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SSRIs + nefazodone

From: "Steven L. Dubovsky" <Steven.Dubovsky@UCHSC.edu>
Date: Mon, 28 Aug 1995 07:23:09 MDT
Subject: SSRIs + nefazodone

The patient seemed to develop unpleasant stimulation from the combination [of fluoxetine and nefazodone].

--Furey A. Lerro

Nefazodone is metabolized to m-CPP, which is itself metabolized by CYP 2D6. m-CPP is anxiogenic, and in patients who get higher levels of this metabolite, anxiety and insomnia may occur. In some of these patients, levels are raised further by the fluoxetine.

Date: Sat, 10 Feb 1996 19:04:27 -0600
From: Stephen R Saklad <Saklad@uthscsa.edu>
Subject: SSRIs + nefazodone

At 15:32 2/10/96, Kip Doran M.D. wrote:

I recently was covering for a colleague whose patient went to a pharmacy for prescriptions for Zoloft (sertraline) and Serzone (nefazodone), which she was taking in combination. The pharmacist called because she had not heard of the combination. When I talked with my colleague, he said he had been using the two to potentiate each other with considerable success in doses of up to 150 mg of Zoloft and 600 mg of Serzone. He had also been using Zoloft blood levels to spot "rapid metabolizers". If the blood level of Zoloft was low, he felt comfortable raising the dose of *Serzone* up to 1000 mg.

Are you using Zoloft or any other SSRI plus Serzone?

I wouldn't. The pharmacology of the combination is not obvious because of complex serotonin effects (reuptake blockade and blockade of S2), norepinephrine, etc.

I would consider any novel combination (one without at least a case series published) to be a Phase I drug study and certainly would require IRB approval of a written informed consent form. After all, it can't be a "therapeutic use" if you really don't have a clue what is going to happen.

Date: Wed, 21 Aug 1996 10:42:58 -0500
From: Ereshefsky@uthscsa.edu (Larry Ereshefsky)
Subject: SSRIs + trazodone

At 1:11 AM 8/21/96, pjnegro@mem.po.com wrote:

How do the SSRIs interefere with trazodone metabolism? I am thinking specifically about m-CPP, which could be anxiogenic.
m-CPP [a metabolite of trazodone and nefazodone] is metabolized by CYP 2D6 (possibly also by CYP 3A), therefore medications like fluoxetine and paroxetine (potent 2D6 inhibitors) are more likely to cause elevations (about 2-4 fold) in m-CPP. In contrast, venlafaxine, bupropion, mirtazipine, sertraline, and possibly fluvoxamine (potent 3A, but weak 2D6 inhibitors) are less likely to interact. Interestingly, alprazolam has been shown to double m-CPP levels as well. Whether this clinically results in anxiogenic effects is not proven. We do know that m-CPP as a probe for panic is psychoactive.

From: Cdbojrab@aol.com (Christopher D. Bojrab, M.D.)
Date: Thu, 28 Nov 1996 09:20:34 -0500
Subject: SSRIs + nefazodone

I had a patient who I switched from fluoxetine to nefazodone on what I thought to be a slow double taper, however, the patient experienced either a serotonin syndrome or possibly effects from a metabolite whose metabolism was inhibited. The patient eventually cleared, but only after several rough days with ataxia, slurred speech, a subjective feeling of confusion, GI pain and bloating.

Date: Sat, 29 Mar 1997 08:10:31 -0600
From: Larry Ereshefsky <Ereshefsky@uthscsa.edu>
Subject: SSRIs + nefazodone

At 21:52 -0600 3/28/97, K. N. Wiesert wrote:

Has anyone had experience with the combination of nefazodone and fluvoxamine?
It depends on how you are using the combination. I have not seen "augmentation" with these two, but I have seen folks use the combination of nefazdone and an SSRI for selective manipulation of side effects. If you desire the later, consider generic trazodone as a much less expensive modulator of the SSRI.

Plan on substantial pharmacodynamic and pharmacokinetic augmentation. For instance, both drugs inhibit CYP 3A4, a pathway used by both drugs for their metabolism. I would use lower doses of both nefazodone and fluvoxamine.

NB: This combination will also significantly interact with many other drugs which use this pathway. There is additive inhibiton of this enzyme, and I would *avoid* this combination in patients on triazolobenzodiazepines, steroids of any kind, or cyclosporine and consider it contraindicated with cisapride, terfenadine, astemizole, or triazolam. (There are cases of benzodiazepine, cyclosporine, and terfenadine toxicity with either nefazodone or fluvoxamine alone.)

Also, both inhibit the serotonin uptake pump (serotonin transporter), so at full doses, the possibility of serotonin syndrome is real.

When I have seen the combination used, it is usually low doses of nefazodone to block out the serotonin 2 receptor mediated adverse effects of the SSRI, e.g., insomnia or sexual dysfunction. However, I have not seen that done specifically with fluvoxamine.

Date: 04 Apr 97 03:04:23 EST
From: "John M. Rathbun" <73162.3513@compuserve.com>
Subject: SSRIs + nefazodone

I just had a call from the husband of a rather stolid, reliable 50-ish woman who came to the phone and complained of a terrible headache with nausea and sweats like she'd never had before. Her thinking seemed clear and rational.

She had been on Zoloft (sertraline), and I had switched her to Serzone (nefazodone) because that dose of Zoloft was incompletely effective and was causing decreased libido.

Date: Fri, 04 Apr 1997 07:32:53 -0500
From: Eric Fier <efier+@pitt.edu>
Subject: SSRIs + nefazodone

I believe that the switch from an SSRI to nefazadone can be an awkward and unpleasant one, as I recall that an incomplete washout of the SSRI prior to initiation of nefazadone contributes to the accumulation a particular metabolite of nefazadone, m-CPP, causing the aforementioned symptoms.

Reccomendations for a smoother transition include waiting for a 5 half-life washout of the SSRI or starting the nefazadone at a fraction of the typical starting dose (e.g., 25 or 50 mg bid).

Date: Wed, 09 Apr 1997 14:20:02 -0400
From: Eric Fier <efier+@pitt.edu>
Subject: SSRIs + nefazodone

As I understand it, m-CPP, which stands for meta-chlorophenylpiperazine, is one of 3 primary metabolites of nefazadone. It has, reportedly, an agonist effect at the 5-HT2c receptor throughout the CNS. Typically, stimulation of 2c will initially produce some degree of anxiety, restlessness, even dysphoria; interestingly, this effect seems to be short-lived and appears eventually to contribute to anxiolysis and affective improvement.

SSRIs typically have an antagonist effect at 2c.

Therefore, when an SSRI is discontinued, its 2c antagonism is lost. Now, add nefazadone, with m-CPP's 2c agonism, and you've created something of a 2c "double-whammy", resulting in profound dysphoria, anxiety, and such.

While likely a time-limited effect, I hear it is quite potent, and hence the SSRI taper and gradual nefazadone introduction crossover approach is recommended.

Worthy of note, trazodone (Desyrel) also has m-CPP as a metabolite. Hence, I imagine, similar caution may be warranted when starting trazodone concomitant with SSRI discontinuation.

Date: Sun, 27 Sep 1998 22:13:28 -0400
From: Mark Rosenberg <mcrosen@erols.com>
Subject: SSRIs + nefazodone

I have reviewed my notes on this topic from Norman Sussman's lecture at NYU last March. He recommended that nefazadone be started and tapered up to 150 mg while the patient is still on the SSRI.

Incidentally, rebound of 5-HT2c may cause the symptoms associated with stopping short half-life SSRIs too quickly.

From: LJGROLD@aol.com
Date: Mon, 28 Sep 1998 00:23:08 EDT
Subject: SSRIs + nefazodone

Stahl states it succinctly:

4% of Caucasians lack the enzyme P450 2D6. Prior treatment with SSRIs inhibits P450 2D6. If 2D6 is [lacking or] inhibited and nefazadone is administered, then m-CPP can be produced, leading to stimulation rather than blockade of 5-HT2a/2c receptors causing the opposite effects of the parent compound (nefazodone itself)... Agitation and flu-like distress upon first dosing (with nefazadone) may indicate genetic lack of 2D6 or SSRI induced inhibition.
He recommends, therefore, titrating down on the SSRI and gradually up on nefazodone to lessen side effects. Stahl's book, Essential Psychopharmacology : Neuroscientific Basis and Practical Applications is excellent and very clear with many diagrams.

Date: Sun, 27 Sep 1998 23:32:02 -0500
From: Larry Ereshefsky <ereshefsky@uthscsa.edu>
Subject: SSRIs + nefazodone

I have not seen the data to support the 5-HT2c antagonist effects of SSRIs...

The role of the 5-HT2a receptor and its inter-relationship with the 2c receptor must also be factored in. 2a indirect agonism via reuptake inhibition leads to sexual dysfunction. 2a blockade (e.g., from nefazodone or mirtazapine) improves sexual function. 2c antagonism accentuates 2a agonism (these are reciprocal systems) and vice versa. So changes in 2c can cause many of the same adverse reactions associated with 2a, except in reverse!

Also, m-CPP is metabolized by CYP 2D6. So be careful with drugs which potently inhibit CYP 2D6. They will tend to elevate m-CPP levels more dramatically, increasing the risk for anxiety and panic.

I agree that overlapping the SRI and nefazodone can be useful, but recall that serotonin syndrome has been documented to occur with the coadministration of trazodone and nefazodone with SSRIs. I would use low starting doses of nefazodone and go up very slowly.

From: ConEmo@aol.com (Ron Podell, M.D.)
Date: Mon, 28 Sep 1998 00:56:32 EDT
Subject: SSRIs + nefazodone

Theory aside, when I add nefazadone to SSRIs, patients get sedated and are most unhappy.

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