Improvement in neuroleptic‐induced akathisia with intravenous iron treatment in a patient with iron deficiency

Iron deficiency may play a role in the pathogenesis of drug‐induced akathisia, but the evidence is conflicting.¹,²,³ There have been no reports of the effect of iron treatment in this condition. We report the case of a patient with iron deficiency whose akathisia had not responded to standard interventions but did respond dramatically to intravenous iron treatment.

A 68‐year‐old man with schizophrenia had been well controlled for 10 years on thioridazine 150 mg/day. His treatment was changed to respiridone 1 mg twice daily. Within 2 weeks, he had developed a severe sensation of inner restlessness and anxiety associated with increased leg movements and body rocking. No depressive or psychotic symptoms were noticed, although the patient was greatly distressed. Acute drug‐induced akathisia was diagnosed.

No improvement in akathisia symptoms was noticed when the dose of respiridone was reduced or when respiridone was discontinued and thioridazine restarted. Therapeutic trials of alprazolam, benztropine and propranolol failed to alleviate his symptoms and led to side effects.

When seen in our clinic, the patient had had symptoms for >6 months. He reported a “terrible feeling” of restlessness and anxiety “gnawing inside me” each day. Symptoms were present throughout the day, with no worsening at night, and no limb paraesthesias were noticed. There was no personal or family history suggestive of restless legs syndrome (RLS). Neurological examination was normal apart from reduced facial expressiveness. The Barnes Akathisia Rating Scale (BARS), a well‐validated scale of akathisia severity comprising objective and subjective components, was 11/14, which is consistent with severe akathisia.²

Electrolytes, serum urea, creatinine and glucose, thyroid function tests, erythrocyte sedimentation rate, C reactive protein, vitamin B₁₂, and folate levels were normal. Haemoglobin was 13.1 g% (abnormal in our laboratory <13 g%), transferrin saturation 12% (abnormal <15%), serum ferritin 36 μg/l (abnormal <12 μg/l), total iron‐binding capacity 490 μg/l (abnormal >400 μg/l) and serum iron 520 μg/l (abnormal <600 μg/l). A diagnosis of iron deficiency was made on the basis of the abnormal transferrin saturation combined with a serum ferritin <50 μg/l.⁴ Gastrointestinal examination was normal and serial tests for faecal occult blood were negative. He had a distant history of peptic ulcer disease. Dietary history showed inadequate intake of iron‐containing foods. His dentition was poor. The patient refused endoscopic investigation of the intestinal tract. Screening tests for coeliac disease were negative.

Oral iron supplements caused unacceptable nausea and epigastric discomfort. The patient was given 400 mg intravenous ferrous sucrose in divided doses (100 mg in 100 ml normal saline on days 1 and 3, and 200 mg on day 5). On day 7, the patient reported that he felt normal for the first time in months. The BARS score was now 3/14 (corresponding to mild or questionable akathisia); haemoglobin was 13.8 g%, ferritin 52 μg/l and transferrin saturation 17%. Dietary advice was given to increase the intake of iron‐containing food. Subsequently, he was able to tolerate 300 mg ferrous gluconate (containing 35 mg of elemental iron) every second day. Clinical (BARS score 3/14) and haematological (haemoglobin 13.7 g% and ferritin 68 μg/l) improvement were maintained on review at 5 months.

Both akathisia and RLS are characterised by motor restlessness and sleep disturbances, and RLS can be precipitated by dopamine‐blocking drugs. There is convincing evidence that iron status is an important factor in the pathogenesis of RLS, and correction of iron deficiency improves symptoms in RLS.⁵ The balance of evidence from previous studies does not suggest that iron deficiency plays a similarly critical role in the development of drug‐induced akathisia in most patients. However, many studies either focused on serum iron,¹,² which is not a good guide to iron status, or used an inappropriately low cut‐off for normal serum ferritin.⁴ Nevertheless, studies that examined ferritin levels reported that patients with akathisia had lower levels than controls without akathisia.³

Studies comparing blood tests with bone marrow examination have shown that serum ferritin at a cut‐off of 50 μg/l is the best screening test for iron deficiency in patients with and without anaemia.⁴ Furthermore, serum ferritin <50 μg/l has also proved useful for predicting responsiveness to iron supplementation in people with RLS.⁵

The patient in this report had several haematological indices suggestive of iron deficiency and several risk factors for iron deficiency. His serum ferritin of 36 μg/l is also consistent with mild iron deficiency. His haemoglobin level of 13.1 g% was at the low end of normality for a man. As a general rule, 8 mg of storage iron corresponds to 1 μg/l ferritin. Thus, in an iron replete person, 400 mg of intravenous iron would lead to a rise in serum ferritin of about 50 μg/l; the relatively small rise in ferritin levels in our patient suggests that the iron supplement was indeed used to correct a tissue deficiency in iron.

It is unlikely that this patient had an atypical RLS. No night‐time worsening of symptoms (a necessary diagnostic feature in RLS) was noticed. The feeling of inner restlessness and body rocking are characteristic of acute drug‐induced akathisia. It is not uncommon for akathisia, once provoked, to fail to resolve when the precipitating drug change is reversed.

The close temporal relationship between administration of intravenous iron and resolution of hitherto resistant symptoms in our patient suggests that iron deficiency can contribute to the development or persistence of akathisia in some patients. Iron repletion may be valuable in such cases, although this requires further evaluation. There are, of course, other potential benefits to treating and identifying the cause of iron deficiency. We suggest that haemoglobin, serum ferritin and transferrin saturation should be checked in patients with akathisia, and that patients with iron deficiency should be treated until haemoglobin is normal and serum ferritin is more than 50 μg/l. Although the use of intravenous iron formulations may facilitate examination of the potential effects of iron repletion on akathisia in future studies, biochemical improvement is usually seen within 2–4 weeks of starting oral iron supplements in patients with deficiency and this should remain the initial treatment.