Question re: Augmentation

[sasha]

Hi. I'm new to the forum, so hope this is the right place to ask this? I have Major (unipolar) Depression & have been on 300mgm. of Effexor for 5 years with good results, until the past 6 months when the effectiveness of Effexor has decreased & I've foung myself fighting the "black edges" more often again. My doctor has suggested that I augment the Effexor with 25 mg. of Seroquel once a day. This surprised me, since Seroquel is an atypical anti-psychotic. After checking side-effects of Seoquel I am extremely reluctant to take it, particularly since there is a Health Canada warning on the drug that it can cause diabetes, along with several other rather serious side-effects. So my questions are:

- Does anyone had any luck combining Effexor with any other drug or agent for good results in Augmentation?
- Is anyone on a dose of Effexor XR that is higher than 300mg per day?
- Any comments re experiences with Seroquel?
Thanks so much!

[David Baxter]

Hi. I'm new to the forum, so hope this is the right place to ask this?

Yes it is, and welcome to PsychLinks Online, Sasha :o)

I have Major (unipolar) Depression & have been on 300mgm. of Effexor for 5 years with good results, until the past 6 months when the effectiveness of Effexor has decreased & I've foung myself fighting the "black edges" more often again. My doctor has suggested that I augment the Effexor with 25 mg. of Seroquel once a day. This surprised me, since Seroquel is an atypical anti-psychotic. After checking side-effects of Seoquel I am extremely reluctant to take it, particularly since there is a Health Canada warning on the drug that it can cause diabetes, along with several other rather serious side-effects.

Recently, SSRIs and SNRIs have been augmented with low doses of one of the so-called "atypical antipsychotics" with increasing frequency and for some patiens seem to be quite effective.

Two points:

1. The usual dosage of seroquel is listed as "75, 150, 300, 600, 750 mg/day" -- when prescribed to augment antidepressant medications, nthey are prescribed at much lower doses with a consequently lower risk of adverse side-effects.

2. The side-effects you are concerned about are listed as "infrequent" to "rare" even at the higher normal doses of seroquel.

Having said that, if you are worried about using this medication, I would strongly urge you to bring your concerns to the attention of your doctor and ask him or her about it.

Does anyone had any luck combining Effexor with any other drug or agent for good results in Augmentation?

Yes - two of my clients within the past 6 months or so.

Is anyone on a dose of Effexor XR that is higher than 300 mg per day?

I have seen one client whose psychiatrist had him at 450 mg. I think for many people, the more common side-effects of Effexor (sleepiness, nausea, sexual dysfunction) become increasingly likely at higher doses and that may be the reason few people are given a dose beyong 300 mg.

Any comments re experiences with Seroquel?

see above

[sasha]

Thank you so much for your reply, Dr. Baxter! I really appreciate the information. I wonder if I could get clarification on one of the points you made.
I am presently having to work with my family physician re augmentation issue, since seeing my psychiatrist for a med check will take 6-8 months (I'm on the waiting list!). My family dr. is great, but not especially knowledgable about psychotropics, as she is quick to acknowledge. I am a public health nurse with background in mental health issues, so I am the one who usually has to do the research, make suggestions, etc. to the family dr. This is why I would appreciate a bit of further guidance here.
I am planning to raise my concerns about Seroquel with her, & I have been considering asking to try augmentation with Thyroxin, though I've found a couple of different approaches to dosage in the research.
My question is: I would like to know, if possible, with which medication your Effexor patients were succesfullly augmented?
Again, my deep appreciation for your reply to my questions and for this wonderful website.
Sasha
[/b]

[David Baxter]

I am planning to raise my concerns about Seroquel with her, & I have been considering asking to try augmentation with Thyroxin, though I've found a couple of different approaches to dosage in the research.

Hmmm... now there's one I haven't heard about. Why thyroxin?

My question is: I would like to know, if possible, with which medication your Effexor patients were succesfullly augmented?

I would need to double check the files but I am fairly certain that one (perhaps both) of them were prescribed small doses of olanzapine (Zyprexa). See the articles following this post for some additional information.

Again, my deep appreciation for your reply to my questions and for this wonderful website.

Thank you, Sasha -- I appreciate the compliment!

[David Baxter]

Augmentation With Atypical Antipsychotics
by Gordon Parker, M.D., Ph.D.
Psychiatric Times, October 2002, Vol. XIX, Issue 10

My experience of 15 years in a tertiary referral mood disorders unit has validated many recent studies suggesting that resistance to antidepressant treatment is more common than previously judged or conceded. About four years ago, I commenced testing augmentation of antidepressant drugs with atypical antipsychotics in treatment-resistant subjects and observed dramatically rapid improvement in a percentage of my patients. I have since learned that other psychiatrists have come to a similar conclusion by a similar testing process. This should not be viewed as necessarily challenging the zeitgeist of evidence-based treatment guidelines and consensus statements as the gold standard, but should encourage discussion as to how formalized efficacy data and clinically observed effectiveness data may best complement each other.

I observed two distinct improvement patterns in those patients who responded to the augmenting strategy. The first group of patients described a rapid improvement in mood, often in response to a low-dose atypical (e.g., olanzapine [Zyprexa] 2.5 mg to 5 mg) and generally in close association with restoration of sleep and a reduction in any anxiety symptoms. Improvement in these patients was usually evident in one to three days. Once improvement had occurred and patients were euthymic, the atypical could generally be ceased after another day or two, allowing the antidepressant and/or mood-stabilizing medication as the only necessary maintenance strategy -- at least, until any future episode.

In a second group of subjects, there was a slow and generally incomplete remission. There was a specific augmenting effect, since the patient would usually report a worsening of mood if the atypical was ceased. When the atypical was recommenced, the patient would again generally report partial benefit. In such patients, a higher dose of the atypical was generally required.

I was unable to find any treatment or practice guidelines advocating the use of antipsychotic or neuroleptic drugs for the management of depression, although one review suggested that the older antipsychotic drugs had antidepressant properties. Robertson and Trimble (1982) had evaluated more than 30 double-blind trials of typical antipsychotics, which were generally compared with a tricyclic or irreversible monoamine oxidase inhibitor antidepressant drug. Thus, their review did not consider typical neuroleptics as augmenting agents only as singleton antidepressants in head-to-head comparisons with antidepressant drugs. Their review data indicated that the antipsychotics were just as effective as the antidepressants, appeared comparatively free of side effects and tended to have an earlier onset of action. It is of interest that this antidepressant potential of antipsychotic drugs has been ignored in formal treatment guidelines, perhaps reflecting concerns about side effects of the older antipsychotic drugs, particularly tardive dyskinesia.

My colleague and I elected to write up a case series of two dozen non-psychotically depressed patients treated with an atypical antipsychotic (Parker and Malhi, 2001). However, journal assessors were critical of case series data and judged that only a randomized, controlled treatment study was acceptable. Our paper, in which we described clinical features and considered the possible psychopharmacological rationale for atypicals, was eventually published.

In a case series report, Ostroff and Nelson (1999) described eight non-psychotic responders to a selective serotonin reuptake inhibitor remitting within one week of risperidone (Risperdal) augmentation. In 2001, Shelton et al. reported a controlled study whereby a small number of subjects with recurrent, non-psychotic, treatment-resistant depression were randomly assigned to receive olanzapine alone, fluoxetine (Prozac) alone, or the two drugs in combination. The combination produced significantly greater improvement than either monotherapy strategy over the next eight weeks, with the combination therapy being associated with a very rapid improvement in mood state. This report is the only published randomised, controlled trial examining the impact of augmenting with an atypical antipsychotic and hopefully will encourage studies of other atypical drugs as augmenting agents.

Atypical augmentation is now being built into treatment recommendations and guidelines. While Trivedi and Kleiber (2001) included the theoretical combined use of an antidepressant and an antipsychotic, Fava (2001) noted the positive reports of the combination of an antidepressant and an atypical in reviewing strategies for managing treatment-resistant depression.

Can we add to the story? Perhaps by offering more clinical impressions. Our observations suggest that patients with narrowly defined melancholic depression (particularly when their depression is marked by psychomotor disturbance) are more likely to receive augmenting benefit. Patients with bipolar disorder also appear highly likely to respond. Thus, not only did some of our patients with established bipolar disorder describe "riding a high" out of their depression -- but several patients who had never previously responded did so following atypical initiation. Our patients did not always report this improvement, so clinicians may need to probe for this information. When a severely depressed patient improves rapidly, both the patient and the physician may judge it as a rapid return to an euthymic state and miss features indicative of a "high." In such patients, these "highs" are generally slight and transient, but can be dissected from abrupt euthymia. This might suggest that atypicals act on the putative "switch" mechanism.

In a refined observational study, I treated 10 consecutive patients with treatment-resistant melancholic depression with olanzapine augmentation and monitored improvement over the next week (Parker, 2002). Six patients showed rapid and substantive improvement over that brief interval. This study is informative in that daily ratings of mood, anxiety, insomnia and depression identified differential effects across those parameters. Thus, these six patients showed dramatic improvements in insomnia and anxiety, while their depression improved somewhat more slowly.

Such results raise the possibility that atypicals might be of benefit merely because they restore sleep, but most patients contemplating that possibility with me have generally rejected it on the basis that mood improvement occurs somewhat more slowly than sleep and anxiety benefits.

I began seeking views of other clinicians, expecting few to have tried such an augmentation strategy. The majority of clinicians I consulted also reported positive results using atypicalsas augmenting agents. It has now become quite rare for us to see a treatment-resistant patient at our tertiary referral service who has not been tried on an atypical antipsychotic prior to our assessment.

In the last decade there have been major advances in newer antidepressants. Each advance has emerged after careful evaluation involving controlled studies of large samples and up to a decade in investigation time. Following introduction of each drug, clinicians seek to understand their clinical effectiveness (as against their tested efficacy) and generally develop some gradual understanding about each drug's profile and, more important, the comparative benefits and situations where the drug might be recommended. This is obviously a slow process, respecting the scientific paradigm.

By contrast, the augmentation story overviewed here is extraordinary. We now have atypical antipsychotic drugs -- that lack an indication as either antidepressants or as antidepressant-augmenting drugs -- being widely used by psychiatrists when the published literature comprises only one controlled study and two case series.

Quo vadis? We need to be very cautious in using atypical antipsychotics as either antidepressant drugs (unsupported at the moment) or as augmenting antidepressant agents (the presumptive strategy) until clarification studies accrue. We need to establish that true augmentation occurs and is not merely a reflection of an anxiolytic phenomenon, or there is a risk that these antipsychotics may be used for patients who have a primary anxiety disorder, as occurred with the typical antipsychotic drugs in the past. Even if atypicals are beneficial, we must be aware of both immediate and long-term side effects, which must be respected in cost-benefit decisions. Since we do not know the long-term side effects of these drugs, great caution needs to be exerted, particularly when used on an ongoing basis. We need to establish whether there is an intra-class differential or whether there is a non-specific class augmentation benefit and if there is depression subtype specificity when we hypothesize that melancholic and bipolar depression is preferentially responsive.

My observations suggest that augmentation by an atypical requires a potentially effective antidepressant to be augmented, a situation generally not readily judged in advance. Thus, I have seen patients who failed to benefit from augmentation while receiving an SSRI or a selective norepinephrine reuptake inhibitor but, when the antidepressant drug has been substituted with a TCA or an irreversible MAOI, have shown an almost immediate response. We need to establish if augmentation can be rapidly tapered or ceased in those patients who have returned to a euthymic state and, conversely, those situations that might determine a true need for an ongoing augmenting strategy. Finally and most important, we need to understand the biological rationale for such an augmentation phenomenon, as it may provide us with a greater understanding of the perturbations underpinning bipolar disorder and melancholic depression in particular.

Dr. Parker is professor of psychiatry at University of New South Wales, Euroa Centre, The Prince of Wales Hospital.

References
Fava M (2001), Augmentation and combination strategies in treatment-resistant depression. J Clin Psychiatry 62(suppl 18):4-11.

Ostroff RB, Nelson JC (1999), Risperidone augmentation of selective serotonin reuptake inhibitors in major depression. J Clin Psychiatry 60(4):256-259.

Parker G (2002), Olanzapine augmentation in the treatment of melancholia: the trajectory of improvement in rapid responders. Int Clinical Psychopharmacol 17(2):87-89.

Parker G, Malhi G (2001), Are atypical antipsychotic drugs also atypical antidepressants? Aust N Z J Psychiatry 35(5):631-638.

Robertson MM, Trimble MR (1982), Major tranquillisers used as antidepressants. A review. J Affect Disord 4(3):173-193.

Shelton RC, Tollefson GD, Tohen M et al. (2001), A novel augmentation strategy for treating resistant major depression. Am J Psychiatry 158(1):131-134.

Trivedi MH, Kleiber BA (2001), Using treatment algorithms for the effective management of treatment-resistant depression. J Clin Psychiatry 62(suppl 18):25-29.

[David Baxter]

Schizophrenia Drug Used for Depression
Early Findings Show Geodon, SSRI Combo May Help Non-Responders
Wednesday, March 24, 2004
By Salynn Boyles, WebMD

March 24, 2004 -- Medications used to help alleviate symptoms of schizophrenia may help severely depressed people who do not respond to initial treatment, too. If confirmed, the findings may lead to new treatment options for hard-to-treat depression.

The small study involved people who suffered from major depressive disorder and who failed to respond to prior use of medications used to treat depression. Half of the study participants improved when the antipsychotic drug, Geodon (ziprasidone) -- used to treat schizophrenia -- was combined with a serotonin reuptake inhibitor (SSRI), the most widely used type of drug to treat depression.

While encouraged by the findings, researcher George Papakostas, MD, says testing must be duplicated in larger, more rigorously designed studies before the combination treatment can be recommended for use in people with depression.

He says Geodon works significantly different from other antipsychotic drugs similar to it. He also says it works differently from other available antidepressants. "But this study is only suggestive of this treatment being effective. It is far from definitive."

Study Findings
Geodon is one of the newer medication classes known as atypical antipsychotics, which are the most widely prescribed drugs for the treatment of schizophrenia.

In the newly published study, funded by Geodon manufacturer, Pfizer Pharmaceuticals, 20 patients with major depressive disorder resistant to treatment with an SSRI alone were treated with an SSRI plus Geodon for six weeks.

Ten of the patients responded to the combination treatment, often within a week of the antipsychotic drug's addition. But seven patients withdrew from the study, with four (20%) dropping out because of Geodon-related side effects. The most commonly reported side effects included fatigue and tiredness, sleep disturbance, dry mouth, and restlessness.

The findings were reported in the February issue of the Journal of Clinical Psychiatry.

Other Research
Mental health researcher A. John Rush, MD, tells WebMD that atypical antipsychotic drugs such as Geodon are increasingly being combined with other medications to treat severely depressed patients who fail to respond to SSRIs alone.

Rush is the principal investigator of a largest trial ever to examine treatment options for people with depression who do not respond to initial therapies. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study includes roughly 4,000 people, but atypical antipsychotic medications are not among the drugs being studied in this trial.

"The atypicals were not really on the radar screen for depression when we launched the study four years ago, but if the study is extended we would certainly like to add them," the University of Texas Southwestern psychiatry professor tells WebMD. "Treatment-resistant depression is much more common than we thought just five or 10 years ago and there is a real need to identify therapies that will help these patients."

Source: Papakostas, G. Journal of Clinical Psychiatry, February 2004; vol 65: pp. 217-221.

[David Baxter]

The role of atypical antipsychotics in bipolar depression and anxiety disorders
McIntyre R, Katzman M.

Mood Disorder Psychopharmacology Unit, University of Toronto, University Health Network, Toronto Western Hospital, 399 Bathurst Street, ECW-3D-003, Toronto, Ontario, M5T 2S9, Canada. rmcintyr@uhnres.utoronto.ca

Bipolar disorder is a complex condition that includes symptoms of mania, depression, and often anxiety. Diagnosing and treating bipolar depression is challenging, with the disorder often being diagnosed as unipolar depression. In addition, comorbid anxiety can be a significant detractor to successful outcomes, increasing symptom severity, frequency of episodes and suicide rates, and decreasing response to antidepressant therapy. Anxiety often precedes and hastens the onset of bipolar disorder, and a shared genetic etiology has been suggested. Studies have demonstrated the efficacy of atypical antipsychotics for the acute and maintenance treatment of mania. Evidence from studies in patients with treatment-resistant major depressive disorder and bipolar depression indicate that these agents may also have antidepressant effects. In open trials in patients with bipolar mania, risperidone therapy has led to significant reductions in depression scores compared with baseline. Reductions in depression scores in patients with bipolar mania have been significantly greater with olanzapine compared with placebo. In patients with bipolar depression, the combination of olanzapine and fluoxetine resulted in significant improvement in depression compared with olanzapine alone or placebo. Although little data are available on the effects of these agents on comorbid anxiety in patients with bipolar disorder, some atypical antipsychotics have demonstrated efficacy in patients with anxiety disorders, including obsessive-compulsive disorder, post-traumatic stress disorder, and generalized anxiety disorder. Thus, atypical antipsychotics represent an important therapeutic option for the treatment of bipolar disorder, providing improvements in manic, depressive, and anxiety symptoms.

Bipolar Disord. 2003;5 Suppl 2:20-35.

[David Baxter]

Off-label indications for atypical antipsychotics: A systematic review
Konstantinos N Fountoulakis , Ioannis Nimatoudis , Apostolos Iacovides and George Kaprinis
Annals of General Hospital Psychiatry 2004, 3:4

The electronic version of this article is the complete one and can be found online at: http://www.general-hospital-psychiat.../content/3/1/4.

With the introduction of newer atypical antipsychotic agents, a question emerged, concerning their use as complementary pharmacotherapy or even as monotherapy in mental disorders other than psychosis.

Material and method
MEDLINE was searched with the combination of each one of the key words: risperidone, olanzapine and quetiapine with key words that refered to every DSM-IV diagnosis other than schizophrenia and other psychotic disorders, bipolar disorder and dementia and memory disorders. All papers were scored on the basis of the JADAD index.

Results
The search returned 483 papers. The selection process restricted the sample to 59 papers concerning Risperidone, 37 concerning Olanzapine and 4 concerning Quetiapine (100 in total). Ten papers (7 concerning Risperidone and 3 concerning Olanzapine) had JADAD index above 2. Data suggest that further research would be of value concerning the use of risperidone in the treatment of refractory OCD, Pervasive Developmental disorder, stuttering and Tourette's syndrome, and the use of olanzapine for the treatment of refractory depression and borderline personality disorder.

Discussion
Data on the off-label usefulness of newer atypical antipsychotics are limited, but positive cues suggest that further research may provide with sufficient hard data to warrant the use of these agents in a broad spectrum of psychiatric disorders, either as monotherapy, or as an augmentation strategy....

Depression
There was only 1 paper found involving the use of olanzapine in the treatment of refractory non-psychotic depression, by Shelton et al in 2001. It was supported both by Eli Lilly and NIMH grants. It included a randomized design (not described), and the double blind procedure included an identical procedure of administration for both agent and placebo. Withdrawals and dropouts are well described. Thus, it is given a Jadad score of 3. The study included 28 patients out of 34 initially screened (75% female). All suffered from unipolar non-psychotic treatment resistant depression. Their age was 42 ± 11 years. The study period was 8-weeks long and included the comparison of three groups: one under olanzapine monotherapy, one under fluoxetine monotherapy and one under a combination of both. Placebo was used to make the administration procedure identical for all groups. At endpoint, the mean fluoxetine dose was 52 mg per day for both groups and the mean olanzapine dose was 12.5 mg/day for the monotherapy group and 13.5 mg/day for the combination group (Note: If memory serves, I believe this was higher than the dose used by my client/s, which I think was in the range of about 5 mg/day. See article below this one for further information about lower doses -- D.J. Baxter). The combination of olanzapine with fluoxetine produced superior improvements over either agent alone. Either agent alone was ineffective in this population. Clinical response was evident by the first week. The main adverse effect was weight gain, averaging more than 6 kgr for the olanzapine treated patients over the double-blind period.

The possible mechanism for this favorable combined administration may lay in the fact that in animals the combined administration of fluoxetine and olanzapine increased by 269% the norepinephrine and by 349% the dopamine levels in the prefrontal cortex. Olanzapine alone stabilizes and returns the levels to baseline, while fluoxetine alone increases them by 188% and 143% respectively.

[David Baxter]

Depression: The Invisible Illness: Q & A
Excerpt from an interview with Jay D. Fawver, M.D. Clinical Associate Professor of Psychiatry, Indiana University School of Medicine, Atlanta, 1999.

We're getting a lot of benefit from using the atypical antipsychotic medications for augmentation for unipolar depression. Zyprexa, for instance, increases the norepinephrine and dopamine in the prefrontal cortex. By doing that, you can add on Zyprexa with an SSRI at 10 mgs at bedtime and sometimes get an augmentation to your antidepressant effect. Risperdal, at doses as small as 1 mg at bedtime, can augment an antidepressant because Risperdal is indirectly affecting the serotonin transmission by blocking serotonin two-way receptors. So, yes, the atypical antidepressant medications can certainly be used for augmentation with the antidepressants. Even if a person does not have psychotic depression and even if a person does not have bipolar depression.

By itself, Zyprexa does not appear to be a good medication for unipolar depression. So if you have some patient with major depression and you only give them Zyprexa, it's probably not going to work that well. But you give that patient Prozac and they partially respond, and then add Zyprexa 5 to 10 mgs to it, they can get a dramatic improvement in their response. For some reason, Zyprexa needs a little bit of an antidepressant to help squeeze out that extra dopamine and norepinephrine from the frontal lobes.

[sasha]

Thanks for the articles & info, David. Very useful info.

Re: your question about Thyroid Hormone & Augmentation:

Augmentation with thyroxin has been used for some time, as has Lithium. The depressed pt. doesn't have to have blood tests showing hypothyroid. By some (as far as I know) unknown mechanism, thyroxin apparently potentiates anti-depressants in some people. The usual thyroxin dose is very small, but there is at least one study that had very good results with a high dose. There are quite a few articles available, though not really specific - it doesn't appear a lot of research has been done on the mechanisms or the types & doses or thyroid hormone used. This is, I think, partly because so much of the research $$ has gone to testing the efficacy of the many new drugs. Anyway, a Google search will show up references to this form of augmentation if you're interested, & I'll add a couple of URL's here for a couple (if I can get the URL thing to work! Sorry if I don't manage the linking process! :-!

Thanks again! Sasha

http://www.biopsychiatry.com/t3.htm
http://www.biopsychiatry.com/augment.html
http://www.biopsychiatry.com/thyroidt3t4.htm
http://www.aafp.org/afp/981200ap/cadieux.html