Walter Watts
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virus: How to adjust your brain
« on: 2004-08-29 11:46:17 » |
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Evaluating levels of neurotransmitters
The first question considered by a clinician is "Is it likely that
elevating dopamine levels will benefit the patient?" The authors feel
this question must be asked first because dopamine is the only
neurotransmitter whose levels can be increased, decreased, or left
unchanged by specific antidepressants (see Summary of neurotransmitter
action and its potential desirable and desirable effects, Table 2, page 37).
* The SSRIs, which do not block the serotonin receptor 5H[T. sub. 2a],
are associated with a suppression of dopamine
* Serotonergic antidepressants that do block the receptor 5H[T. sub. 2a]
(eg, nefazodone and mirtazapine) are generally neutral with regard to
dopamine levels
* Bupropion, an antidepressant with very distinct dopaminergic activity,
has been shown to increase dopamine by blocking its reuptake.
For these reasons, the authors believe it makes good clinical sense to
consider dopamine first.
The next step in the therapeutic decision-making process assesses the
potential benefits of serotonin, followed by norepinephrine. In this
way, the authors believe that simple application of the known clinical
correlates of neurotransmission can be used as a very powerful tool in
the selection of an initial antidepressant--a synthesis of science and
clinical expertise.
Potential benefits of specific neurotransmitter activity on patient symptoms
By first evaluating dopamine, the authors think it may be possible to
alleviate common patient complaints of apathy, tiredness, and lack of
motivation--all of which may be improved by increasing dopamine levels.
The authors have observed that when these complaints persist in patients
treated with a nondopaminergic antidepressant, reevaluation often
reveals the depression itself to be in remission, although apathy and
tiredness remain. The authors believe that this patient may benefit from
the use of a dopaminergic antidepressant, either alone or as part of
combination therapy.
Additionally, it has been noted that patients who experience cravings,
(1-3) attention deficit hyperactivity disorder (ADHD),(4,5) hyposexual
desire disorder (low libido), (6) and low motivation (7, may benefit
by elevation of dopamine levels.
Patient characteristics: potential benefits of neurotransmitter modulants
The clinician can also assess the potential impact of an agent. For
instance, a patient whose personality suggests that he/she is easy to
anger may benefit from reduced dopamine levels. (9)
Increasing serotonin levels may be helpful in patients who experience
premature ejaculation[TM] or who seem prone to worry or panic. However,
in situations involving marital discord, this agent may be
counterproductive, potentially increasing the risk of reduced libido or
patient apathy. (11,12)
Chronic pain and daydreaming (poor vigilance) may be helped if a
patient's depression is treated with an agent that supports
norepinephrine, while unstable hypertension would possibly be worsened.
(3,13)
If the clinician has difficulty in determining whether a certain
neurotransmitter would be beneficial to a patient, the authors recommend
that the choice be "No." Specific neurotransmitter support can always be
added after the fact.
Biochemical properties and the individual patient: a case study using
the algorithm
As an example of how to use these principles, consider the obese
patient. Facilitating dopaminergic neurotransmission might diminish
obesity-related symptoms such as excessive eating. Conversely,
decreasing dopaminergic neurotransmission (for example, with an SSRI)
might stimulate cravings and exacerbate weight gain. Therefore, the
authors believe that this patient might be a good candidate for bupropion.
An obese patient with comorbid attention deficit hyperactivity disorder
(4-5) might also be most appropriately treated with an agent with known
benefits for patients with this disorder, while the same would be true
for patients with hypoactive sexual desire disorder (HSDD). (6)
The clinician is then asked to consider serotonin. Since serotonergic
medications are useful in patients with anxious comorbidities, cotherapy
with an SSRI might be advised if the patient exhibits worry, panic, or
obsessive-compulsive (OCD) symptoms. However, if the patient assessment
has not uncovered anxious comorbidities, the addition of a serotonergic
drug is not indicated.
Selecting a first-line serotonergic drug might be considered if the
patient has a comorbid anxiety disorder--eg, OCD, social anxiety
disorder, panic disorder, generalized anxiety disorder, or
post-traumatic stress disorder.
Patients who experience comorbid chronic pain may benefit from increases
in both noradrenergic and serotonergic neurotransmitter activity. An
agent such as venlafaxine, mirtazapine, and nefazodone might provide the
most appropriate options. There is literature suggesting their
effectiveness in neuropathic pain.
Issues to be considered for all patients Is sexual function relevant to
the patient? Altered sexual desire is often associated with depression;
family physicians should consider whether altered sexual functioning is
of concern to the patient. Additionally, clinicians should remain alert
to its occurrence during follow-up and reassessment. SSRI-induced sexual
dysfunction may surface as early as 2 weeks after initiating medication
(around the time of the first patient reassessment), even before full
antidepressant response occurs. (11) During the progression into
remission, practitioners should evaluate sexual side effects and address
it early to decrease potential effect on compliance.
Is dose adjustment useful for elderly patients? Sudden onset of
depression may reflect an underlying medical cause. Neurovegetative
symptoms such as anorexia, insomnia, anergia, loss of concentration, and
anhedonia are more common than depressed mood; referral to a geriatric
psychiatrist for assessment and management may be appropriate. Many
late-onset patients only respond to electroconvulsive therapy.
Titration and duration of agents
Whatever antidepressant is chosen, the practitioner should "start low
and go slow." Begin at or below the usual adult starting dose if
clinically possible and, as necessary, titrate slowly up to the maximum
prescribed amount in accordance with the prescribing information, over a
6- to 12-week period. (14)
Management of patients vulnerable to acute unwanted side effects.
Starting at a dose below prescribing information recommendations may be
advised for patients who may be vulnerable to acute or unwanted side
effects. Even for only a few days, this may comfort the apprehensive
patient and allow those who are prone to acute side effects to
acclimate. The dose can then be titrated to achieve remission. (15-18)
Antidepressant dose titration studies invariably observe a direct and
linear correlation between antidepressant dose, adverse effects, and
discontinuation. This supports the recommended titration schedule.
Attaining on adequate trial of therapy
As for any medication, escalating an antidepressant's dose titration
beyond the maximum recommended dose is not advised. The goal is an
adequate trial of medication, defined as one that reaches the maximum
dosage within 6 to 12 weeks of initiating therapy, with at least 1 month
at the maximum tolerable dose. Clinicians should emphasize the concept
of what constitutes an adequate trial, as well as the importance of an
adequate trial in determining a patient's response to medication. Many
patients discontinue their medication before completion of an adequate
trial, and thus clinicians cannot determine patient response.
Assessing patient response to treatment
"Response" to antidepressant medication is typically defined as a 50% or
greater reduction in depressive symptoms on a standardized scale of
depression; a less than 50% reduction in the depression score is
technically considered a "partial response." (8,19) By the same
criteria, a "nonresponse" to medication occurs when virtually no change
from the baseline occurs.
Best practice recommends use of a standardized scale or a visual analog
to monitor individual (and often incremental) patient response to
medication management. The examination room door chart provided on the
back cover may be helpful in this important aspect of longitudinal care.
Strategies to improve adherence Importance of patient education. Patient
education is essential. (20) Patients who are more educated about their
condition, and who consider it as treatable, are more likely to comply
with treatment. Because many patients now have access to the Internet,
it may be helpful to refer them to responsible patient-specific Web
sites, where they can learn about their illness and further substantiate
depression as their diagnosis.
Patient/physician interactions. Many physicians use a behavioral
approach to increase patient compliance. Methods include having a
patient take the first antidepressant dose in the office, or making the
referral appointment before the patient leaves. In case of problems,
setting up an interactive phone communication can be effective.
Managing side effects associated with the use of antidepressants
Educating patients is recommended to manage routine acute side effects.
This increases compliance, and simultaneously decreases the possibility
of abrupt discontinuation. (21) Moreover, educating patients about the
realistic possibilities for potential side effects (as opposed to merely
reading the package insert to them, or having them read it alone) can
help patients know what to expect, while allowing them to voice their
concerns in the office.
Review patient history prior to changing antidepressants
Before considering a medication change to manage a side effect, the
authors recommend that the clinician review the patient's history to
ascertain the specific time of onset for the complaint. For example, if
the patient had the same complaint prior to the initiation of
antidepressant therapy, it is not a side effect of the medication but a
separate problem. If the complaint arose with the start of the new
antidepressant medication, it should be considered to be caused by the
medication.
For some nuisance side effects (eg, GI upset, mild sedation or
activation, insomnia, etc), it may appropriate to allow time for them to
abate on their own. Other acute side effects, such as rash, sweating, or
akathisia, may require discontinuing the current medications. (14)
Agitation: a side effect or evidence of comorbidity? For patients
experiencing central nervous system (CNS) agitation, if all else is
equal, the physician should revisit the possibility of bipolar disorder.
If this is unlikely, agitation may sometimes be mitigated by slowing the
titration of the medication. This typically resolves agitation that
falls within the normal definition of acute (temporary) side effects.
However, switching medication is recommended if agitation lasts for 4
weeks or more, or if it escalates after week 2 on the current regimen.
Early agitation encountered in the treatment of depression should prompt
a reexamination to evaluate for bipolar disorder.
Sweating may occur early and persist. Much anecdotal evidence suggests
that patients of either sex with stable estrogen levels may experience
an increase in perspiration when receiving antidepressant therapy.
Conversely, perimenopausal women with falling estrogen levels may
actually sweat less when given a serotonergic antidepressant. (22)
Unfortunately, the physiologic basis of these observations remains
undefined; no conclusive studies have elucidated the complex
relationship between estrogen and serotonin.
Cotherapies to manage sweating include terazosin hydrochloride or
oxybutynin chloride, as well as the topical antiperspirant Drysol. To
date, the largest study of successfully treated patients with serotonin
reuptake inhibitor-induced sweats utilized cyproheptadine. (23)
Serotonin fatigue: potential tong-term side effect. The authors believe
that serotonin fatigue, often referred to as "poop out" and apathy, is a
serious and long-term side effect. In most cases, it is related to
dopamine suppression and surfaces as a result of treatment with SSRIs,
since SSRIs have the potential to suppress CNS dopamine.
(24) The condition may manifest either as apathy or as another CNS state
associated (at least in part) with low levels of dopamine: decreased
concentration, decreased libido, increased cravings, and decreased sense
of pleasure and enjoyment. Serotonin fatigue differs from depression:
* In serotonin fatigue, the patient does not feel as if the depression
is returning
* Serotonin fatigue has no element of sadness or decreased mood
* Serotonin fatigue responds to therapy aimed at increasing CNS dopamine.
Serotonin fatigue differs from relapse, defined as the return of
depression in its entirety and a loss of efficacy. The patient may
respond well to an increase in SSRI dose. Those experiencing serotonin
fatigue usually will state that they do not necessarily feel
depressed--they just don't feel anything. Patients will prefer this over
their depression but it need not be tolerated.
The loss of libido, apathy, and the increase of cravings seen in
serotonin fatigue usually do not respond to increased SSRI dose; rather,
they require augmentation with, or a switch to, a dopaminergic
antidepressant.
Weight gain and antidepressant use. Weight gain is commonly seen in
prolonged SSRI use. (25) It often manifests after many months of
treatment and is frequently not attributed to the medication. If the
increase in body weight is indeed mediated by an SSRI, diet and exercise
may have little impact. When added to an established regimen of SSRI
therapy, both bupropion and topiramate have been reported to help some
patients lose weight. Research suggests using sustained release
bupropion at an antidepressant dose, (26) or possibly using dosages of
topiramate lower than indicated for treating epilepsy. (27) The SSRI
dose may also be reduced after augmentation with bupropion.
Serotonin syndrome: rare but potentially fatal. Serotonin syndrome is an
extremely rare but life-threatening event associated with the SSRIs.
(28) It manifests with the clinical picture of delirium, tremulousness,
and autonomic instability. Early flu-like symptoms, such as diarrhea,
cramping, and GI upset, become complicated with distinguishing clinical
characteristics such as myoclonus (jerking), confusion, disorientation,
stupor, and autonomic arousal (eg, tachycardia, hyperpyrexia,
diaphoresis, or hypertension). The risk of developing serotonin syndrome
is increased when an SSRI is administered concurrently with another
serotonin-enhancing agent such as an MAOI or tryptophan. When one
suspects serotonin syndrome, the SSRI must be discontinued.
Movement disorders: rarely reported side effects. Rarely encountered
SSRI-induced movement disorders include restless legs syndrome,
akathesia, dystonia, and Parkinsonism. In some cases, it is believed
that these conditions represent the exacerbation of an underlying but
previously unrecognized movement disorder. In addition, in patients who
are concurrently receiving antipsychotic drugs, SSRIs may exacerbate
extra-pyramidal symptoms.
Treatment strategies for SSRI-linked movement disorders consist of
either discontinuation of the SSRI, or dosage reduction. In addition,
benzodiazepines may be considered for akathisia, anticholinergic agents
for the coarse resting tremor of pseudoparkinsonism, and beta-blockers
for the fine intention tremor associated with SSRIs and SNRIs. (29)
Strategies to deal with insomnia as a side effect. Insomnia falls under
the acute category and may dissipate with time on medication; however,
it can become an ongoing problem. In addressing this side effect, the
authors recommend that physicians begin by emphasizing some helpful
rules regarding good sleep hygiene, specifically:
* Sleep in a cool, dark room
* No reading or watching TV in bed
* If you can't fall asleep, don't lie in bed. Get up
* No alcohol or caffeine consumption within 4 hours before bedtime
* No snooze button use.
Other potentially beneficial strategies include moving the time of
antidepressant dose (away from bedtime), relaxation exercises, hot
baths, and avoidance of naps. In addition, some patients may require the
administration of a hypnotic such as diphenhydramine HCl or trazodone
before bedtime. It is also important to rule out the presence of a
preexisting sleep disorder, which may require additional testing and
treatment.
Sexual dysfunction: data lacking concerning treatment. Decreased libido
is a common complaint of patients with major depression and may affect
compliance. Good data remain lacking concerning the most effective
treatments. While treating depression can sometimes correct sexual
dysfunction (eg, premature ejaculation), (30) many antidepressant
medications also have the potential to cause sexual problems.
The risk of medication-induced occurrence as demonstrated by Clayton and
colleagues showed a prevalence of sexual dysfunction on the basis of
Changes in Sexual Functioning Questionnaire total scores to average 24%
for all antidepressants combined and ranged from 7% for bupropion SR to
30% for citalopram and venlafaxine.
(11) This study was first powered to evaluate the direct attributable
risk of sexual dysfunction associated with antidepressants.
Patients reluctant to discuss sexual issues. Although amelioration of
drug-induced sexual dysfunctions can increase patients' treatment
compliance and quality of life, many patients are reluctant to discuss
sexual issues. Therefore, family physicians must take a very direct
approach in asking patients about sexual dysfunction. The success of
direct inquiry is substantiated by results from a 344-patient,
prospective, multicenter study in which only 14% of depressed
outpatients experiencing SSRI-related sexual dysfunction reported the
problem spontaneously to their physicians, compared with 58% when the
physicians asked direct questions about sexual side effects. (31)
When a patient undergoing SSRI or venlafaxine therapy reveals the
existence of sexual problems, the family physician should refrain from
automatically attributing these problems to the effects of medication.
Although it is true that antidepressant- and depression-related sexual
dysfunction are very prevalent, causes other than the antidepressant
should also be considered whenever a patient in remission shows no
improvement in libido. These other causes include hormonal changes,
lifestyle risk factors (ie, drug or alcohol abuse), concurrent medical
conditions, and the adverse effects of other medications. (32)
Treatment options for sexual dysfunction. Once the family physician has
concluded that a patient's sexual dysfunction is probably related to
antidepressant therapy, 4 management options are available:
* Watchful waiting
* Dose adjustment
* Augmentation with another medication
* Switching medications.
Currently, very few controlled studies exist in the literature. Very
little data exist to suggest which of these options is the best choice
for specific types of patients. (33)
Watchful waiting. This approach generally has been found to be
ineffective. Ashton and Rosen reported only a 9.8% success rate in the
resolution of sexual problems among depressed patients with sexual
dysfunction who simply continued with their current medication regimen
(watchful waiting) for as long as 38 months. (34) Likewise,
Montejo-Gonzalez et al reported an even lower success rate: a mere 5.8%
after 6 months. (31)
Decreasing dose. The authors believe that decreasing the dose of the
SSRI or venlafaxine sometimes relieves patients' sexual dysfunction;
however, dose reduction carries the disadvantages of possible reduced
antidepressant efficacy, or frank relapse. In a similar way, a brief
drug holiday may assist some patients in restoring sexual function, but
it may also promote noncompliance by encouraging patients to skip doses
prior to sexual activity.
Augmentation. Augmentation may be efficacious in certain types of
patients, although this strategy requires that the specific type of
sexual dysfunction be identified so that the proper medication can be
prescribed.
Patients with erectile dysfunction may benefit from sildenafil, as
evidenced by results of a recent study by Nurnberg and colleagues. This
prospective, randomized, double-blind study found that 54.5% of patients
with SSRI-related sexual dysfunction were "much or very much improved"
after treatment with sildenafil, compared with only 4.4% of patients who
received placebo. (35)
Data are lacking for patients with delayed orgasm; however, anecdotal
reports suggest that adding a 5H[T. sub. 2a]-blocker (cyproheptadine,
buspar, trazodone) can be helpful.
Treatment of decreased libido should begin by ruling out abnormalities
in thyroid function, testosterone level, and sleep hygiene (lack of
sleep), lf no abnormalities are found, augmentation with bupropion
(delayed release formula) may be appropriate. Perlis studied patients
with hyposexual desire disorder and found bupropion to be an effective
treatment option. (6)
Switching. Switching medications to ameliorate treatment-induced sexual
dysfunction may be efficacious. The new antidepressant should have a
comparatively benign sexual side effect profile, such as bupropion or
nefazodone. The relatively low risk of sexual dysfunction associated
with these 2 antidepressants has been supported by the results of a
large, multicenter, observational study by Clayton et al. This study
enrolled more than 6,000 adult outpatients receiving antidepressant
monotherapy. The investigators reported a low risk of sexual dysfunction
for patients receiving bupropion (sustained release) and in those
receiving nefazodone, as compared with a 4 to 6 times greater prevalence
of sexual dysfunction in patients receiving SSRIs, mirtazapine, or
venlafaxine. (11)
In summary, management of SSRI- or venlafaxine-induced sexual
dysfunction is a challenging therapeutic area in which more
well-designed clinical trials are necessary. Practically speaking,
augmentation with a second medication may be better than switching if
the depression was severe and the patient is within the first few months
of remission (patient is at the highest risk of relapse).
The Depression Clinical and Research Group at Massachusetts General
Hospital recently reported that augmentation (with bupropion) was the
most popular treatment choice (43%) of 439 clinicians who responded to a
survey regarding the pharmacologic management of serotonin-related
sexual side effects. (36) Another 36% of clinicians responded that
"switching agents" would be their preferred management strategy.
Whatever the family physician's initial thoughts regarding a treatment
approach, however, the risks and benefits of the various management
strategies should always be considered and discussed with the patient
beforehand.
Reassessment to monitor patient response
In spite of a thorough assessment and diagnostic work-up by the family
physician, many patients who begin treatment with an appropriate
antidepressant never follow through with therapy and achieve full
response and remission. In some cases, the patient is diagnosed with
depression and prescribed an antidepressant, and then simply not seen
again. In other cases, the patient returns intermittently for follow-up
care, but remains only partially treated. He or she continues to
function poorly, often as a result of receiving a subclinical dose of
antidepressant (failure to titrate to full response).
The full scope of this problem of under-treatment or partial-treatment
with respect to depressed patients in primary care is evidenced by
results of a large population-based studies, in which it was found that
only 39% of patients treated for depression were on an adequate dose of
an antidepressant. (37) This underscores the difficulty clinicians face
in managing patients' depression.
Strategies for reassessment. Periodic patient reassessment requires that
the family physician take the time and initiative to define exactly what
the patient means by "feeling better," or not (ie, has there been a full
response to medication, only a partial response, or no response).
This may be done using any of the standard instruments (depression
scales). In patients who have demonstrated a true response (defined as
50% or greater reduction in depressive symptoms on a standardized
depression scale), then side effects and continuing compliance are the
main treatment issues as one moves toward remission. However, when
reassessment reveals that a patient has experienced either a partial
response (less than 50% reduction in depression score) or a nonresponse
(virtually no change in depressive score compared with baseline), then a
reevaluation of treatment strategies is clearly indicated. As a guide in
this reevaluation process, the authors suggest reviewing the 4 Ds (see
Reassessment: The 4Ds).
Review and reassessment of the treatment plan
When the family physician has answered "No" to the fourth "D" question,
and there is uncertainty as to whether the correct drug has been used as
first-line therapy, the first step is to review the decision tree. These
suggestions may also help treat the patient who has shown nonresponse or
only partial response to initial antidepressant therapy.
Nonresponse or minimal response to treatment. In the case of a patient
who shows minimal or no response to treatment, the authors note that
either a failure of first-line drug therapy has occurred or the patient
is truly treatment-resistant. For failures of first-line therapy,
treatment options include switching to another antidepressant in the
same class, or switching to a medication in a different class. For the
truly treatment-resistant patient, one with a history of failing to
respond to at least two different classes of antidepressants,
psychiatric consultation or referral is recommended.
Partial response to treatment. When a partial response to antidepressant
therapy is observed, the authors recommend that the family physician
ascertain that the patient has had an adequate trial of the medication.
This can be done by reviewing the patient's dose level (ie, has maximum
dose been prescribed?), as well as by confirming patient compliance.
Once a partial response to an adequate trial of first-line
antidepressant has been verified, the authors recommend the following
options:
* Combination therapy with another antidepressant. Some common
combinations include: a SSRI and a NDRI; a SSRI and mirtazapine; a NDRI
and a SNRI; or a SNRI and mirtazapine
* Cotherapy with another drug that is not an antidepressant--for
example, a stimulant, lithium, or triodothyronine
* Switching drugs. As with nonresponders, the options include switching
to a different antidepressant in the same class, or switching out of class.
Cotherapy and combination therapy may be particularly beneficial
options, since they allow the family physician to titrate each
medication independently. They also may allow the family physician to
prescribe lower doses of one or both agents, thus increasing the desired
effects of the medications on patient response.
Whenever a patient shows a nonresponse or a partial response to
antidepressant therapy, effects of any comorbid illnesses or concurrent
medications should be considered. Specifically, the family physician may
need to reevaluate the patient for concurrent substance abuse, the
presence of severe psychosocial stressors, physical or sexual abuse, or
the influence of an undiagnosed bipolar disorder or personality
disorder. As discussed previously, the presence of these complicating
factors may suggest the need for a team approach that includes referral
to a psychiatrist.
* TREATMENT: SECOND-LINE THERAPY
Studies show that as many as 50% of patients will fail to demonstrate an
adequate response to antidepressant monotherapy, 38 while a full 20%
will follow a chronic course requiring multiple interventions. When
first-line therapy for depression fails (ie, the patient has shown no
response, partial response, or is treatment resistant), there are
currently no available algorithms to help the clinician choose the next
course. However, the authors recommend that if the methods outlined in
our discussion of first-line treatment fail to elicit a positive
antidepressant response, the clinician should evaluate 2 options for
further treatment: switching the patient to another antidepressant
medication or cotherapy with a different class of antidepressant.
Switching or augmenting medications: common practices
Switching is becoming more common in the primary care setting as family
physicians become comfortable with treatment of depressive conditions
and learn more about available pharmacologic alternatives. Furthermore,
a review of the literature suggests that switching may be the most
appropriate course of action in the patient with minimal or no response
to first-line therapy.
Augmentation. Lam et al recently published a review of the widespread
clinical practice of combining antidepressants by examining 27 published
studies. After considering the dearth of available evidence, the authors
of this review strongly caution against the use of antidepressant
combinations as the first step in the pharmacotherapy of refractory
depression. (38)
Switching within or outside of class. Once the family physician has made
the decision to switch a patient's antidepressants, 2 clinically sound
choices are available:
* Switching classes to provide a new drug with a different mechanism of
action
* Using an alternate drug in the same class with the same mechanism of
action.
Presently, no sound clinical evidence to supports one choice over the
other. For example, Thase concluded that patients who failed treatment
with an SSRI showed a better chance of remitting after being switched to
venlafaxine (a different antidepressant class) as opposed to a second
SSRI. (39) In clinical practice, however, many physicians can attest to
the fact that all SSRIs are not created equal, even though they share
allegedly similar mechanisms of action. Just as patients might prefer
and report better response to a particular analgesic (eg, naproxsyn vs.
ibuprofen), an individual patient may respond better to one SSRI over
another; however, it is difficult to recommend one strategy over another
when switching within class.
A survey of practitioners (most of whom were psychiatrists) showed that,
after 8 weeks of an adequate SSRI trial, 44% would switch out of class
in the case of a nonresponsive patient, while only 17% would switch
within class to a second SSRI. (40) Of those clinicians who opted to
switch class in this study, 14% specified they would use a dual-acting
agent, and 12% named bupropion as the dual acting agent to which they
would switch. These findings are consistent with the logic that, if a
patient fails a reasonable trial with one class of anti-depressant,
another class might be more successful, provided that it has a different
mechanism of action.
* COTHERAPY: BENEFITS AND RISKS
In managing depression, the practice of using cotherapy at the onset of
treatment, rather than titrating a single agent to its maximum dose,
might be utilized to manage key symptoms and side effects. A caveat to
this practice is that by initiating 2 medicines for the same illness in
concert, it is difficult to then know if one of the agents is providing
all of the benefit in the case of successful treatment. Likewise, it may
also be difficult to discern which agent is causing a given side effect,
since both drugs were initiated at the same time.
In terms of advantages, cotherapy can sometimes ameliorate a patient's
symptoms faster than switching to another antidepressant. This is
because utilizing a second antidepressant may result in a faster onset
of response than the timing required to wash out and switch a patient to
a different monotherapy. (38)
Issues of toxicity
If a patient truly requires cotherapy (as opposed to switching), the
absolute guiding principle requires the addition of an antidepressant
from a different class to avoid toxicity and other critical safety
concerns. Selection of this additional antidepressant should be guided
by targeting resolution of the residual symptoms and reduction of side
effects. Despite the lack of a universally accepted algorithm, several
commonly accepted strategies exist. For instance, when a minimally
responsive patient receives an SSRI as first-line treatment, most
physicians would add bupropion. This strategy uses the noradrenergic and
dopaminergic properties of bupropion to enhance the serotonergic
activity of the SSRI. In addition, bupropion might also affect
concentrations of certain SSRIs by way of inhibition of CYP2D6. (41)
Regarding the efficacy of specific cotherapy combinations, a wealth of
small studies have explored strategies for specific patient subtypes.
For example, in a study of patients who had been minimally responsive to
SSRIs and had exhibited sleep disturbance or nausea, half of the
subjects responded positively to the addition of mirtazapine. (42)
Larger studies may be anticipated as industry research on augmentation
continues to explore the clinical response and chemical foundations of
popular combinations of antidepressants currently used in cotherapy.
While many options for managing patients with suboptimal response to
antidepressant therapy, it should be noted that these strategies are
best guided by careful reassessment of the particular patient, as
opposed to generalized practice trends or algorithms. As with first-line
therapy, careful attention should be paid to specific side effects and
manifestations of depression (primary and residual) when selecting the
second-line agent for any particular patient.
REASSESSMENT: THE 4 Ds
In the case of either a partial response or nonresponse to
antidepressant medication, practitioners are strongly advised to ask
themselves the following questions:
* Did I make the wrong Diagnosis? Review the patient's diagnosis to make
certain that it is correct.
* Did I fail to prescribe an adequate Dosage? Be sure you have given the
maximum package insert dosage or maximum tolerable dose before you
conclude that your patient is not responding.
* Did I ensure sufficient Duration of treatment? Remember, an adequate
trial is one that lasts between 6 and 12 weeks from initiating therapy,
with at least 1 month on the maximum tolerable dose.
* Did I prescribe the correct Drug? Several different strategies to make
your pharmacologic decision have been presented. Review the clinical
decision tree (Figure 1). Are the correct symptoms being targeted?
[FIGURE 1 OMITTED]
If answers to these 4 questions are "Yes," second-line treatment is
advised. If the answer to any one of them is "No," review and
reassessment of the treatment plan is indicated. In addition, consider
the option of referring the patient to a specialist, especially when you
are unsure of the next step.
REFERENCES
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Adam Keller Ashton, MD
Clinical Professor of Psychiatry
SUNY at Buffalo School of Medicine
Buffalo, NY
Dr Ashton is a clinical associate professor of Psychiatry at the State
University of New York in Buffalo, and is in fulltime private practice
with the Buffalo Medical Group. He has written extensively for
psychiatric journals on treatment-induced sexual dysfunction. He is a
distinguished clinical fellow of the American Psychiatric Association.
Dr Ashton received his medical degree from the State University of New
York at Buffalo School of Medicine after completing his master's degree
at the same facility. He completed his residency also at the State
University of New York at Buffalo with subsequent training in sex
therapy at the Robert Wood Johnson School of Medicine in New Jersey.
Dale A. O'Mello, MD
Associate Professor
Department of Psychiatry
Michigan State University
Lansing, MI
Dr D'Mello is an associate professor in the department of psychiatry at
Michigan State University. Dr D'Mello is the medical director for MSU
Inpatient Psychiatry at St. Lawrence Hospital and serves on the
editorial board for Journal of Psychotic Disorders. Dr D'Mello is a
member of the American Psychiatric Association and the American Academy
of Clinical Psychiatrists. He has a special interest in pharmacologic
management of psychotic disorders and biological and social concomitants
of major psychoses and affective disorders.
Dr D'Mello received his medical degree from Bombay University, Bombay,
India and completed his residency in psychiatry at Michigan State
University in East Lansing.
Bezalel Dantz, MD
Assistant Professor of Clinical Medicine and Psychiatry
University of Chicago
Chicago, IL
Dr Dantz is an assistant professor of clinical medicine and psychiatry
at the University of Chicago. He is the director of the Behavioral
Medicine Clinic at the University of Chicago Hospital and is a primary
care physician there as well. His main interest is in training
non-psychiatric clinicians to recognize and treat mental health
disorders. He lectures on the interface between medical and psychiatric
disorders, and writes about psychiatric aspects of medicine.
Dr Dantz received his medical degree from Stanford University School of
Medicine in Stanford, CA, and completed residencies in both internal
medicine and psychiatry at the New York Presbyterian Hospital-Cornell
Medical Center in New York City, NY.
Jaye Hefner, MD
Assistant Professor of Medicine
University of Pittsburgh Medical Center
Pittsburgh, PA
Dr Hefner is an assistant professor of medicine in the section of
general internal medicine, division of medicine at the University of
Pittsburgh Medical Center (UPMC). She serves as director of Women's
Health at UMPC Shadyside Hospital and is the medical director of the
UMPC Weight Management Center and the UMPC Magee-Women's Hospital
Comprehensive Healthcare Center for Women with Physical Disabilities.
She is the site director for the 2nd-, 3rd-, and 4th-year medical school
clerkships in internal medicine. Dr Hefner has published and lectured in
the areas of women's health, medical education, and physical medicine
and rehabilitation. Dr Hefner has received funding for research in the
areas of hypertension, depression, weight management, disability
medicine, and migraine headaches.
Dr Hefner received her medical degree at Northeastern Ohio Universities
College of Medicine. She completed an internal medicine residency and a
fellowship in general internal medicine/women's health at the University
of Pittsburgh Medical Center. She is board certified in internal
medicine and has a dual appointment with the departments of internal
medicine and physical medicine and rehabilitation.
F. George Leon, MD
Medical Director
Leon Medical Center
Waldorf, MD
Dr Leon is medical director of the Leon Medical Center, a family
practice group, combined with a multispecialty group practice. He is a
member and diplomat of the American Academy of Family Practice and the
American Board of Family Medicine. Dr Leon has special interest in
chronic pain management psychopharmacology, fibromyalgia, Lyme disease,
and nutritional medicine.
Dr Leon received his medical degree from the University of Zaragoza in
Zaragoza, Spain. He completed his pediatric internship at Thomas
Jefferson University Hospital in Philadelphia, PA, and his family
practice residency at Polyclinic Medical Center in Harrisburg, PA.
Gary A. Matson, MD
Primary Care Practice
Fresno, CA
Dr Matson is board-certified in family practice. In addition to a
private primary care practice, he is medical director of a weight
management program for Sante Community Physicians. His educational video
on the obese teenager is now used throughout the school systems.
Dr Matson received a medical degree from Georgetown University School of
Medicine and completed a residency through University of California, San
Francisco, UCSF-San Joaquin Valley. Dr Matson also has an undergraduate
degree in psychology and a master of science degree in physiology.
C. Brendan Montano, MD
Assistant Clinical Instructor
Department of Family Practice
University of Connecticut Medical School
Private Practice
Cromwell, CT
Dr Montano is an assistant clinical instructor at the University of
Connecticut School of Medicine in the Department of Family Practice in
Farmington, CT. He practices internal and preventative medicine in
Cromwell, CT, with a special interest in treating depression and anxiety
disorders. He also serves as the director of Connecticut Clinical Research.
Dr Montano earned his bachelor's degree from the College of The Holy
Cross in Worcester, MA, and his medical degree from Albany Medical
College in Albany, NY. In
1972, Dr Montano served as chief medical resident at St. Francis
Hospital in Hartford, CT, where he completed his residency training in
internal medicine.
Dr Montano is recognized internationally as an expert in the recognition
and treatment of mood disorders in the primary care setting. In 1998, he
presented his interview techniques at a tutorial for the World Health
Organization at the AEP congress in Copenhagen. Dr Montano presents CME
conferences and lectures through a variety of media. He has authored
several articles in the Journal of Clinical Psychiatry.
James F. Pradko, MSc, MD
Family Practice
Director Bay Pointe Depression Clinic
New Baltimore, Michigan
Dr Pradko is in private family practice in New Baltimore, MI, on staff
at Mount Clemens General Hospital, and is a part-time instructor in the
department of family practice at St. John Hospital in Detroit, MI. In
addition, he is the director of Bay Pointe Depression Clinic, which
specializes in treating the side effects caused by antidepressants. Dr
Pradko lectures nationally on the topic of neurotransmitters and
antidepressants. He conducts research in the areas of
antidepressant-induced sexual dysfunction and serotonin fatigue. His
most recent research appeared in the May 2002 issue of the Journal of
Clinical Psychiatry.
Dr Pradko received his master of science (theoretical physics) and
medical degree from the University of Alberta, Canada. He completed his
internship at the University of Toronto and his residency in family
medicine at St. John Hospital in Detroit, MI.
Norman Sussman, MD
Professor of Psychiatry
New York University School of Medicine
New York, New York
Dr Sussman is a professor of psychiatry at the New York University
School of Medicine. He is a graduate of New York Medical College and
completed his internship and residency at Metropolitan Hospital in New
York City and the Westchester County Medical Center in Valhalla, NY.
He has served as director of residency training at the NYU Medical
Center for 4 years and is currently co-director of the Center for Study
of Depression in Parkinson's Disease at the NYU Medical Center. He is
editor of the journal Primary Psychiatry, and has been a contributor to
The Comprehensive Textbook of Psychiatry for the past
6 editions. He is consulting editor for the next edition of The
Comprehensive Textbook of Psychiatry and the current edition of The
Handbook of Psychiatric Drug Therapy.
Dr Sussman's research activities have included studies of various
psychotropic drugs. He is also a frequent contributor to medical
literature. Dr Sussman is a Fellow of the American Psychiatric
Association and a member of the American Medical Association. He also
serves on the Board of Governors of the NYU/Bellevue Psychiatric Society.
Bertrand Winsberg, MS, MD
Research Professor
Department of Psychiatry
New York University School of Medicine
New York City, New York
Dr Winsberg is a research professor in psychiatry at NYU Medical School
and an attending physician in child psychiatry and pediatrics at
Brookdale University Hospital and Medical Center in Brooklyn, NY. He has
conducted research in developmental and pediatric neuropsychiatry with a
special interest in pediatric psychopharmacology. Recent work includes
molecular genetic mechanisms of drug response to stimulant medication.
He is a reviewer for the American Journal of Psychiatry and the
recipient of research grants from the NIH. His work on the dopamine
transporter received a National Research Award from the American Academy
of Child and Adolescent Psychiatry.
Dr Winsberg received his medical degree from the University of Michigan,
where he also completed his training in adult psychiatry. He completed
his training in child psychiatry at the University of Michigan and
developmental pediatrics at Mount Sinai Hospital in New York. Current
research interests include the neurohormonal basis of weight gain with
atypical antipsychotic drugs in children.
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