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First Administration of Cytidine Diphosphocholine and Galantamine in Schizophrenia: A Sustained alpha7 Nicotinic Agonist Strategy

Stephen I. Deutsch, MD, PhD, Barbara L. Schwartz, PhD, Nina R. Schooler, PhD, Richard B. Rosse, MD, John Mastropaolo, PhD, and Brooke Gaskins, BA

Abstract

Converging lines of evidence suggest pathophysiology of alpha7 nicotinic acetylcholine receptors (alpha7 nAChRs) in schizophrenia. This pilot study was designed to test the tolerability, safety, and preliminary efficacy of chronic administration of an  alpha7 nAChR agonist strategy involving combination treatment of cytidine diphosphocholine (CDP-choline; 2 g/d), a dietary source of the  alpha7 nAChR agonist choline, and galantamine (24 mg/d), a positive allosteric modulator of nAChRs that was prescribed to prevent choline from becoming a functional antagonist and improve the efficiency of coupling the binding of choline to channel opening. The combination of CDP-choline (Citicoline) and galantamine was administered to 6 schizophrenic patients with residual symptoms in a 12-week, open-label trial. Patients were maintained on stable dose regimens of antipsychotic medications for 4 weeks before study entry and for the trial duration. All reached target doses of both agents and completed the trial. Transient side effects resolved without slowing of dose titration. Gastrointestinal adverse effects were most common. Of the 6 patients, 5 showed reduction in Clinical Global Impressions severity scores and Positive and Negative Syndrome Scale total scores. Three patients requested continuation of the adjunctive combination at the end of the trial. These results suggest further investigation of the combination of CDP-choline and galantamine as an  alpha7 nAChR agonist intervention.

The alpha7 nicotinic acetylcholine receptor (alpha7 nAChR) has been proposed as a promising target for medication development in schizophrenia. The converging evidence implicating ‘‘hypofunction’’ of this receptor in schizophrenia includes epidemiological data on the high prevalence of smoking, electrophysiological data, genetic linkage and association studies, and postmortem studies.1-10 Schizophrenic patients and their closely related biological relatives, including unaffected ones, manifest a deficit in inhibitory auditory gating that is inherited in an autosomal dominant manner and seems to result from diminished expression of the  alpha7 nAChR, a cation channel receptor that is gated by acetylcholine (ACh), in the hippocampus.4,11 This deficit is reflected in a failure to blunt the amplitude of the positively evoked potential appearing about 50 milliseconds (P50 wave) after the second of a pair of identical auditory stimuli presented 500 milliseconds apart relative to the amplitude evoked in response to the first stimulus of the pair. Linkage and association studies implicate the gene for the alpha7 nAChR polypeptide subunit located in the q13-q14 region of chromosome 15, referred to as CHRNA7, with schizophrenia.6-8 Autopsy studies support diminished expression of the alpha7 subunit in the frontal cortex, hippocampus, and thalamus in patients with schizophrenia.9,10,12

The hypothesis of  alpha7 nAChR ‘‘hypofunction’’ in schizophrenia has stimulated exploration of nicotinic receptor agonists in preclinical and clinical models, including selective alpha7 interventions in animal models relevant to schizophrenia. Unfortunately, there are problems in exploring this strategy in humans, including limited availability of safe and selective  alpha7 nAChR agonists and rapid desensitization of the receptor. The potential for rapid desensitization of nAChRs raises the concern that administration of an  alpha7 nAChR agonist, especially for a long-term indication, will have the unintended pharmacological consequence of functional antagonism of the receptor, whose expression is already reduced. Prior study of a partial alpha7 nicotinic cholinergic agonist in schizophrenia has been limited to a single-day administration crossover study of an anabaseine derivative.13

We hypothesize that selective and sustained stimulation of  alpha7 nAChRs using a combination of galantamine and cytidine diphosphocholine (CDP-choline) offers therapeutic advantages to schizophrenic patients maintained on stable regimens of antipsychotic medications. Choline is a selective  alpha7 nAChR agonist that mimics the electrophysiological and pharmacological effects of ACh itself at this receptor. Cytidine diphosphocholine (citicoline) is a dietary source of exogenous choline, elevating its plasma and brain levels.14 Cytidine diphosphocholine is safe and well tolerated in dosages of up to 2000 mg/d for periods of up to 6 weeks in patients with acute ischemic stroke.15,16 Unfortunately, the  alpha7 nAChR, like nAChRs in general, desensitizes rapidly upon exposure to agonist; thus, a putative agonist such as choline becomes a functional antagonist with chronic administration. This rapid desensitization can account for the generally disappointing results associated with previous trials of dietary choline or lecithin administration in schizophrenia.17,18 The availability of galantamine, an allosteric potentiating ligand that is specific for nAChRs and also a cholinesterase inhibitor, has sparked our interest in examining the selective  alpha7 nAChR agonist properties of choline derived from dietary CDP-choline administration. Theoretically, galantamine will improve the efficiency of coupling between the binding of choline by the  alpha7 nAChR and channel opening while preserving the receptor in a responsive, as opposed to refractory, state, allowing choline to retain its agonist properties over time.19-22

Thus, we hypothesize that CDP-choline/galantamine combination will have sustained therapeutic efficacy in a clinically meaningful time frame. Our first step was a 12-week open-label pilot study to evaluate dose titration and safety because this combination has never been systematically administered to patients with schizophrenia before.


METHODS

Six outpatients fulfilling the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for schizophrenia based on the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition provided informed consent and participated in the 12-week trial consisting of baseline, titration (weeks 2-4), and maintenance-adjuvant treatment of combined CDP-choline and galantamine (weeks 5-12). Patients were on stable regimens of atypical antipsychotic medications for at least 4 weeks before enrollment and were maintained on their stable regimen throughout the duration of the study. Clinical assessments, including the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impressions (CGI), and a measure of nicotine craving and use, were administered at baseline and weeks 4, 8, and 12.23-25 A brief cognitive assessment battery (tests of attention, memory, and processing speed) was administered at baseline and weeks 8 and 12, and safety measures (vital signs, treatment-emergent adverse events) were obtained weekly. A safety laboratory screen and electrocardiogram were completed at baseline and week 12. Positive and Negative Syndrome Scale and CGI scores reflected consensus ratings of at least 2 experienced raters (S.I.D., B.L.S., J.M.). Cytidine diphosphocholine was titrated to its fixed maintenance dose of 2000 mg/d in 2 divided doses beginning on week 2. Galantamine was titrated to its fixed maintenance dose of 24 mg/d in 2 divided doses, with 8, 16, and 24 mg/d on weeks 2, 3, and 4, respectively. This phase 1 study was conducted under Food and Drug Administration Investigational New Drug no. 72,622 for the combination treatment of CDP-choline and galantamine. Pharmaceutical-grade CDP-choline was supplied by LifeLink, Inc. Adherence was measured using weekly pill counts and patient/caregiver report.


RESULTS

T1 Table 1 presents characteristics of patients who participated in the trial. All patients completed the 12-week trial, tolerated the titration schedule, and achieved the target dose for both agents. Adherence, measured by pill counts for both, indicated that 1 patient missed 7 of 42 doses during titration and approximately 25% of doses during maintenance treatment. A second patient missed 10% of doses, 2 patients missed 1 dose, and 2 patients took all medication. Treatment-emergent side effects were transient, resolved within a few days, and were rated as mild to moderate (Table 2). T2 These included diarrhea (n = 5), other gastrointestinal side effects, including nausea (n = 4), restlessness (n = 3), and syncope (n = 3). Over the course of the trial, no significant cardiovascular effects were observed; specifically, there was no lowering of pulse rate or blood pressure or prolongation of the QT interval. Of the 6 patients, 2 experienced an increase in salivation rated as mild. Five patients showed transient increases in pulse rate. Five patients showed transient increases in diastolic blood pressure. Week 12 diastolic readings showed that 5 of 6 patients had not only normal diastolic readings (G80 mm Hg) but also readings that were lower than baseline. At screening, all laboratory values were judged by one of us (R.B.R.) either as within normal range or as not clinically significant. At week 12, there were no clinically significant changes from baseline values, with 1 exception. In this patient, we observed an elevated white blood count at week 12, but this finding occurred in the presence of cloudy urine. Follow-up laboratory tests indicated that this patient had a urinary tract infection.

All patients were at least moderately ill at baseline according to the CGI-Severity scale (Table 1). At week 12, no patient worsened, and 5 of 6 patients showed a reduction in CGI-Severity score. Total PANSS scores also decreased in 5 of 6 patients over the 12-week trial. There were no consistent findings on the cognitive and nicotine-use measures across the 6 patients. One patient requested to remain on study medication at the end of the trial. Two additional patients and their caregivers requested that the patients be put back on study medications after adjuvant treatments were discontinued at the end of the trial: 1 patient 8 days after discontinuation and the other 18 days later. Anecdotally, 4 patients reported subjective benefits of the study treatments such as feeling more motivated, energetic, and focused. Auditory hallucinations resolved in 2 patients during the course of the study.

TABLE 1. Patient Characteristics, CGI, and Total PANSS Scores at Baseline and Week 12
Patient No.
1
2
3
4
5
6
Sex
Male
Male
Female
Male
Male
Male
Age (yrs)
57
47
29
52
47
49
Race
AA
C
AA
AA
AA
AA
Duration of
illness (yrs)
6
23
3
31
20
34
Smoking
status
Smoker
Nonsmoker
Smoker
Smoker
Nonsmoker
Smoker
Antipsychotic
medication
Risperidone LA
(50 mg q 2 wk);
quetiapine
(200 mg/d)
Risperidone
(6 mg/d)
Aripiprazole
(30 mg/d);
quetiapine
(200 mg/d)
Aripiprazole
(30 mg/d);
risperidone
(50 mL/2 mL
inj q 2 wk)
Aripiprazole
(10 mg/d);
olanzapine
(2.5 mg/d)
Fluphenazine
decan
(25 mg/mL
inj q 2 wk)
Baseline
CGI/total
PANSS
5/92
5/66
4/59
5/94
6/94
5/91
Wk 12
CGI/total
PANSS
4/56
5/68
3/47
4/84
5/76
4/55


TABLE 2. Treatment-Emergent Adverse Effects and Vital Signs (Baseline rating/highest rating)
Patient No.
1
2
3
4
5
6
Nasal
--
--
1/2
1/2
--
1/2
Vision
--
--
--
1/2
--
--
Dermatological
--
--
--
1/2
--
--
Itching
--
--
--
1/2
--
--
Headache
--
1/2
--
--
--
--
Fever
--
1/2
--
1/2
--
--
Sweating
--
1/2
--
1/4
--
--
Dry mouth
--
--
--
1/2
--
--
Salivation
1/2
--
--
--
--
1/2
Constipation
--
--
--
1/2
--
1/2
Diarrhea
1/3
1/3
1/2
2/3
1/2
--
Malaise
--
1/3
--
--
--
1/2
GI upset
1/2
2/3
1/2
1/3
--
--
Increased appetite
--
1/2
--
--
--
1/2
Decreased appetite
--
--
--
1/2
--
--
Restlessness
--
1/2
--
1/3
--
2/3
Insomnia
--
1/2
--
--
--
1/3
Drowsy
--
--
--
1/3
--
--
Other sleep
1/2
--
--
1/3
--
--
Syncope
--
1/2
--
1/3
--
1/2
Tachycardia
--
--
--
1/3
--
1/2
Pulse rate
68/74
83/109
92/111
88/88
71/93
76/83
BP (systolic)
145/146
122/130
137/145
154/154
107/124
124/133
BP (diastolic)
83/100
68/84
80/88
81/81
68/86
78/93


DISCUSSION

The combination treatment was well tolerated by the patients in this 12-week open-label trial. The adverse events that we saw were mild to moderate and transient. Importantly, all patients completed the trial, and 3 expressed interest in continuing to receive the treatment. We did not measure plasma concentration of either CDP-choline or galantamine; thus, we have no direct evidence regarding adherence. However, pill count information suggests that most patients took most of the medication. Preliminary data regarding symptom efficacy suggest that improvement was seen in 5 of 6 patients. The open nature of the trial requires great caution in attributing the improvement to the treatment but encourages further study of this combination. Our anecdotal observation of the patients’ positive subjective experiences suggests that subjective experiences should be measured systematically in future trials.

Olincy et al13 found that a partial  alpha7 nAChR agonist, a derivative of anabaseine, had positive effects on cognitive measures in a double-blind crossover design. Specifically, 12 patients received 2 doses of the agonist or placebo, with each treatment given on 1 day. The anabaseine derivative improved a measure of sensory processing (P50 inhibitory gating) and a composite score on a cognitive battery, including attention and memory tests providing evidence of efficacy, after a single day of treatment with a partial  alpha7 nAChR agonist. Ideally, improvements in attention and memory that are noted acutely with the anabaseine derivative would be sustained with an  alpha7 nAChR agonist strategy that remains effective with chronic administration. The absence of consistent improvement in attention and memory in the current study may reflect differences between the acute and chronic designs-our first post treatment testing occurred after 8 weeks, the nature of the patient population studied-our cohort was not selected for cognitive impairment, administration of a partial agonist versus the combination of an allosteric potentiating ligand and full agonist, and small and heterogeneous samples with respect to smoking and medication status, among other variables. However, in this early phase 1 study, our goal was to explore the safety and tolerability of the combination as a therapeutic intervention added to a variety of antipsychotic medications.

The present results provide encouraging preliminary evidence that combination treatment with galantamine and CDP-choline is a viable pharmaco-therapeutic strategy for chronic administration. Based on the results of this small open-label trial of a first administration of CDP-choline and galantamine, we believe that the next step is to conduct a larger, double-blind, randomized, placebo controlled study of efficacy. Such a study will serve as a ‘‘proof of concept,’’ suggesting that the combination treatment is effective because galantamine prevents desensitization of the receptor and prevents choline from becoming a functional antagonist.


ACKNOWLEDGMENT

We thank David Blanco from LifeLink, Inc., for generously providing the CDP-choline.


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