David Baxter PhD
Late Founder
Starting, Ending Antidepressants: Educating patients about what to expect in the course of antidepressant therapy is critical
By Carl Sherman
Clinical Psychiatry News, Volume 35, Issue 6, Page 14 (June 2007)
Difficulties can develop at any time in the course of antidepressant therapy, but they seem to cluster at the beginning and the end.
Although it usually takes weeks for a therapeutic response, many adverse reactions?nausea, headache, somnolence, and agitation?appear soon after the first dose.
On the other hand, when some of the most widely used agents are discontinued, multiple symptoms across diverse bodily systems are common.
Early and late difficulties may be understood in terms of antidepressant neurobiology, said Dr. Pierre Blier, professor of psychiatry at the University of Ottawa.
?When serotonin reuptake inhibitors [SRIs] are initiated, there's an immediate surge in the neurotransmitter throughout the brain,? Dr. Blier said.
?It appears to be accentuated in certain regions [such as those that regulate nausea], while in areas involved in depression, like the hippocampus and frontal cortex, the surge of serotonin goes down because of negative feedback actions.?
Specifically, autoreceptors on serotonin neurons are activated by elevated levels of the neurotransmitter, inhibiting its release. Over time?the weeks before an effective response?these receptors become desensitized, allowing serotonin to rise in a consistent manner.
Discontinuation phenomena probably involve multiple neurotransmission systems that must adapt to reduced serotonin, Dr. Blier said.
Problems at the outset can complicate treatment.
?Part of depression is being discouraged, frustrated, and pessimistic. When you don't get better quickly, it compounds these feelings,? said Dr. Jonathan W. Stewart, professor of clinical psychiatry at Columbia University, New York.
Add early side effects and ?it's a good recipe for disaster,? he noted. Dropout during the first weeks of treatment is common.
Patient education helps.
?The worst thing you can do is take the patient by surprise,? Dr. Stewart said. ?When Prozac [fluoxetine] first came out, we didn't know that some people would get very anxious on it. The first three patients who told me about this refused to try it again.
?Since I've started explaining the possibility beforehand, I've never had anyone refuse to continue.?
Dr. Michael Thase, professor of psychiatry at the University of Pennsylvania, Philadelphia, emphasizes the importance of patient education. ?I'd share with the patient that side effects often precede therapeutic effects and explain it in terms of how the medication works,? according to Dr. Thase.
Early side effects are usually self-limiting and remit within a week or two, and they can be eased by reducing antidepressant dosage, he said.
Anxiety, restlessness, and insomnia, if severely distressing, might require a brief course of a benzodiazepine or an atypical antipsychotic.
Although nothing has been proved to accelerate therapeutic effect, there is increasing interest in combining medications initially, rather than reserving this approach for more resistant cases.
Dr. Blier had promising results in a pilot study combining an SSRI and mirtazapine (Remeron); the latter drug, an α2-adrenergic antagonist, appears to hasten adaptations within the serotonergic system.
?Not only was therapeutic onset more rapid, we doubled remission over 6 weeks of treatment,? Dr. Blier said.
The SSRI may often be titrated more rapidly because mirtazapine, a 5-HT3 and 5-HT2 blocker, attenuates nausea and insomnia.
Dr. Blier offers patients this option in his practice, he said.
Early studies suggest that combining a serotonergic antidepressant (escitalopram [Lexapro]) with an adrenergic one (bupropion [Wellbutrin]) can similarly accelerate and improve therapeutic outcome.
A multicenter trial examining this approach is ongoing, Dr. Stewart said.
Discontinuation symptoms have received attention in association with newer drugs, but such symptoms can occur with any antidepressant that engages the serotonin system, such as clomipramine (Anafranil), said Dr. Richard Shelton, professor of psychiatry at Vanderbilt University, Nashville, Tenn.
A condition that has been called antidepressant discontinuation syndrome (ADS) can include neurologic, gastrointestinal, or psychiatric symptoms, but ?the most prevalent is dizziness,? Dr. Shelton said.
He noted that ?paresthesias [typically electric shock-type sensations] and muscle jerks and twitches are also common and disconcerting but not dangerous.?
No reliable prevalence figures are available, but it seems clear that drugs with a short half-life, notably paroxetine (Paxil) and venlafaxine (Effexor), carry the highest risk of ADS.
Problems are usually milder and less frequent with intermediate-acting drugs such as citalopram (Celexa) and escitalopram. When those with the longest half-lives, sertraline (Zoloft) and especially fluoxetine, are used, reactions are minimal at worst, Dr. Shelton said.
Timing also varies: Symptoms typically appear 48?72 hours after venlafaxine withdrawal, at 5?7 days with citalopram, and 2 or even 3 weeks after fluoxetine withdrawal.
The symptoms generally remit within a week or two.
Some of the original mood symptoms may return as part of ADS, but this can readily be distinguished from relapse, which tends to be more gradual and delayed. One symptom can follow the other, however.
?It's fairly common to see discontinuation blend into reemergence of depression. Mood starts to decline just when the initial flurry of discontinuation symptoms begins to improve,? according to Dr. Shelton.
There is no evidence that ADS increases the risk of depression relapse, but it can trigger new-onset anxiety symptoms in a sensitive individual, he said.
Here, too, patient education is paramount.
?If they don't know where these symptoms are coming from, patients can get really scared,? he said.
Extensive, unnecessary medical evaluations might follow.
Dr. Shelton informs patients of the possibility of ADS when initiating antidepressant treatment.
?I suggest it's a reason not to miss doses. I'll reiterate the explanation at the time of tapering,? he said.
Women and people who have long-standing, early-onset depression seem to be more prone to ADS, Dr. Shelton said, and patients who have had ADS before are likely to have it again.
?Those with anxiety disorders and anxiety in the context of depression are particularly vulnerable,? he said.
Dr. Blier pointed out that people who had difficulty starting an antidepressant are likely to have problems with discontinuation.
?They probably have an oversensitive subtype of serotonin receptor,? Dr. Blier said.
?Clinically, ADS is quite easy to manage,? Dr. Blier said. Antidepressants, particularly those with a short half-life, should be tapered rather than discontinued abruptly.
?If you run into problems, slow the taper. If problems persist, put the patient on fluoxetine for a week, then stop it?its long half-life provides a gradual withdrawal,? he said.
Tapering timetables can vary but usually involve halving the dose at intervals that might be as long as 2 weeks or even a month for sensitive patients on short-acting drugs.
?If I've been treating someone for 6?12 months, I see no problem in taking an extra 2 months for discontinuation,? Dr. Blier said.
If a patient is extremely vulnerable, with coexisting panic, for example, ?I may just want to avoid discontinuation symptoms,? Dr. Shelton said.
?I won't wait till they emerge, but add fluoxetine before starting discontinuation, and then taper both drugs.?
Early Improvement Predicts Outcome
A connection between antidepressant response onset and ultimate outcome has been noted since the mid-1990s. ?The earlier the drug starts to work, the better the chance for a good outcome,? said Dr. George Papakostas of Massachusetts General Hospital and Harvard Medical School, Boston.
His own research found a correlation between earlier clinical improvement and more robust recovery, as measured by residual symptoms at 8 weeks. The association extended to some domains (depression, anxiety, and hopelessness) but not to somatic symptoms or hostility (Psychiatry Res. 2007;149:195?200).
How to put this information to clinical use is unclear. ?The further out you go, the more of an argument can be made that something needs to be done in the face of nonresponse,? Dr. Papakostas said. After 1 week, ?the overwhelming number of clinicians would agree it's too early to make a treatment decision based on efficacy alone,? but by the 4th week the need for some sort of change would seem reasonable, if not urgent, to many.
Whether this means increasing the dosage, augmentation, or switching to another agent depends on several drug and patient factors, he said.
To Dr. Thase, a failure to respond at all by the second week ?may or may not reflect on the efficacy of the drug, but I would take it to mean that you can't capitalize on a placebo response or a natural remission?that this will be a more difficult-to-treat patient.? A lack of early response to treatment might also be an indicator that combined treatments, including the combination of psychotherapy and pharmacotherapy, might be necessary, he said.
Dr. Papakostas, citing his own findings, said a delayed response could suggest that certain symptoms, such as anxiety, will need treatment after the episode has for the most part resolved. ?It may be worthwhile to start thinking about adjunctive treatment with a benzodiazepine or benzodiazepine-type drug, or a second antidepressant,? he said.
By Carl Sherman
Clinical Psychiatry News, Volume 35, Issue 6, Page 14 (June 2007)
Difficulties can develop at any time in the course of antidepressant therapy, but they seem to cluster at the beginning and the end.
Although it usually takes weeks for a therapeutic response, many adverse reactions?nausea, headache, somnolence, and agitation?appear soon after the first dose.
On the other hand, when some of the most widely used agents are discontinued, multiple symptoms across diverse bodily systems are common.
Early and late difficulties may be understood in terms of antidepressant neurobiology, said Dr. Pierre Blier, professor of psychiatry at the University of Ottawa.
?When serotonin reuptake inhibitors [SRIs] are initiated, there's an immediate surge in the neurotransmitter throughout the brain,? Dr. Blier said.
?It appears to be accentuated in certain regions [such as those that regulate nausea], while in areas involved in depression, like the hippocampus and frontal cortex, the surge of serotonin goes down because of negative feedback actions.?
Specifically, autoreceptors on serotonin neurons are activated by elevated levels of the neurotransmitter, inhibiting its release. Over time?the weeks before an effective response?these receptors become desensitized, allowing serotonin to rise in a consistent manner.
Discontinuation phenomena probably involve multiple neurotransmission systems that must adapt to reduced serotonin, Dr. Blier said.
Problems at the outset can complicate treatment.
?Part of depression is being discouraged, frustrated, and pessimistic. When you don't get better quickly, it compounds these feelings,? said Dr. Jonathan W. Stewart, professor of clinical psychiatry at Columbia University, New York.
Add early side effects and ?it's a good recipe for disaster,? he noted. Dropout during the first weeks of treatment is common.
Patient education helps.
?The worst thing you can do is take the patient by surprise,? Dr. Stewart said. ?When Prozac [fluoxetine] first came out, we didn't know that some people would get very anxious on it. The first three patients who told me about this refused to try it again.
?Since I've started explaining the possibility beforehand, I've never had anyone refuse to continue.?
Dr. Michael Thase, professor of psychiatry at the University of Pennsylvania, Philadelphia, emphasizes the importance of patient education. ?I'd share with the patient that side effects often precede therapeutic effects and explain it in terms of how the medication works,? according to Dr. Thase.
Early side effects are usually self-limiting and remit within a week or two, and they can be eased by reducing antidepressant dosage, he said.
Anxiety, restlessness, and insomnia, if severely distressing, might require a brief course of a benzodiazepine or an atypical antipsychotic.
Although nothing has been proved to accelerate therapeutic effect, there is increasing interest in combining medications initially, rather than reserving this approach for more resistant cases.
Dr. Blier had promising results in a pilot study combining an SSRI and mirtazapine (Remeron); the latter drug, an α2-adrenergic antagonist, appears to hasten adaptations within the serotonergic system.
?Not only was therapeutic onset more rapid, we doubled remission over 6 weeks of treatment,? Dr. Blier said.
The SSRI may often be titrated more rapidly because mirtazapine, a 5-HT3 and 5-HT2 blocker, attenuates nausea and insomnia.
Dr. Blier offers patients this option in his practice, he said.
Early studies suggest that combining a serotonergic antidepressant (escitalopram [Lexapro]) with an adrenergic one (bupropion [Wellbutrin]) can similarly accelerate and improve therapeutic outcome.
A multicenter trial examining this approach is ongoing, Dr. Stewart said.
Discontinuation symptoms have received attention in association with newer drugs, but such symptoms can occur with any antidepressant that engages the serotonin system, such as clomipramine (Anafranil), said Dr. Richard Shelton, professor of psychiatry at Vanderbilt University, Nashville, Tenn.
A condition that has been called antidepressant discontinuation syndrome (ADS) can include neurologic, gastrointestinal, or psychiatric symptoms, but ?the most prevalent is dizziness,? Dr. Shelton said.
He noted that ?paresthesias [typically electric shock-type sensations] and muscle jerks and twitches are also common and disconcerting but not dangerous.?
No reliable prevalence figures are available, but it seems clear that drugs with a short half-life, notably paroxetine (Paxil) and venlafaxine (Effexor), carry the highest risk of ADS.
Problems are usually milder and less frequent with intermediate-acting drugs such as citalopram (Celexa) and escitalopram. When those with the longest half-lives, sertraline (Zoloft) and especially fluoxetine, are used, reactions are minimal at worst, Dr. Shelton said.
Timing also varies: Symptoms typically appear 48?72 hours after venlafaxine withdrawal, at 5?7 days with citalopram, and 2 or even 3 weeks after fluoxetine withdrawal.
The symptoms generally remit within a week or two.
Some of the original mood symptoms may return as part of ADS, but this can readily be distinguished from relapse, which tends to be more gradual and delayed. One symptom can follow the other, however.
?It's fairly common to see discontinuation blend into reemergence of depression. Mood starts to decline just when the initial flurry of discontinuation symptoms begins to improve,? according to Dr. Shelton.
There is no evidence that ADS increases the risk of depression relapse, but it can trigger new-onset anxiety symptoms in a sensitive individual, he said.
Here, too, patient education is paramount.
?If they don't know where these symptoms are coming from, patients can get really scared,? he said.
Extensive, unnecessary medical evaluations might follow.
Dr. Shelton informs patients of the possibility of ADS when initiating antidepressant treatment.
?I suggest it's a reason not to miss doses. I'll reiterate the explanation at the time of tapering,? he said.
Women and people who have long-standing, early-onset depression seem to be more prone to ADS, Dr. Shelton said, and patients who have had ADS before are likely to have it again.
?Those with anxiety disorders and anxiety in the context of depression are particularly vulnerable,? he said.
Dr. Blier pointed out that people who had difficulty starting an antidepressant are likely to have problems with discontinuation.
?They probably have an oversensitive subtype of serotonin receptor,? Dr. Blier said.
?Clinically, ADS is quite easy to manage,? Dr. Blier said. Antidepressants, particularly those with a short half-life, should be tapered rather than discontinued abruptly.
?If you run into problems, slow the taper. If problems persist, put the patient on fluoxetine for a week, then stop it?its long half-life provides a gradual withdrawal,? he said.
Tapering timetables can vary but usually involve halving the dose at intervals that might be as long as 2 weeks or even a month for sensitive patients on short-acting drugs.
?If I've been treating someone for 6?12 months, I see no problem in taking an extra 2 months for discontinuation,? Dr. Blier said.
If a patient is extremely vulnerable, with coexisting panic, for example, ?I may just want to avoid discontinuation symptoms,? Dr. Shelton said.
?I won't wait till they emerge, but add fluoxetine before starting discontinuation, and then taper both drugs.?
Early Improvement Predicts Outcome
A connection between antidepressant response onset and ultimate outcome has been noted since the mid-1990s. ?The earlier the drug starts to work, the better the chance for a good outcome,? said Dr. George Papakostas of Massachusetts General Hospital and Harvard Medical School, Boston.
His own research found a correlation between earlier clinical improvement and more robust recovery, as measured by residual symptoms at 8 weeks. The association extended to some domains (depression, anxiety, and hopelessness) but not to somatic symptoms or hostility (Psychiatry Res. 2007;149:195?200).
How to put this information to clinical use is unclear. ?The further out you go, the more of an argument can be made that something needs to be done in the face of nonresponse,? Dr. Papakostas said. After 1 week, ?the overwhelming number of clinicians would agree it's too early to make a treatment decision based on efficacy alone,? but by the 4th week the need for some sort of change would seem reasonable, if not urgent, to many.
Whether this means increasing the dosage, augmentation, or switching to another agent depends on several drug and patient factors, he said.
To Dr. Thase, a failure to respond at all by the second week ?may or may not reflect on the efficacy of the drug, but I would take it to mean that you can't capitalize on a placebo response or a natural remission?that this will be a more difficult-to-treat patient.? A lack of early response to treatment might also be an indicator that combined treatments, including the combination of psychotherapy and pharmacotherapy, might be necessary, he said.
Dr. Papakostas, citing his own findings, said a delayed response could suggest that certain symptoms, such as anxiety, will need treatment after the episode has for the most part resolved. ?It may be worthwhile to start thinking about adjunctive treatment with a benzodiazepine or benzodiazepine-type drug, or a second antidepressant,? he said.
