Augmentation with Atomoxetine in Treatment-Resistant Depression with Psychotic Features

• Case Report
• Discussion
• References

The selective norepinephrine reuptake inhibitor atomoxetine has recently been reported to be effective as an augmenting agent in treatment-resistant depression. We report on a patient with major depression with psychotic features and a history of severe treatment-resistance who responded to a trial of atomoxetine augmentation. Various adequate and experimental treatment trials (including electroconvulsive therapy [ECT]) had previously failed to effect response. Discontinuation of atomoxetine resulted in a severe relapse. The initial treatment response was achieved once more after reapplying atomoxetine. This case report is congruent with previous articles on successful atomoxetine augmentation. In addition, this is the first report on the compatibility of this treatment strategy with psychotic symptoms accompanying major depression.

Case Report

Sixty-four year-old Mrs. W. was diagnosed with treatment-resistant (including [ECT]) recurrent major depressive disorder according to DSM IV criteria. She had a 30-year old history of 22 clinical admissions. Mrs. W. was hospitalized in February 2004 for a severe depressive episode with psychotic features persistent for four years. Her score on the Hamilton Rating Scale for Depression (HAMD-21) was 34 when she was referred to our department in June 2004. Adequate treatment trials in the current episode had been performed with amitriptyline, imipramine, trimipramine, tranylcypromine, moclobemide, fluoxetine, reboxetine, venlafaxine, lithium augmentation, haloperidol, perazine, chlorpromazine, chlorprothixene, risperidone, clozapine and olanzapine, either as monotherapies or in combination, as well as with 83 ECTs. An initial augmentation of the patient’s basic medication [nortriptyline (300 mg/d) and clozapine (400 mg/d)] with methylphenidate (40 mg/d) for 17 days elicited an increment of psychotic symptoms (delusions of guilt, auditory hallucinations). We discontinued methylphenidate and augmented instead with atomoxetine (100 mg/d). Within 20 days, the depressive syndrome improved significantly (HAMD-21 : 17) with no concomitant increase of psychotic symptoms. Mrs. W. noted that she had never felt as stable since the beginning of the current episode.

We discharged her after nine months of continuous inpatient treatment in November 2004. The maintenance treatment with atomoxetine had to be stopped on discharge because it had not yet been approved in Germany. Four weeks later the patient suffered a severe relapse of her depression (HAMD-21 : 39) and was readmitted. Once again we augmented with atomoxetine (up to 100 mg/d within 10 days) and Mrs. W. responded significantly (HAMD-21 after one week: 19). She was discharged in a stable state after four weeks (HAMD-21 : 17).

Discussion

Our patient presented an improvement in motivation and a decrease of fatigue and executive dysfunction. These symptoms are presumably attributable to norepinephrine deficient malfunctioning circuits in the dorsolateral prefrontal cortex (DLPFC) [7]. The selective norepinephrine reuptake inhibitor atomoxetine is established in the treatment of attention-deficit-hyperactivity-syndrome. The substance elevates dopamine- and norepinephrine levels in the DLPFC of rats [2]. Although it has been rated as a potential antidepressant on the basis of preclinical [9] and clinical [4] findings, it has not figured highly in the treatment of depression.

An early phase II trial on ten newly admitted patients in 1983 provided the first clinical evidence for the antidepressive properties of atomoxetine [4] in monotherapy. Our case conforms to recent case reports [1] and a retrospective chart review [6] in which 12 out of 14 patients with treatment-resistant depression showed at least partial response after augmentation with atomoxetine. These findings were most recently confirmed by an open label case series study [3] rating 9 out of 15 treatment-resistant outpatients as responders to atomoxetine augmentation. While methylphenidate proved to aggravate psychotic symptoms [8], supposably because of its stimulating effect on subcortical limbic areas, the non-stimulating atomoxetine was well tolerated. According to the authors’ knowledge, our paper is the first to report about the effectiveness and safety of atomoxetine in treatment-resistant depression with psychotic features. Effective and safe augmentation strategies are of high clinical value in this severe subtype of depression which is associated with a less favorable course and outcome [5] than non-psychotic depression. More research is needed to replicate these findings.

References

• 1 Berigan T. Atomoxetine used adjunctively with selective serotonin reuptake inhibitors to treat depression.  Prim Care Companion J Clin Psychiatry. 2004;  6 93-94
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• 2 Bymaster F P, Katner J S, Nelson D L, Hemrick-Luecke S K, Threlkeld P G, Heiligenstein J H, Morin S M, Gehlert D R, Perry K W. Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder.  Neuropsychopharmacology. 2002;  27 699-711
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• 3 Carpenter L L, Milosavljevic N, Schecter J M, Tyrka A R, Price L H. Antidepressant augmentation with open-label atomoxetine.  J Clin Psychiatry. 2005;  66 1234-1238
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• 4 Chouinard G, Annable L, Bradwejn J. An early phase II clinical trial of atomoxetine (LY139603) in the treatment of newly admitted depressed patients.  Psychopharmacology (Berl). 1984;  83 126-128
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• 5 Marneros A. Affective disorders: basic principles regarding clinical course, long-term therapeutic and prophylactic strategies.  Pharmacopsychiatry. 2004;  37 (Suppl. 2) 148-151
  Thieme ConnectPubMedSearch in Google Scholar
• 6 Papakostas G I, Petersen T J, Burns A M, Fava M. Adjunctive atomoxetine for residual fatigue in major depressive disorder. J Psychiatr Res 2005; June 21 [Epub ahead of print]
  Search in Google Scholar
• 7 Stahl S M, Zhang L, Damatarca C, Grady M. Brain circuits determine destiny in depression: a novel approach to the psychopharmacology of wakefulness, fatigue, and executive dysfunction in major depressive disorder.  J Clin Psychiatry. 2003;  64 (Suppl. 14) 6-17
  CrossrefPubMedSearch in Google Scholar
• 8 Yui K, Ikemoto S, Goto K, Nishijima K, Yoshino T, Ishiguro T. Spontaneous recurrence of methamphetamine-induced paranoid-hallucinatory states in female subjects: susceptibility to psychotic states and implications for relapse of schizophrenia.  Pharmacopsychiatry. 2002;  35 62-71
  Thieme ConnectPubMedSearch in Google Scholar
• 9 Zerbe R L, Rowe H, Enas G G, Wong D, Farid N, Lemberger L. Clinical pharmacology of tomoxetine, a potential antidepressant.  J Pharmacol Exp Ther. 1985;  232 139-143
  PubMedSearch in Google Scholar

Mazda Adli, M.D.

Department of Psychiatry and Psychotherapy

Charité - Universitätsmedizin Berlin

Campus Charité Mitte

Schumannstrasse 20-21

10117 Berlin

Germany

Phone: +49 30 450 517 146

Fax: +49 30 450 517 944

Email: mazda.adli@charite.de

References

• 1 Berigan T. Atomoxetine used adjunctively with selective serotonin reuptake inhibitors to treat depression.  Prim Care Companion J Clin Psychiatry. 2004;  6 93-94
  PubMedSearch in Google Scholar
• 2 Bymaster F P, Katner J S, Nelson D L, Hemrick-Luecke S K, Threlkeld P G, Heiligenstein J H, Morin S M, Gehlert D R, Perry K W. Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder.  Neuropsychopharmacology. 2002;  27 699-711
  CrossrefPubMedSearch in Google Scholar
• 3 Carpenter L L, Milosavljevic N, Schecter J M, Tyrka A R, Price L H. Antidepressant augmentation with open-label atomoxetine.  J Clin Psychiatry. 2005;  66 1234-1238
  PubMedSearch in Google Scholar
• 4 Chouinard G, Annable L, Bradwejn J. An early phase II clinical trial of atomoxetine (LY139603) in the treatment of newly admitted depressed patients.  Psychopharmacology (Berl). 1984;  83 126-128
  CrossrefPubMedSearch in Google Scholar
• 5 Marneros A. Affective disorders: basic principles regarding clinical course, long-term therapeutic and prophylactic strategies.  Pharmacopsychiatry. 2004;  37 (Suppl. 2) 148-151
  Thieme ConnectPubMedSearch in Google Scholar
• 6 Papakostas G I, Petersen T J, Burns A M, Fava M. Adjunctive atomoxetine for residual fatigue in major depressive disorder. J Psychiatr Res 2005; June 21 [Epub ahead of print]
  Search in Google Scholar
• 7 Stahl S M, Zhang L, Damatarca C, Grady M. Brain circuits determine destiny in depression: a novel approach to the psychopharmacology of wakefulness, fatigue, and executive dysfunction in major depressive disorder.  J Clin Psychiatry. 2003;  64 (Suppl. 14) 6-17
  CrossrefPubMedSearch in Google Scholar
• 8 Yui K, Ikemoto S, Goto K, Nishijima K, Yoshino T, Ishiguro T. Spontaneous recurrence of methamphetamine-induced paranoid-hallucinatory states in female subjects: susceptibility to psychotic states and implications for relapse of schizophrenia.  Pharmacopsychiatry. 2002;  35 62-71
  Thieme ConnectPubMedSearch in Google Scholar
• 9 Zerbe R L, Rowe H, Enas G G, Wong D, Farid N, Lemberger L. Clinical pharmacology of tomoxetine, a potential antidepressant.  J Pharmacol Exp Ther. 1985;  232 139-143
  PubMedSearch in Google Scholar

Mazda Adli, M.D.

Department of Psychiatry and Psychotherapy

Charité - Universitätsmedizin Berlin

Campus Charité Mitte

Schumannstrasse 20-21

10117 Berlin

Germany

Phone: +49 30 450 517 146

Fax: +49 30 450 517 944

Email: mazda.adli@charite.de