synaptic
receptors. The blockade of the 5-HT2A, 5-HT2C, and 5-HT3 receptors
is postulated to result in a selective increase in serotonin
availability to the 5-HT1A receptor which has been implicated
in the pathophysiology of clinical depression. Regardless
of whether this postulated mechanism is correct, mirtazapine
has been shown in clinical trials to have antidepressant activity.
The pharmacology of mirtazapine is consistent with its beneficial
and adverse effects.
- Good safety in overdose.33,151
- Probably good safety in terms of pharmacokinetically
mediated drug-drug interactions based on in vitro
studies which show minimal potency for inhibiting any of
the major drug-metabolizing CYP enzymes.178
However, this in vitro prediction should be tested
by appropriate in vivo studies.
- Mirtazapine does not cause many of the adverse effects
seen with SRIs (Tables 6.5
and 6.7). Specifically,
it does not:
- Cause nausea or loose stools
- Disturb sleep physiology (actually, it increases sleep
efficiency, most likely as a result of its blockade of both
histamine-1 and 5-HT2A receptors)77
- Cause sexual dysfunction.
- Efficacy in patients with prominent anxiety consistent
with the fact that mirtazapine blocks the 5-HT2A and 5-HT2C
receptors.267
- Efficacy in severely depressed patients. Mirtazapine
was found to be superior to fluoxetine in the treatment
of hospitalized patients with clinical depression in one
double-blind random assignment clinical trial.267
- Simplicity of dosing. Mirtazapine can be started on a
dose which is effective in treating clinical depression
and is taken once a day.
- Safety: There were three cases of agranulocytosis out
of 3000 patients in its clinical trial program.151,178
That incidence was too low to draw a
cause and effect conclusion. Postmarketing experience with
the drug has not inidicated an unusual number of cases of
agranulocytosis in patients on this antidepressant. Nevertheless,
the package insert contains a warning that a white blood
cell count should be done if a patient on mirtazapine develops
signs of fever or infection.
- Tolerability: Consistent with its histamine-1 receptor
blockade, mirtazapine is sedating, which can be helpful
for the patient with prominent insomnia, but can persist
well into the next day consistent with its half-life. Sedation
was listed as the reason for early termination in 10% of
patients in its double-blind registration studies.203
Although it may initially seem paradoxical, higher doses
of mirtazapine theoretically could decrease its sedative
effects. The postulated explanation is that mirtazapine's
most potent action is histamine-1 receptor blockade, but
at higher levels, mirtazapine also blocks the alpha-2-adrenergic
receptor (Figure 6.4).
That latter action causes an alerting effect which could
counteract the sedation produced by the more potent effect,
central histamine blockade (Figure
6.4).
- Consistent with its 5-HT2C blockade, mirtazapine can cause
an increase in appetite and weight gain (Table
6.7). These effects can be desirable in specific patients
(eg, patients with clinical depression and a concomitant
medical problem such as cancer which causes failure to thrive).
However, these effects were also listed as the reason for
early termination in 8% of patients in the mirtazapine registration
studies.203
- Difficulty establishing the optimal dose. Appropriate
double-blind, fixed-dose studies have not
been published with mirtazapine. Therefore, the optimal
dose has not been established. There is also no rigorous
information on what is the appropriate course of action
if the patient does not respond to the initial dose.
Mirtazapine may never achieve the level of use of some of
the other newer antidepressants (Table 8.1).
Nevertheless, its unique pharmacology make it a useful antidepressant
option for selected patients.
Dopamine and Norepinephrine Reuptake
Inhibitors
Bupropion is the only drug in this class labeled for the
treatment of clinical depression. However, psychostimulants
(eg, methylphenidate) share its pharmacological actions on
the dopamine and norepinephrine uptake pumps.
- Better safety in overdose than tricyclic antidepressants,
but can cause seizures.57
- Risk of pharmacodynamically mediated drug-drug interactions
comparable to that of the NSRIs.
- Tolerability profile comparable to an NSRI and distinct
from that of an SSRI (Table
6.7 versus Table 6.5).
Specifically, bupropion does not disturb sleep physiology.
It causes minimal, if any, sexual dysfunction.213
In fact, some practitioners have reported success in using
bupropion as an add-on to treat SSRI-induced sexual dysfunction
(Chapter 11).
- Efficacy: Consistent with its dopamine and norepinephrine
uptake inhibition, bupropion is an activating
antidepressant and could be particularly useful in patients
with prominent psychomotor retardation (Tables 6.5
and 6.7). Given its dopamine
agonistic properties, it could also be uniquely helpful
in the patient with Parkinson's disease as well as in patients
with attention deficit/hyperactivity disorder.265
Theoretically, bupropion may work in patients who have not
benefited from a trial of an SRI since bupropion inhibits
norepinephrine as well as dopamine uptake (Table
6.2 and Figure 6.4).30
Recall that NSRIs such as desipramine have been found to
work in 50% of patients who do not benefit from SSRIs.245
Nevertheless, no formal studies have been done with bupropion
to test this possibility.
- Efficacy: Bupropion has also gained FDA approval as an
aid in smoking cessation.274
That is relevant to its use as an antidepressant because
smokers have an increased incidence of clinical depression
in comparison to nonsmokers and clinical depression impairs
the ability to stop smoking. Thus, bupropion could serve
a dual role-both to treat the clinical depression and as
an aid to stop smoking.
- Safety: This antidepressant has a narrow therapeutic index
in terms of the dose needed for antidepressant
efficacy versus the dose that causes seizures.57
The minimum recommended dose for antidepressant response
is 300 mg/day and a number of patients will need the maximum
recommended dose of 450 mg/day. At doses of 450 mg/day or
less, the seizure risk is 0.4%. Doubling the dose to 900
mg/day causes a five-fold increase in the seizure risk.57
Given the dose-dependent nature of the seizures, patients
who seize on lower doses are probably slow metabolizers
who accumulate unusually high levels of bupropion or its
three active metabolites.180
For that reason, TDM is a potential way to further minimize
this risk, but TDM with bupropion has not been adequately
studied.180 Particular
care should be taken when switching from an antidepressant,
which substantially inhibits specific drug-metabolizing
CYP enzymes (ie, fluoxetine, fluvoxamine, nefazodone, or
paroxetine), to bupropion, or when adding bupropion to the
treatment regimen of patients on these antidepressants or
on other drugs which substantially inhibit CYP enzymes (eg,
macrolides, fluoroquinoles, antifungals, protease inhibitors).
- Uncertainty about its potential to cause pharmacokinetically
mediated drug-drug interactions. Bupropion is one of the
oldest of the new antidepressants.196
The clinical trials that originally led to its registration
were conducted in the middle to the late 1970s. For that
reason, little has been done to formally test the potential
effects of bupropion on CYP enzymes. Following case reports,225
a formal study was done demonstrating that coadministration
of bupropion produces a 500% increase in plasma levels of
the CYP 2D6 substrate, desipramine. Thus, bupropion produces
substantial inhibition of this CYP enzyme comparable to
that of fluoxetine and paroxetine. Its potential in vivo
effects on other CYP enzymes have not yet been tested. Conversely,
case reports suggest that coadministration of fluoxetine
can substantially increase the plasma levels of two of the
metabolites of bupropion.180
Again, the CYP enzyme mediating this effect has not been
established, but raises the possibility
that bupropion could be the target as well as the cause
of CYP enzyme-mediated pharmacokinetic drug-drug interactions.
That is potentially important due to the dose and hence
concentration-dependent nature of the risk of seizures in
patients on bupropion.57
- Simplicity of dosing: The recommended dosing guidelines
with the immediate-release version of bupropion is for 3
times a day administration. Doses should not be administered
closer than 4 hours apart.57
This schedule was based on the half-life of bupropion and
the concern about its seizure risk being related to peak
levels of bupropion and/or its metabolites. A sustained-release
version of bupropion has been marketed. Unfortunately, this
formulation did not achieve the goal of once-a-day dosing.
Instead, the recommendation is to give the sustained-release
formulation twice a day. Even with this sustained-release
version, there is still the recommendation that the dose
should not be taken closer than 4 hours apart.
- Difficulty establishing the optimal dose. The optimal
dose of bupropion has not been established using fixed-dose
trials. When prescribing this antidepressant, the goal is
to keep the dose as low as possible to minimize the risk
of seizures without compromising therapeutic efficacy.
The seizure risk with bupropion, while
not as serious as the cardiotoxicity of the TCAs, initially
limited its use. Its clinical acceptance has been helped by
its labeling as an aid in smoking cessation and by the development
of a sustained-release formulation (Table
8.1). Bupropion is a useful option for patients who do
not benefit from or tolerate SRIs. It may be the best choice
for the patient with comorbid Parkinson's disease since its
mechanism of action could potentiate the beneficial effects
of L-dopa.195 Certainly,
bupropion should not aggravate Parkinson's disease as can
happen with SRIs because the serotonin is an inhibitory afferent
into the dopamine neurons in the substantia nigra.111,174
Given its pharmacological similarities to methylphenidate,
bupropion might also be uniquely effective in patients with
both residual attention deficit symptoms and clinical depression.
Monoamine Oxidase Inhibitors
These antidepressants are rarely used by psychiatrists, and
even less by other clinicians. Nevertheless, they deserve
some comments for the sake of completeness.
These antidepressants can be used effectively and safely
assuming the prescriber is knowledgeable with regard to proper
patient selection and education, and is conscientious with
regard to monitoring the course of treatment. They can work
in patients whose depressive illness is refractory to other
forms of antidepressant pharmacology. For these reasons, they
remain valuable antidepressant options.243
Potentially fatal pharmacodynamic drug-drug interactions
can occur with MAOIs when combined with a variety of drugs
which are serotonin agonists (ie, the serotonin syndrome),
norepinephrine agonists, or with foods rich in tyramine (ie,
hypertensive crisis).103
The major adverse effect that occurs on MAOIs alone is hypotension
which can present as fatigue and may mimic
worsening of the underlying depressive syndrome. For this
reason, the blood pressure should be monitored when using
these antidepressants.103
For patients who need them, the benefits of the MAOIs can
outweigh their liabilities.
Summary
This chapter provides a framework for understanding the clinical
pharmacology of the various antidepressants and presents the
available clinical data in a way that should aid in optimally
selecting an antidepressant for a specific patient. The relative
advantages and disadvantages are given for the various classes
of antidepressants and within classes for individual members
when appropriate. Given the pharmacological differences between
the various classes of antidepressant, the choice of a specific
medication for a specific patient will often be dependent
on the symptom cluster.
Another basis for choosing a specific antidepressant is when
a patient has not benefited from an earlier trial with an
antidepressant (Chapter 11). Faced
with this situation, many practitioners chose to try another
antidepressant from the same class, particularly in terms
of trying a second or even a third SSRI. Given the unfortunate
lack of data, the wisdom of this approach is debatable. Based
on pharmacology, it would seem more prudent to switch to a
class with a different mechanism of action than to stay within
the same class (Table 6.2
and Chapter 11).
Finally, there are sufficient differences
among the antidepressants that the final decision may come
down to personal preference. For example, does the clinician
prefer the advantages of a single-mechanism-of-action antidepressant
or a dual-mechanism-of-action drug? The former simplifies
dosing and the adverse effect profile, but has potential limitations
in terms of antidepressant response. Should the patient not
benefit from treatment with an antidepressant having a single
mechanism of action, dose escalation is less likely to be
a useful way of increasing efficacy. In such instances, the
practitioner could either switch to an antidepressant with
a different mechanism of action or use an augmentation strategy
by adding a drug with another mechanism of action (Chapter
11).
In the case of the antidepressant with dual mechanisms of
action, the augmentation strategy may be built-in and the
approach would be to escalate the dose. However, that means
the determination of the optimal dose is more of an issue
than is true for an antidepressant with a single mechanism
of action. Moreover, multiple mechanisms can contribute to
more adverse effects and increase the potential for pharmacodynamic
drug-drug interactions. For all of these reasons, the issue
of choosing between a single versus a dual mechanism of action
antidepressant becomes a matter of personal preference and
clinical experience.
|