Pregabalin in the Treatment of Schizophrenic Anxiety

• Introduction
• Patient and Methods
• Results
• Discussion
• References

Introduction

According to DSM-IV-TR, schizophrenia includes two or more of the following symptoms: delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior or negative symptoms such as affective flattening [1]. Anxiety and fear, or even panic attacks, while typical of schizophrenia, are not recognized as core symptoms, and a generally accepted therapeutic approach to anxiety in schizophrenia is lacking. Benzodiazepines (BZDs) are effective, but the combined use of antipsychotic drugs and BZDs is sometimes problematic due to the elevated risk of respiratory depression and falls on the one hand and the addictive potential of the BZDs on the other hand.

Pregabalin, a γ-amino butyric acid (GABA) analogue, was initially licensed in the USA and EU as an anticonvulsant. Meanwhile, pregabalin has also been approved by the FDA for diabetic neuropathic pain, post-herpetic neuralgia and fibromyalgia [13] [17] and by the EMEA for generalized anxiety disorder [4] [8] [11]. In addition, it appears to be effective in social phobia [9] and depression [12] [14]. Here, we report the case of a patient with schizophrenia whose anxiety responded reproducibly to add-on pregabalin treatment.

Patient and Methods

Mr. S was a 33-year-old Caucasian male with a 15-year history of paranoid schizophrenia (DSM-IV 295.30). He had suffered from 10 episodes of severe auditory verbal hallucinations (AVH) meeting Schneiderian first-rank criteria. They were associated with extreme fear and anxiety and required admissions to psychiatric hospitals. Since being put on clozapine, 400–600 mg/d 8 years ago, the severity of AHV decreased and he was subsequently treated as an outpatient. However, his fear and anxiety still interfered with daily activities and social behaviour. Due to AVH-related anxiety he remained in social isolation and was afraid of leaving home. Mr. S was admitted to our department due to an exacerbation of hallucinatory and delusional symptoms with religious and persecutory content, being afraid of not overcoming the devil's suggestions and temptations. There was no psychiatric co-morbidity. Cranial MRI, EEG, ECG and laboratory tests (B12, folic acid, thyroid hormone levels, ESR, CRP, syphilis- and HIV-antibody tests) were unremarkable.

Results

During the 3 months of the inpatient treatment with a clozapine dosage between 600–800 mg/d, clozapine serum levels were always within the desired range (300–600 ng/mL). A dosage increase of clozapine up to 1 000 mg/d (serum level 1 060 ng/mL), even in combination with amisulpride (400 mg/d; serum level 324 ng/mL; range 100–400 ng/mL) only partially reduced the psychotic symptoms and the patient still suffered from strong anxiety. Amisulpride was thus discontinued because of a lack of effect. After obtaining informed consent to an off-label use, pregabalin up to 600 mg/d was added to clozapine ([Fig. 1]). This combination substantially ameliorated both AVHs and anxiety which led to score reductions in the respective items of rating scales (hallucinations: BPRS-12 from 6 to 1, PANSS-P3 from 7 to 2; anxiety: BPRS-2 from 5 to 2, PANSS-G2 from score 5 to 2). Pregabalin add-on was also well tolerated, and, as expected, no pharmakokinetic interactions occurred (serum levels remained stable). Mr. S was transferred to the day clinic, where pregabalin was discontinued in view of the off-label use. Within a few weeks, anxiety again increased and Mr. S. had to be readmitted as an inpatient. Accordingly, pregabalin was reintroduced as an add-on treatment. Anxiety was improved within 2 weeks and almost fully remitted after 5 weeks.

Discussion

To the best of our knowledge, this is the first report on pregabalin as an add-on treatment in schizophrenia-related anxiety. On first exposure to pregabalin, there was a clear-cut reduction of reported anxiety which persisted for several weeks. After discontinuation, anxiety quickly returned to previous levels, while reintroduction of pregabalin resulted in prompt symptom remission.

Pregabalin is a structural analogue of GABA, but is not active at GABA receptors, and does not alter GABA uptake or metabolism. It binds with high affinity to the alpha2-ä subunit protein of presynaptic voltage-gated calcium channels [15] and modulates the release of neurotransmitters such as glutamate, noradrenalin and substance P in hyperactive neurons [2] [3] [5] [6]. This mechanism of action has been hypothesized to be responsible for the anxiolytic, analgesic and anti-epileptic effects. Presynaptic modulation of hyperactive excitatory neurotransmitter systems might also be the mechanism of action in treating psychotic anxiety in schizophrenia. At present, there is no evidence that pregabalin itself exerts a direct antipsychotic activity, even if glutamate and GABA systems are considered as emerging targets for development of new antipsychotic drugs [7] [16]. Pregabalin is almost exclusively eliminated by renal excretion so that pharmacokinetic interactions appear unlikely. There is no evidence for drug-drug interactions with oxycodone, lorazepam or ethanol. Pregabalin is considered to have a limited potential for abuse or dependence, being classified as a Schedule V drug in the U.S.A. [10]. Thus, pregabalin may be a better approach for long-term treatment of anxiety-related target symptoms than benzodiazepines.

In conclusion, its pharmacological properties as well as the easy therapeutic administration of the drug (in 2 to 3 divided doses per day, starting with 75 mg BID) make pregabalin suitable as an add-on medication for anxiety in schizophrenia. However, more observations, in particular open and controlled clinical trials, are needed to further explore the effectiveness of pregabalin in the treatment of anxiety in schizophrenia as an add-on agent.

References

• 1 APA . Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, International Version. Washington, DC, American Psychiatric Association 1995: 279-324
• 2 Brawek B, Loffler M, Dooley DJ. et al . Differential modulation of K(+)-evoked (3) H-neurotransmitter release from human neocortex by gabapentin and pregabalin.  Naunyn Schmiedebergs Arch Pharmacol. 2008;  376 301-307
  CrossrefPubMedSearch in Google Scholar
• 3 Dooley DJ, Donovan CM, Pugsley TA. Stimulus-dependent modulation of [(3) H]norepinephrine release from rat neocortical slices by gabapentin and pregabalin.  J Pharmacol Exp Ther. 2000;  295 1086-1093
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• 4 Feltner DE, Crockatt JG, Dubovsky SJ. et al . A randomized, double-blind, placebo-controlled, fixed-dose, multicenter study of pregabalin in patients with generalized anxiety disorder.  J Clin Psychopharmacol. 2003;  23 240-249
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• 5 Fink K, Dooley DJ, Meder WP. et al . Inhibition of neuronal Ca(2+) influx by gabapentin and pregabalin in the human neocortex.  Neuropharmacology. 2002;  42 229-236
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• 6 Frampton JE, Foster RH. Pregabalin: in the treatment of generalised anxiety disorder.  CNS Drugs. 2006;  20 685-693 , discussion 694–695
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• 7 Gonzalez-Burgos G, Lewis DA. GABA . Neurons and the mechanisms of network oscillations: implications for understanding cortical dysfunction in schizophrenia.  Schizophr Bull. 2008;  34 944-961
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• 8 Pande AC, Crockatt JG, Feltner DE. et al . Pregabalin in generalized anxiety disorder: a placebo-controlled trial.  Am J Psychiatry. 2003;  160 533-540
  CrossrefPubMedSearch in Google Scholar
• 9 Pande AC, Feltner DE, Jefferson JW. et al . Efficacy of the novel anxiolytic pregabalin in social anxiety disorder: a placebo-controlled, multicenter study.  J Clin Psychopharmacol. 2004;  24 141-149
  CrossrefPubMedSearch in Google Scholar
• 10 Regist USF. Schedules of controlled substances: placement of pregabalin into schedule V. Final rule Drug.  Enforcement Administration, Department of Justice 2005; Fed Regist. 2005;  70 ((144)) 43633-43635 , PMID16050051
  PubMedSearch in Google Scholar
• 11 Rickels K, Pollack MH, Feltner DE. et al . Pregabalin for treatment of generalized anxiety disorder: a 4-week, multicenter, double-blind, placebo-controlled trial of pregabalin and alprazolam.  Arch Gen Psychiatry. 2005;  62 1022-1030
  CrossrefPubMedSearch in Google Scholar
• 12 Showraki M. Pregabalin in the treatment of depression.  J Psychopharmacol. 2007;  21 883-884
  CrossrefPubMedSearch in Google Scholar
• 13 Stacey BR, Dworkin RH, Murphy K. et al . Pregabalin in the treatment of refractory neuropathic pain: results of a 15-month open-label trial.  Pain Med. 2008;  , Mar 11 [Epub ahead of print]
  PubMedSearch in Google Scholar
• 14 Stein DJ, Baldwin DS, Baldinetti F. et al . Efficacy of pregabalin in depressive symptoms associated with generalized anxiety disorder: a pooled analysis of 6 studies.  Eur Neuropsychopharmacol. 2008;  18 422-430
  CrossrefPubMedSearch in Google Scholar
• 15 Taylor CP, Angelotti T, Fauman E. Pharmacology and mechanism of action of pregabalin: the calcium channel alpha2-delta (alpha2-delta) subunit as a target for antiepileptic drug discovery.  Epilepsy Res. 2007;  73 137-150
  CrossrefPubMedSearch in Google Scholar
• 16 Woo TU, Shrestha K, Lamb D. et al . N-Methyl-d-Aspartate receptor and calbindin-containing neurons in the anterior cingulate cortex in schizophrenia and bipolar disorder.  Biol Psychiatry. 2008;  64 803-809
  CrossrefPubMedSearch in Google Scholar
• 17 Zin CS, Nissen LM, Smith MT. et al . An update on the pharmacological management of post-herpetic neuralgia and painful diabetic neuropathy.  CNS Drugs. 2008;  22 417-442
  CrossrefPubMedSearch in Google Scholar

Correspondence

Dr. med. C. Schönfeldt-Lecuona

Department of Psychiatry and Psychotherapy III

University Clinic Ulm

Leimgrubenweg 12-14

89075 Ulm

Germany

Phone: +49/731/500 614 11

Fax: +49/731/500 614 12

Email: carlos.schoenfeldt@uni-ulm.de

References

• 1 APA . Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, International Version. Washington, DC, American Psychiatric Association 1995: 279-324
• 2 Brawek B, Loffler M, Dooley DJ. et al . Differential modulation of K(+)-evoked (3) H-neurotransmitter release from human neocortex by gabapentin and pregabalin.  Naunyn Schmiedebergs Arch Pharmacol. 2008;  376 301-307
  CrossrefPubMedSearch in Google Scholar
• 3 Dooley DJ, Donovan CM, Pugsley TA. Stimulus-dependent modulation of [(3) H]norepinephrine release from rat neocortical slices by gabapentin and pregabalin.  J Pharmacol Exp Ther. 2000;  295 1086-1093
  PubMedSearch in Google Scholar
• 4 Feltner DE, Crockatt JG, Dubovsky SJ. et al . A randomized, double-blind, placebo-controlled, fixed-dose, multicenter study of pregabalin in patients with generalized anxiety disorder.  J Clin Psychopharmacol. 2003;  23 240-249
  CrossrefPubMedSearch in Google Scholar
• 5 Fink K, Dooley DJ, Meder WP. et al . Inhibition of neuronal Ca(2+) influx by gabapentin and pregabalin in the human neocortex.  Neuropharmacology. 2002;  42 229-236
  CrossrefPubMedSearch in Google Scholar
• 6 Frampton JE, Foster RH. Pregabalin: in the treatment of generalised anxiety disorder.  CNS Drugs. 2006;  20 685-693 , discussion 694–695
  CrossrefPubMedSearch in Google Scholar
• 7 Gonzalez-Burgos G, Lewis DA. GABA . Neurons and the mechanisms of network oscillations: implications for understanding cortical dysfunction in schizophrenia.  Schizophr Bull. 2008;  34 944-961
  CrossrefPubMedSearch in Google Scholar
• 8 Pande AC, Crockatt JG, Feltner DE. et al . Pregabalin in generalized anxiety disorder: a placebo-controlled trial.  Am J Psychiatry. 2003;  160 533-540
  CrossrefPubMedSearch in Google Scholar
• 9 Pande AC, Feltner DE, Jefferson JW. et al . Efficacy of the novel anxiolytic pregabalin in social anxiety disorder: a placebo-controlled, multicenter study.  J Clin Psychopharmacol. 2004;  24 141-149
  CrossrefPubMedSearch in Google Scholar
• 10 Regist USF. Schedules of controlled substances: placement of pregabalin into schedule V. Final rule Drug.  Enforcement Administration, Department of Justice 2005; Fed Regist. 2005;  70 ((144)) 43633-43635 , PMID16050051
  PubMedSearch in Google Scholar
• 11 Rickels K, Pollack MH, Feltner DE. et al . Pregabalin for treatment of generalized anxiety disorder: a 4-week, multicenter, double-blind, placebo-controlled trial of pregabalin and alprazolam.  Arch Gen Psychiatry. 2005;  62 1022-1030
  CrossrefPubMedSearch in Google Scholar
• 12 Showraki M. Pregabalin in the treatment of depression.  J Psychopharmacol. 2007;  21 883-884
  CrossrefPubMedSearch in Google Scholar
• 13 Stacey BR, Dworkin RH, Murphy K. et al . Pregabalin in the treatment of refractory neuropathic pain: results of a 15-month open-label trial.  Pain Med. 2008;  , Mar 11 [Epub ahead of print]
  PubMedSearch in Google Scholar
• 14 Stein DJ, Baldwin DS, Baldinetti F. et al . Efficacy of pregabalin in depressive symptoms associated with generalized anxiety disorder: a pooled analysis of 6 studies.  Eur Neuropsychopharmacol. 2008;  18 422-430
  CrossrefPubMedSearch in Google Scholar
• 15 Taylor CP, Angelotti T, Fauman E. Pharmacology and mechanism of action of pregabalin: the calcium channel alpha2-delta (alpha2-delta) subunit as a target for antiepileptic drug discovery.  Epilepsy Res. 2007;  73 137-150
  CrossrefPubMedSearch in Google Scholar
• 16 Woo TU, Shrestha K, Lamb D. et al . N-Methyl-d-Aspartate receptor and calbindin-containing neurons in the anterior cingulate cortex in schizophrenia and bipolar disorder.  Biol Psychiatry. 2008;  64 803-809
  CrossrefPubMedSearch in Google Scholar
• 17 Zin CS, Nissen LM, Smith MT. et al . An update on the pharmacological management of post-herpetic neuralgia and painful diabetic neuropathy.  CNS Drugs. 2008;  22 417-442
  CrossrefPubMedSearch in Google Scholar

Correspondence

Dr. med. C. Schönfeldt-Lecuona

Department of Psychiatry and Psychotherapy III

University Clinic Ulm

Leimgrubenweg 12-14

89075 Ulm

Germany

Phone: +49/731/500 614 11

Fax: +49/731/500 614 12

Email: carlos.schoenfeldt@uni-ulm.de