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Keywords:

  • headache;
  • migraine;
  • migraine prophylaxis;
  • refractory depression;
  • selective serotonin reuptake inhibitors;
  • valproate

Abstract

  1. Top of page
  2. Abstract
  3. CASE HISTORY
  4. COMMENTS
  5. REFERENCES

We report the successful use of valproate in a 44-year-old woman with migraine induced by selective serotonin reuptake inhibitors. Valproate should be considered for those patients who develop serious migraine for the first time, or worsening of previous migraine, after the initiation of treatment with selective serotonin reuptake inhibitors and for whom continued treatment with this class of drugs is important.

Abbreviations:
SSRI

selective serotonin reuptake inhibitor

Selective serotonin reuptake inhibitors (SSRIs) can induce or worsen migraine, 1,2 although they have also been used for its prophylaxis. 3-5 Valproate has been shown to prevent migraine with and without aura, 6-11 chronic daily headache, 12 cluster headaches, 13 and intractable headaches. 14 A MEDLINE search up to June 1999 produced no reports on the use of valproate in SSRI-induced migraine.

CASE HISTORY

  1. Top of page
  2. Abstract
  3. CASE HISTORY
  4. COMMENTS
  5. REFERENCES

The patient, a 44-year-old mother of two children, had suffered from major depression for more than 20 years. She had not experienced migraine before the onset of depression. For 15 years, she had been treated with tricyclic antidepressants, and during this period she had only a single attack of migraine with an aura, while pregnant with her first child. Tricyclic agents proved to be unsatisfactory in controlling the depression, and a number of other treatments were tried. Of these, SSRIs provided the best antidepressant effect.

Unfortunately, the SSRIs produced serious side effects, most importantly migraine. Fluoxetine was discontinued when a rash, fever, joint swelling, and pain occurred after 6 weeks of treatment. Fluvoxamine was then administered, but migraine attacks began to occur after 6 months. The headaches were initially infrequent but eventually occurred at a rate of one every second day. Each attack consisted of a visual aura followed by a severe headache that was most severe in the left retro-orbital and temporal areas, and prohibited participation in daily activities. A single dose of sumatriptan produced no therapeutic benefit and caused aggravation of the headache, sweating, flushing, and tachycardia. A trial of diltiazem also proved to be ineffective. Fluvoxamine was then replaced by sertraline, which was both effective as an antidepressant and well tolerated for 6 months but then required discontinuation after the development of a gastrointestinal motility disorder that resulted in weight loss of 15 lb. A subsequent trial of paroxetine resulted in severe migraine from the start; auras consisting of left facial numbness and irritation around the left eye lasting up to 2 hours were followed by severe headaches that prevented normal daily activities. Consequently, paroxetine was also discontinued. Sertraline was then reintroduced because it had produced no adverse effects during the initial 6 months of its use, it had been an effective treatment for depression, and it had not been previously associated with migraine. However, this time intense daily headaches began immediately. Periods of facial numbness were followed by severe and disabling headaches. A 1-month trial of pizotifen was ineffective.

At this point, treatment with divalproex, which comprises valproic acid and sodium valproate in equimolar quantities, produced an immediate decrease in the frequency, severity, and duration of the migraines. The patient described the effect of valproate as “dramatic.” Three months after starting valproate, while receiving it in the form of divalproex 750 mg/day (serum level 240 μmol/L), the patient was free of headache on most days. Trigger factors included fatigue, changes in weather, and the onset of menses. Auras occurred several times per week but only one of four episodes of numbness was followed by headache, which was reduced in severity and did not prohibit daily activities. The patient's mood was equivalent to that during the previous period of treatment with sertraline before significant side effects developed. A gradual increase in the frequency of the migraines prompted an increase in the dose of divalproex to 1500 mg/day after 7 months of treatment, with benefit but the side effect of sedation. Divalproex was administered in this fashion for 1 year along with sertraline, 100 mg/day, and oxazepam, 15 mg, as needed.

COMMENTS

  1. Top of page
  2. Abstract
  3. CASE HISTORY
  4. COMMENTS
  5. REFERENCES

Until now, the only effective treatment reported for migraine induced by SSRIs has been the elimination of the SSRI in question. 1,2 This approach may be inappropriate for patients with refractory depression for whom no therapy other than SSRIs is efficacious. Our experience indicates that valproate can be a useful treatment for this subset of migraine, thus enabling the continuation of SSRI treatment in patients with depression that does not respond to other classes of antidepressants. It is noteworthy that valproate was effective in our patient even after the apparent development of sensitization to SSRI therapy, as evidenced by the immediate development of migraine with paroxetine and the second trial of sertraline. Clinical guidelines for the use of valproate in headache have recently been provided by Silberstein. 15

Migraine and major depression are commonly comorbid conditions 16 and, thus, often require concurrent treatment. 17 In addition to its effects on migraine, valproate also has important effects on mood. Although it does not appear to have a significant role in the acute treatment of depression, 18 there is evidence that it is effective as prophylactic treatment for recurrent depression. 19-21 Our patient did not appear to experience a direct beneficial effect of valproate on her mood, although the reduction in the frequency and severity of migraines allowed our patient to have a much more normal and satisfying life, thus indirectly helping to treat the depression. In other patients, however, it is possible that both the affective disorder and migraine could benefit directly from treatment with valproate. Sumatriptan, a 5-HT1D agonist used in the treatment of acute migraine, has been found to be safe and effective when administered concurrently with SSRIs to individuals with histories of migraine. 22,23 In the only case report in which sumatriptan was used to treat migraine that had increased in frequency and severity with SSRI treatment, the sumatriptan was less effective than before SSRI therapy. 2 This finding and the poor results with several conventional migraine treatments in our patient suggest that SSRIs may not only induce migraine in susceptible patients, but they may also change the nature of the response to migraine treatments.

Although the mechanism of action of valproate in the treatment of migraine is not known, its effects on gamma-aminobutyric acid (GABA), serotonin, or prolactin may be important. 4,10,24-26 During migraine attacks, a decrease in blood flow occurs locally and spreads contiguously along the cerebral cortex. 27 A study examining the effect of valproate 28 on spreading cortical depression, however, showed that valproate does not reduce the rate of propagation of cortical depression. Cutrer et al have suggested two possible mechanisms for the antimigraine effect of valproate: (1) it may increase the cortical thresholds for spreading depression propagation rather than acting as an absolute migraine block, and (2) valproate may block the initiation of spreading but not its propagation once triggered. 24 Valproate may, thus, possibly reduce the frequency, severity, and duration of migraine symptoms without correcting the underlying mechanisms that induce migraines.

In conclusion, we suggest that valproate be considered for those patients who develop serious migraines for the first time, or worsening of previous migraine, after the initiation of SSRI treatment and for whom continued treatment with SSRIs is important.

Acknowledgment:  The preparation of this report was assisted by a bequest.

REFERENCES

  1. Top of page
  2. Abstract
  3. CASE HISTORY
  4. COMMENTS
  5. REFERENCES