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Nefazodone in Diabetic Neuropathy: Response and Biology

Department of Psychiatry & Behavioral Sciences, University of Miami School of Medicine, Miami, Florida, and
Department of Pharmacology, Medical University of South Carolina, Email: pgoodnick@aol.com

Previous review has shown the important role of serotonin in glucose use (1). Pain pathways include both norepinephrine and serotonin neurons. Thus, it is not surprising that tricyclic antidepressants, focusing on norepinephrine, have treated diabetic neuropathy successfully. However, these medications are limited in usefulness in diabetes mellitus, because they can worsen diabetic control (2). Therefore, attention has turned to serotonin-based treatments. Nefazodone (NFZ) previously has been shown to reduce glucose levels, even causing hypoglycemic attacks in one stabilized diabetic patient (3). The current open-label study is an extension of these previous reports to look for clinical benefit of nefazodone in patients with both diabetes mellitus as well as pain, ie, diabetic neuropathy. Because platelet 5-HT content has been previously been shown to be reduced by the SSRIs as well as to predict clinical response to those medications (4), we examined their response to nefazodone.

After obtaining informed consent, patients needed to meet inclusion criteria for diabetic neuropathy. Patients were excluded if they met criteria for major depressive disorder or other major psychiatric disorder. Patients were administered NFZ at doses of up to 450 mg/d for an 8-week period but less if they responded sooner. They were evaluated at baseline and after 1, 2, 4, and 8 weeks on 1) visual analog scales (0–100 mm) for pain, paresthesia, numbness; 2) physician-observer rating (0–2) on each of pain, paresthesia, numbness; 3) Hamilton Depression Rating Scale (HDRS); and 4) Beck Depression Inventory (BDI). Furthermore, blood samples were collected at baseline and at 8 weeks for platelet serotonin content and HbA_1c as well as a plasma nefazodone level. Nine of the 10 patients cooperated with biological measures of platelet 5-HT content; 7 with plasma nefazodone. Nine of the 10 patients had complete sets of data on plasma HbA_1c.

Ten men with type II diabetes mellitus participated with a mean age of 65.8 ± 11.4 years and a mean duration of diabetic neuropathy of 4.9 years. The mean dose of nefazodone was 340 ± 77 mg/d. The mean baseline HDRS was 2.8 ± 2.3; mean final HDRS was 1.4 ± 1.5. Mean baseline BDI was 6.9 ± 4.4; mean final BDI was 3.7 ± 2.9. In terms of clinical response, pain, paresthesias, and numbness all improved significantly on both self-ratings and MD ratings. A temporary worsening in self-ratings of pain at week 4 is because 2 patients uniquely rated themselves as much worse by self-report, although the observer report did not agree. For MD ratings, improvement from baseline scores reached significance for both pain and paresthesias at week 1 and for numbness at week 2 (Table 1). For six patients with baseline HbA_1c values > 7.0, values dropped during treatment from 9.8 ± 1.4 to 8.9 ± 1.4 (t = 4.1, p < .01). Platelet 5-HT content did not change consistently with a baseline value of 50.1 ± 22.6 to a final one of 46.4 ± 21.9 ng/10⁸ plt. However, there was a range of changes from a reduction of 53.7 to an increase of 33.7. Mean plasma nefazodone level completed in eight patients was 434 ± 316 ng/ml. Change in platelet 5-HT content correlated significantly with later improvements in self-ratings of pain (r = 0.92, p = .02). Baseline platelet 5-HT content levels showed a tendency to correlate to improvement in HbA_1c levels (r = 0.57, p = .10). Plasma nefazodone levels showed a trend to correlate with improvement in self-rating of paresthesias (r = 0.79, p = .10).

ACKNOWLEDGMENTS

Presented in part at the Annual Meetings of the American Psychiatric Association, May 1998, Toronto, Ontario, Canada and May 1999, Washington, DC.

REFERENCES

1. Goodnick PJ. Diabetes mellitus and depression: issues in theory and treatment. Psychiatr Ann 1997; 27: 353–9.
2. Lustman PJ, Griffith LS, Clouse RE, Free dland KE, Eisen SA, Rubin EH, Carney RM, McGill JB. Effects of nor-triptyline on depression and glycemic control in diabetes: results of a double-blind, pla-cebo-controlled trial. Psychosom Med 1997; 59: 241–50.[Abstract/Free Full Text]
3. Warnock JK, Biggs F. Nefazodone-induced hypoglycemia in a diabetic painduced hypoglycemia in a diabetic patient with major depression. Am J Psychiatry 1997; 154: 288–9.[Medline]
4. Goodnick PJ, Kumar A, Henry JH, Buki VM, Goldberg RB. Sertraline in coexisting major depression and diabetes mellitus. Psychopharmacol Bull 1997; 33: 261–4.[Medline]

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