Improvement of Movement Disorders with Mirtazapine: A
Preliminary Open Trial
Fernando Alarcón, MD*; Juan Carlos Maldonado, MD**;
Galo Estrada, MD*
Department
of Neurology, Eugenio Espejo Hospital* and Department of
Pharmacology, Universidad
Central, Quito, Ecuador
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Correspondencia:
Dr.
Fernando Alarcón,
Chief of
Department of Neurology, Eugenio
Espejo
Hospital. P.O. Box 17-07-9515
Quito, Ecuador.
E-mail: falarcon@ramt.com
SUMMARY:
We
performed a non-controlled open trial in 22 patients who had movement
disorders. Patients received 30 mg of Mirtazapine per day. Twenty
patients (90.9%) had a favorable response and their scores on the severity
and functional scale improved after treatment. The time needed to control
abnormal movements was 30 days in almost 70% of the subjects. Further
randomized controlled trials could determine the effectiveness of
Mirtazapine for movement disorders.
RESUMEN:
Realizamos un estudio no controlado abierto en 22 pacientes, quienes
tuvieron desórdenes del movimiento. Los pacientes recibieron 30 mg de
Mirtazapina por día. Veinte pacientes (90.9%) tuvieron una respuesta
favorable y sus puntajes en la severidad y escala funcional mejoraron
después del tratamiento. El tiempo necesario para controlar los
movimientos anormales fue 30 días en 70% de los pacientes. Posteriores
estudios randomizados y controlados podrían determinar la efectividad de
la Mirtazapina para desórdenes del movimiento
Movement
disorders tend to be chronic and persistent. Drugs that are available to
control and treat movement disorders are generally not very effective.
Mirtazapine is an anti-depressant with a mechanism that is different from
traditional drugs; that is why it has been referred to as a specific
noradrenergic and serotoninergic drug (1-3). Recent reports of isolated
cases have indicated that various movement disorders responded to
Mirtazapine (4-6). To obtain more data about the potential effectiveness
of Mirtazapine for treating movement disorders, we performed a
non-controlled open trial on 22 patients.
PATIENTS AND METHODS
Patients
who had tremor, dystonia, hemifacial spasms and tardive dyskinesia, with
functional disability sufficiently severe to require pharmacological
treatment and who came consecutively to our Movement Disorders
Unit between January and December 2000 were included. Consent paper was
signed previously.
Patients
had not taken any treatment for their movement disorders at the moment of
recruitment. We excluded patients with infectious or neurological
diseases, pregnant women, patients with a clinically significant
psychiatric diagnosis, patients who were taking hypnotic, ansiolytic or
anti-depressant drugs as well as patients with another relevant disease.
We used previously accepted clinical criteria to define the presence of
tremor, dystonia, hemifacial spasm and tardive dyskinesia (7-11).
At the
start of the study, we performed a complete neurological and general
examination, which included complementary and hematological tests. At the
time of each evaluation, severity and functional incapacity and response
to treatment were evaluated by one of us (FA) on the basis of a modified
scale (12) according to the following scoring system: 1 = none; 2 =
intermittent, which may interfere only slightly with daily activities; 3 =
moderate, present between 50% and 75% of the time, which interferes with
several activities that the patient tends to avoid; 4 = severe, present
75% of the time or more, which limits many activities of the patient, who
is unable to hold a regular job.
We
started treatment with 15 mg of Mirtazapine administered at night; a week
later, the dose was increased to 30 mg. Patients were assessed at the
start of treatment, every week during the first two months and afterwards
at least once a month. The main end-point was an improvement in the
severity of the functional incapacity. We determined that therapy failed
when patients did not respond favorably to Mirtazapine in 60 days. The
secondary end-point was the time (in days) in which the patients reached
their highest functional capacity. For the patients who showed adverse
effects when the dose was increased, we reduced it to the previous one,
and one or two weeks later we increased the dose again and then kept it at
that level if it was tolerated by the patient. If they did not respond to
treatment in 60 days, we dropped the Mirtazapine and indicated other
therapeutic alternatives. The patients with depression could continue
taking it.
We analyzed the severity and
functional incapacity before and after treatment and the possible
difference in time of response with non-parametric tests. The
statistically significant level was p<0.05.
RESULTS
A total
of 8 men and 14 women, with ages ranging from 27 to 89 years (median age:
57.5 years; percentiles 25-75%; 49-65 years) were studied. Tremor
(40.9%) and dystonia (36.3%) (Table 1) were the most frequent movement
disorders. Patients with hemifacial spasm were the youngest (51 ± 13.9
years). The idiopathic etiology (45.5%) predominated. Four patients had
moderate depression. In patients with a vascular etiology, we found a
focal motor deficit. Before starting treatment, the abnormal movement was
severe in 13 patients (59%) and moderate in 9 patients (40.9%). In all
cases, the movement disorder was present for more than four months.
A total
of 20 patients (90.9%) responded favorably to treatment and improved their
functional capacity by at least one or two points on the scale (Table 2).
We found a significant statistical relation (rs = 0.96; p <
0.05) between the scores obtained in the scale of severity and functional
incapacity before and after treatment. Four patients (18.1%), two with
tremor and two with dystonia, experienced complete functional recovery.
Fourteen patients (63.6%) improved their condition to mild functional
disability, and two (9%) shifted from the severe functional stage to the
moderate functional stage. The etiology of these patients was idiopathic
(n = 9, 45%), post-stroke (n = 5, 25%), family history (n = 5, 25%) and
secondary to drugs in one case.
Two
patients did not respond to treatment until two months later: one, the
oldest, with idiopathic tremor, and another with dystonia secondary to
thalamic infarcts. In both patients, treatment with Mirtazapine was
continued for depression. Treatment compliance was good in all patients.
In the
first month of treatment, 70% of the patients responded favorably. The
abnormal movements of 19 patients (86.3%) improved between 8 and 60 days
(median: 30, percentiles 25-75%: 15-30 days). The patient with
linguofacial dyskinesia reached his peak improvement in more than 60
days.
The
response to treatment was more rapid in the patients with hemifacial spasm
(between 8 and 21 days) compared to the group with tremor and dystonia
(from 15 to 60 days each) with a statistically significant difference (p <
0.05). The calculated probability of a favorable response between 15 and
60 days of treatment with Mirtazapine was 82% for tremor and 79% for
dystonia; after 60 days, the functional change could be expected to occur
in 0.8% and 13% of the patients, respectively. Meanwhile, the probability
of hemifacial spasm responding between 8 to 21 days was estimated to be
69%, and no more than 21% favorable modifications over a greater period of
time should be expected (Table 2).
Six
patients showed slight adverse events. A patient had somnolence and
another developed cramps in the lower limbs. Both effects appeared when
the dose of Mirtazapine was increased to 30 mg and disappeared when the
dose was reduced. With a new increase the symptoms appeared again and
therefore the causal relationship was definitive. We reduced the dose in
these cases to 15 mg and kept the dose at this level. Two patients
reported increased appetite, and two had dry mouth. None of the patients
had increases in their hepatic transaminases or alterations in other
hematological tests during the follow-up period.
DISCUSSION
In this
study we found that Mirtazapine, used as a single drug, improved the
functional condition of 90% of the patients with tremor, dystonia,
hemifacial spasm and tardive dyskinesia. The majority of the patients
experienced significant control over their involuntary movements,
improving their functional capacity in a shorter lapse of time (70%
achieved a response within the first 30 days). Although response to
treatment was relatively variable between individuals, it was evident that
the patients experienced clinically significant improvement, regardless of
their age, cause of disorder or initial degree of severity and functional
incapacity.
Patients
improved without showing any marked sedation and with few adverse events
during the follow-up period. Cramps in the lower limbs of one of our
patients have not been described before.
Mirtazapine could have a broader biochemical spectrum rather than a narrow
effect on serotonin (1). Mirtazapine could have binding sites in the
basal ganglia output structures and, through this mechanism, might be
improving movement disorders.
The
present study, although open and non-controlled, provides more data about
the potential benefits of Mirtazapine as treatment for movement
disorders. Randomized controlled trials need to be undertaken to
determine the effectiveness of the drug and to confirm the preliminary
results that we have found in our study.
REFERENCES
1. Anttila SAK, Leinonen EVJ.
A review
of the pharmacological and clinical profile of mirtazapine. CNS Drug
Reviews 2001;7:249-264.
2.
Holm KJ, Markham A. Mirtazapine: review of its use in major depression.
Drugs 1999;57:607-631.
3.
Kent JM. SnaRIs, NaSSAs, and NaRIs: new agents for the treatment of
depression.
Lancet
2000;355:911-918.
4. Alarcón F, Estrada G. Tratamiento con Mirtazapina del
temblor en 20 pacientes con enfermedad de Parkinson.
IX
Ecuadorian Congress of Neurology, Quito, 1999.
5.
Pact V, Giduz T. Mirtazapine treats resting tremor, essential tremor and
levodopa induced dyskinesias. Neurology 1999;53:1554.
6.
Wunsh H. Could the antidepressant Mirtazapine be used to treat tremor?
Lancet 1999;354:1100.
7.
Alarcón F, Dueñas G, Cevallos N, Lees AJ.
Movement
disorders in 30 patients with tuberculous meningitis. Mov Disord
2000;15:561-569.
8.
Fahn S. Concept and classification of dystonia. In: Fahn S, Marsden CD,
Calne BD (eds.) Advances in Neurology, Vol. 58. Dystonia 2. New York:
Raven Press, 1988.
9.
Findley LJ. Tremors: Differential diagnosis and pharmacology. In:
Jankovic J, Tolosa E (eds) Parkinson's Disease and Movement Disorders.
Baltimore, Munich: Urban and Schwartzenberg, 1988.
10.
Kurkan R, Shoulson I. Differential diagnosis of facial chorea. In:
Jankovic J, Tolosa E, eds. Advances in Neurology, Vol. 49. Facial
Dyskinesias. New York: Raven Press, 1988.
11.
Tolosa E, Alom J.
Drug-induced dyskinesia. In: Jankovic J, Tolosa E (eds.) Parkinson's
Disease and Movement Disorders. Baltimore, Munich: Urban and
Schwartzenberg, 1988.
12. Tolosa E, Marti MJ, Kulisevksy J.
Botulinum
toxin injection therapy for hemifacial spasm. In: Jankovic J, Tolosa E
(eds.) Advances in Neurology, Vol. 49. Facial Dyskinesia. New York:
Raven Press,
Autor:
Ecuadorian
magazine of neurology
