1 | D O N A T

Feelings of PUR Elation: Allopurinol as Adjunctive Therapy for Bipolar Mania

Alisha D. Donat, Pharm.D. PGY-2 Psychiatry Pharmacy Resident

South Texas Veterans Health Care System The University of Texas at Austin College of Pharmacy

University of Texas Health San Antonio

Pharmacotherapy Grand Rounds November 9, 2018

Objectives 1. Identify the epidemiology, risk factors, and diagnostic criteria for bipolar disorder2. Summarize the role of the purinergic system in the pathophysiology of bipolar disorder3. Analyze pertinent available literature for the use of allopurinol as adjunctive treatment for acute

bipolar mania4. Formulate an evidence-based recommendation concerning the use of allopurinol as adjunctive

treatment for acute bipolar mania

2 | D O N A T

Bipolar Disorder I. Definition

a. Bipolar disorder (BP) is a recurrent, cyclic mental disorder characterized by fluctuations in mood episodes1

i. Manic episodes ii. Hypomanic episodes iii. Depressive episodes

II. Epidemiology a. Bipolar disorder affects approximately 5.7 million adult Americans or about 2.8% of the

adult population2 b. Mean age of onset for bipolar disorder is 17 years2 c. An equal number of men and women develop bipolar I disorder, but more women are

affected by bipolar II3 d. It is the sixth leading cause of disability in the world and costs an estimated $45 billion

per year, mostly related to reduced functional capacity and loss of work 4 III. Risk factors

a. Environmental17 i. More common in high- income countries

ii. Separated, divorced, or widowed individuals have higher rates of bipolar I disorder

b. Genetics5,6,7 i. One of the most heritable psychiatric disorders

ii. Average two-fold increased risk among adult relatives of individuals with bipolar disorder

iii. Estimated 50% of patients have a family history of bipolar disorder iv. Many gene polymorphisms have also been implicated in development of bipolar

disorder IV. Clinical course

a. Average delay between illness onset and diagnosis is 5-10 years8 b. Most common comorbid diagnoses are anxiety disorders, substance use disorders,

personality disorders, and attention deficit/hyperactivity disorder (in children)9 c. Natural course of bipolar disorder often includes euthymic mood, but illness recurrence

is common, especially if adherence to treatment is poor10 d. Manic episodes have an average duration of 6 to 12 weeks, while depressive episodes

tend to last longer with an average duration of 11 to 20 weeks11,12 e. Factors contributing to a decreased probability of recovering from a mood episode

include cycling from one pole to another with no periods of euthymia and a high degree of comorbid conditions13

f. Suicide rates among people with bipolar disorder can be more than 20 times higher than the general population, especially when patients are untreated14,15,16

i. One third to one-half of patients with bipolar disorder attempt suicide in their lifetime with ~15-20% of attempts completed

ii. Risk factors for an attempt include: female sex, young age of onset, depressive polarity of current episode, comorbid anxiety, comorbid substance use, borderline personality disorder, and family history of suicide

3 | D O N A T

V. Diagnostic and Statistical Manual of Mental Health Disorders (5thed; DSM-5) Criteria a. Two subtypes:17

i. Bipolar I disorder A. At least one lifetime manic episode is required B. Hypomanic or depressive episodes may occur but are not required

ii. Bipolar II disorder A. At least one hypomanic episode and at least one major depressive

episode B. No history of manic episodes

b. Mood episodes17 Table 1. DSM-5 Criteria for Mood Episodes

Manic Episode § Period of at least 1 week (or any duration if hospitalization is necessary) of abnormal and

persistently elevated, expansive, or irritable mood and increased energy or goal-directed activity ≥ 3 symptoms (≥ 4 if mood is only irritable)

1. Inflated self-esteem or grandiosity 2. Decreased need for sleep 3. Increased quantity of speech or speech that is pressured 4. Flight of ideas or subjective racing thoughts 5. Easily distracted 6. Increase in goal-directed activity or psychomotor agitation 7. Engaging in activities that can result in detrimental outcomes (e.g., buying

sprees, risky/increased sexual behavior) § Causes significant social/occupational impairment, hospitalization is necessary, or psychotic

features are present

§ Not a result of substances or caused by other medical conditions

Hypomanic Episode § Period of at least 4 days of abnormal and persistently elevated, expansive, or irritable mood and

increased energy or goal-directed activity § Same criteria for number of symptoms as a manic episode § Does not cause significant social/occupational impairment, hospitalization is not required and no

psychotic symptoms are present Depressive Episode

§ Period of two weeks with depressed mood or loss of interest most of the day, nearly every day ≥5 symptoms 1. Depressed mood

2. Decreased interest in pleasure in daily activities 3. Significant changes in weight (weight loss or gain) 4. Significant changes in sleep (insomnia or hypersomnia) 5. Psychomotor agitation or retardation 6. Fatigue or decreased energy 7. Feelings of worthlessness or guilt 8. Decreased concentration 9. Thoughts of death or suicidal ideation

4 | D O N A T

VI. Standardized rating scales Table 2. Standardized Rating Scales for Mania in Bipolar Disorder Scale Name Description Interpretation Young Mania Rating Scale (YMRS)18,19

§ 11-item clinician rated scale

§ Used in research for screening and assessing symptom severity

Items are rated from 0 (none/absent) to 4 (most severe) Scoring: >25 = severe mania 19-24 = moderate mania <11 = euthymia Response: ³ 50% reduction in score Remission: £ 7

Clinical Global Impression Scale – Bipolar Version (CGI-BP)18,20

§ 3- item clinician rated scale

§ Used in research to provide a global rating of illness severity and to assess change from baseline or response to treatment

§ Item 1 – severity of illness from 1 (not ill) to 7 (very severely ill)

§ Item 2 – change from preceding phase

§ Item 3 – change from worst phase of illness from 1 (very much improved) to 7 (very much worse)

§ Items 2 & 3 can note whether score is for mania, depression, or overall BP illness

VII. Pathophysiology a. Relatively unknown and complex with many purposed theories18,21 b. Anatomical structures involved22,23,24,25

i. Amygdala – identifies emotionally relevant stimuli A. Hyperactivity can lead to emotional sensitivity

ii. Prefrontal cortex, basal ganglia, and dorsal anterior cingulate – relevant in emotional control

A. Diminished activity in the prefrontal cortex can interfere with planning and goal pursuit, leading to decreased ability to regulate emotions

B. Hyperactivity in the basal ganglia can contribute to increased reward and motivation

c. Other theories26 i. Widely believed that dysregulation in dopamine and serotonin have a role in the

interactions of deficits in other neurotransmitters, such as gamma-aminobutyric acid (GABA) and Substance P to produce symptoms of mood disorders

Table 3. Major Theories of Bipolar Disorder Pathophysiology Type of Theory Overview Dopamine (DA) dysregulation27,28 § Dysregulation of DA in nucleus acumbens, ventral

tegmentum, and striatum have been involved in increase in reward and motivation

5 | D O N A T

Type of Theory Overview Serotonin (5-HT) dysregulation26 § Decreased sensitivity of 5-HT receptors can lead to

mood disorders such as bipolar disorder but the nature of dysregulation is largely unknown

GABA dysregulation21 § Deficiency in GABA or excess in glutamate can cause changes in DA and norepinephrine levels leading to mania symptoms seen in bipolar disorder

Cyclic adenosine monophosphate/protein kinase A/ cAMP response element binding protein (cAMP/PKA/CREB pathway)29

§ G-protein coupled signal transduction pathways regulate the neuronal circuits modulating mood, appetite, and wakefulness

§ In bipolar disorder, increased concentrations of G-protein are found, leading to symptoms often seen in mania

d. Additional theories can be found in appendix A VIII. Acute mania treatment

a. Pharmacologic treatment i. Lithium (LI)

ii. Anticonvulsants A. Divalproex sodium (DVP) or valproic acid (VPA) B. Carbamazepine (CBZ) C. Oxcarbazepine (OXC)

iii. Antipsychotics A. Asenapine (ASE) B. Aripiprazole (ARI) C. Cariprazine (CAR) D. Paliperidone (PAL) E. Risperidone (RIS) F. Olanzapine (OLA)

G. Quetiapine (QUE) H. Haloperidol (HAL) I. Ziprasidone (ZIP) J. Clozapine (CLO) K. Chlorpromazine (CHL)

iv. Other

A. Clonazepam (CPM) B. Tamoxifen (TAM)

b. Nonpharmacologic treatment i. Electroconvulsive therapy (ECT)

c. Treatment guidelines30,31,32 i. Canadian Network for Mood and Anxiety Treatments (CANMAT)

ii. National Institute for Health and Care Excellence (NICE) iii. British Association of Psychopharmacology (BAP)

Table 4. Treatment Guidelines for Acute Mania Treatment Level of Intervention CANMAT- 201830 NICE- 201631 BAP- 201732 First- line Monotherapy:

LI, VPA, QUE, ASE, ARI, PAL, RIS, CAR Combination: QUE+ LI/VPA, ARI+ LI/VPA, RIS+LI/VPA, ASE+ LI/VPA

Monotherapy: HAL, OLA, RIS, QUE

Monotherapy: LI, VPA, CBZ, HAL, OLA, RIS, QUE, ARI

6 | D O N A T

Level of Intervention CANMAT- 201830 NICE- 201631 BAP- 201732 Second-line Monotherapy:

CBZ, OLA, ZIP, HAL Combination: OLA+ LI/VPA, LI+ VPA

Alternative first-line agent monotherapy

Monotherapy: CLO Combination: LI + VPA, LI + first-line antipsychotic Non-Pharm: ECT

Third-line CHL, CPM, CLO, TAM, CBZ/OXC +LI/VPA, HAL +LI/VPA

First-line agent +LI or VPA No specific recommendation

d. Limitations of current pharmacotherapy18,33 i. Lack of efficacy

A. Response rates for acute mania – reduction in YMRS of ³ 50% 1. Lithium: ~42 – 53% 2. Valproic acid: ~40 – 53% 3. Carbamazepine: ~40 – 61% 4. Aripiprazole: ~40 – 53% 5. Haloperidol: ~48 – 56% 6. Olanzapine: ~41 – 65% 7. Paliperidone: ~35 – 42% 8. Quetiapine: ~43 – 55% 9. Risperidone: ~43 – 74%

ii. Regular medication monitoring – see appendix B for monitoring specifics

iii. No drug has been developed to target specific pathophysiology of bipolar disorder

Role of the Purinergic System in Bipolar Disorder I. Purinergic system

a. The purinergic system is a signaling system where purine nucleotides ATP (adenosine 5’-triphosphate), ADP (adenosine diphosphate), and nucleoside, ADO (adenosine), act as extracellular messengers34,35

b. Uric acid is the end product of purine breakdown36

i. Plays a role in regulation of mood, motor activity, aggressive behavior, social interaction, sleep, and sexual drive

c. Increased uric acid levels (i.e. gout) results in decreased ADO availability35

Figure 1. Purinergic System

7 | D O N A T

d. ADO acts on many receptors including adenosine-1 (A1), 2a (A2A), 3 (A3) receptors35,36 i. A1 and A2A receptors control synaptic plasticity and the release of glutamate,

dopamine, and GABA ii. A3 receptor controls the serotonin and glutamate systems

e. A2A is co-located with dopamine- 2 (D2) receptors35,36 i. When A2A is agonized, D2 is antagonized ii. Caffeine is an adenosine receptor antagonist and increased intake can

pharmacodynamically antagonize adenosine’s effects II. Purinergic dysfunction hypothesis in bipolar disorder

a. Emil Kraeplin, founder of modern psychiatry, was the first to describe the association between mania symptoms, uric acid accumulation, and gout in 191336

b. In the 1940’s, John Cade found that while using lithium to treat gout, he observed that it exerted a calming effect on mood and suggested that mania was probably due to autointoxication of uric acid35

c. High serum levels of uric acid have been observed in the manic phase of bipolar disorder and have been associated with impulsivity, excited behavior, irritability, and overall increased severity of manic symptoms35

III. Mood stabilizers and purinergic system a. Carbamazepine can indirectly increase adenosine levels with chronic use35 b. Lithium and valproic acid have been hypothesized to upregulate purine- 2 (P2) receptors,

which may lead to neuroprotective effects35 Allopurinol

I. Chemical structure a. Structural analog of hypoxanthine37

II. FDA indications a. Gout37 b. Calcium oxalate renal stones37 c. Cancer therapy-induced hyperuricemia or tumor lysis

syndrome37 III. Mechanism of action

a. Acts by decreasing serum and urinary uric acid levels by inhibiting xanthine oxidase, which is the enzyme responsible for converting hypoxanthine to xanthine to uric acid37

b. Buildup of hypoxanthine caused by allopurinol is transformed into adenosine, guanosine and inosine via hypoxanthine-guanine-phosphorybosil-transferase (HGPRT)40

Figure 2. Allopurinol Chemical Structure

Figure 3. Mechanism of Action of Allopurinol

8 | D O N A T

IV. Clinical Considerations a. Dosing37

i. 100mg orally daily, increased by 100mg at weekly intervals ii. Doses > 300mg should be given in divided doses

iii. Max 800mg/day b. Administration37

i. Better tolerated if given after meals with a full glass of water and drink 8-10 glasses of water each day

c. Dose adjustments for renal impairment37 i. CrCl 10-20 mL/min: 200mg daily ii. CrCl 3-10 mL/min: do not exceed 100mg daily

iii. CrCl <3 mL/min: 100mg at extended intervals d. Adverse Effects37

i. Dermatologic: rash, Stevens- Johnson syndrome, Toxic epidermal necrolysis ii. Gastrointestinal: diarrhea, nausea

iii. Hematologic: agranulocytosis, aplastic anemia, thrombocytopenia, myelosuppression

iv. Hepatic: hepatotoxicity, hepatic necrosis, granulomatous hepatitis v. Immunologic: hypersensitivity vi. Renal: renal failure

e. Pharmacokinetics37 i. Absorption: 80 – 90% bioavailable ii. Metabolism: 70% via liver to active metabolite oxipurinol

iii. Elimination half-life: allopurinol 1-2 hours and oxipurinol 12-30 hours f. Monitoring37

i. Serum uric acid levels reference range: 2.9 – 8.6 mg/dL ii. Liver function tests: periodically with preexisting liver disease or if pruritus

develops iii. Renal function tests: periodically if renal impairment is present or if

concomitant conditions that affect renal function (hypertension, diabetes)

9 | D O N A T

Clinical Question & Evidence Review

CAN ALLOPURINOL BE USED AS AN EFFECTIVE ADJUNCTIVE TREATMENT FOR ACUTE MANIA?

Table 5. Jahangard L, Soroush S, Haghighi M, et al. In a double- blind, randomized and placebo-controlled trial, adjuvant allopurinol improved symptoms of mania in inpatients suffering from bipolar disorder. European Neuropsychopharmacology. 2014;24(8): 1210- 1221.36

Objectives To investigate, over a period of four weeks, the efficacy of allopurinol add-on in the treatment of patients suffering from bipolar I disorder and currently experiencing a manic episode

Methods Design Four-week, randomized, double-blind, placebo-controlled clinical trial

§ Single-center in Iran from May – December 2012 Patient Population Inclusion Exclusion

§ Ages 18-40 years old § Psychiatric Inpatients § Diagnosis of bipolar disorder I currently

experiencing a manic episode as defined by the DSM-IV

§ Baseline YMRS score of 28 points or higher § Primary treatment: sodium valproate ±

benzodiazepine (BZD)

§ Female patients who were pregnant, breast-feeding, or intending to get pregnant during the study period

§ History of allopurinol use § Co-morbid psychiatric disorders § Co-morbid diabetes, hypertension, hyper-

or hypothyroidism § Allergies to allopurinol

Intervention § All patients treated with sodium valproate (15- 20mg/kg) + BZD if needed § Randomized to receive either allopurinol 300mg twice per day (BID) or matching placebo § YMRS and CGI assessed at baseline and at the end of the first, second, third, and fourth weeks § Uric acid and VPA levels assessed at the beginning and end of the study § Patients reported any physical changes/ side effects due to medications at every assessment

time point Outcomes Primary Secondary

§ D YMRS § D CGI Statistical Analysis § Intention-to-treat analysis with the last observation carried forward (LOCF)

§ Chi square and single t-tests used for baseline characteristics § ANOVA for repeated measures used for YMRS and CGI § Post-hoc analysis performed with Bonferroni-Holm test § T-test and independent samples used for uric acid levels § Chi-square and odds ratio used for remission rates

Results Baseline

Characteristics

§ No significant difference in baseline characteristics were noted between groups

Table 6. Characteristics at baseline for allopurinol and placebo group Variable Allopurinol

N=30 Placebo

N=27 Age, yrs; mean (SD) 35.47 (12.52) 33.30 (10.33) Gender; m/f 19/11 16/11 Duration of illness, yrs; mean (SD)

8.62 (7.00) 9.82 (9.72)

Number of recurrent manic episodes, mean (SD)

3.27 (0.98) 3.19 (1.15)

History of drug use, yes/no 13/17 13/14 Adjunctive BZD, yes/no 23/7 18/9

10 | D O N A T

Outcomes

§ Time (T): YMRS scores decreased significantly over time in the allopurinol group as compared to placebo: p=0.000, h2 (effect size) = 0.93

§ Group (G): Scores differed between the two groups: p=0.001, h2= 0.18 § T x G: Lower YMRS scores in the allopurinol compared to the placebo group: p=0.010, h2= 0.076 § Post-hoc Bonferroni-Holm analysis showed there was no difference in YMRS at baseline but

differed significantly between groups from the end of week 1 to the end of week 4 Table 8. Secondary Outcome

Outcome/ grp Baseline mean (SD)

Wk 1 mean (SD)

Wk 2 mean (SD)

Wk 3 mean (SD)

Wk 4 mean (SD)

CGI severity scores Allopurinol 5.93 (0.64) 4.47 (0.63) 3.23 (0.68) 2.13 (0.73) 1.47 (0.57)

Placebo 6.11 (0.70) 4.93 (0.92) 4.00 (1.00) 3.26 (0.86) 2.67 (0.88) § T: CGI scores decreased significantly over time in the allopurinol group as compared to the

placebo group: p=0.000, h2= 0.297 § G: Scores differed between the two groups: p=0.000, h2= 0.297 § T x G: Lower CGI scores in the allopurinol compared to the placebo group: p=0.000 h2= 0.255 § Post-hoc Bonferroni-Holm analysis showed there was no difference in CGI severity at baseline

but differed significantly between groups from the end of week 1 to the end of week 4 Table 9. Uric Acid Levels

Group Baseline mean (SD)

Week 4 mean (SD)

Allopurinol 5.14 (1.16) 2.79 (1.16) Placebo 5.23 (1.48) 4.48 (1.33)

§ T: Uric Acid levels decreased significantly over time in the allopurinol group as compared to the placebo group: p=0.000, h2= 0.77

§ G: Uric acid levels were lower in the allopurinol group: p=0.007, h2= 0.12 § T x G: Lower uric acid levels in the allopurinol compared to the placebo group: p=0.00 h2= 0.464 § Difference of uric acid levels from baseline to end were significantly higher in the allopurinol

group; p= 0.000 § Baseline uric acid levels did not correlate with YMRS or CGI scores at any time point § Conversely, patients who experienced larger decreases in uric acid levels at the end of the study

were correlated with larger symptom improvements from the end of the first week to the end of the study

Table 10. Valproic acid levels (trough concentration) Group Baseline

mean (SD) Week 4

mean (SD) Allopurinol 66.51 (18.66) 73.43 (14.56)

Placebo 73.54 (41.40) 71.03 (18.57) § Valproic acid levels did not differ significantly between allopurinol or placebo group at baseline

or week 4 § Remission rates (YMRS score £ 7)

o End of week 1: no remitters o End of week 2: none in the allopurinol group and one remitter in the placebo group

Table 7. Primary Outcome Outcome/grp Baseline

mean (SD) Wk 1

mean (SD) Wk 2

mean (SD) Wk 3

mean (SD) Wk 4

mean (SD) YMRS scores

Allopurinol 35.83 (6.56) 23.47 (4.36) 15.23 (4.16) 9.73 (3.81) 6.40 (2.18) Placebo 36.26 (5.89) 27.67 (5.63) 19.63 (5.60) 14.26 (4.35) 10.85 (3.30)

11 | D O N A T

Outcomes o End of week 3: 8/30 in allopurinol and 1/27 in the placebo group § Chance of remission was 9.46 times higher in the allopurinol group; p=0.018

o End of week 4: 24/30 in allopurinol and 4/27 in the placebo group were remitters § Chance of remission was 23 times higher in the allopurinol group; p=0.00

§ Number needed to treat (NNT): o Week 3 remission rate = 4.4 o Week 4 remission rate = 1.5

§ Side effects: Gastritis and sedation were reported; not significantly different between groups Discussion

Author’s Conclusion

Data from this study suggests that add-on allopurinol to sodium valproate ameliorates the symptoms of mania in inpatients with bipolar disorder

Critique Strengths: § Double-blind, randomized, placebo-

controlled trial § 4-week follow-up § Measured uric acid levels – ensured

compliance § Measured VPA levels § Primary treatment was valproate

which theoretically may have synergistic effects with allopurinol

Limitations: § Occurred in Iran § Excluded patients with other comorbid psychiatric

disorders § Excluded patients with hypertension, diabetes,

hyper/hypothyroidism § Only included young patients (18-40 yrs) § Primary treatment was unclear prior to enrolling in

study § Not reported how valproate was adjusted based on

levels § Not specified how often BZDs were utilized in each

group § Did not assess caffeine use

Table 11. Machado- Vieira R, Soares J, Lara D, et al. A double-blind, randomized, placebo-controlled 4- week study on the efficacy and safety of the purinergic agents allopurinol and dipyridamole adjunctive to lithium in acute bipolar mania. Journal of Clinical Psychiatry. 2008; 69(8): 1237- 1245. 38

Objectives To evaluate the efficacy and tolerability of the purinergic agents allopurinol and dipyridamole combined with lithium in bipolar mania

Methods Design Four-week, randomized, double-blind, placebo-controlled, parallel-group inpatient clinical trial

§ Multi-center trial in Brazil from September 2003 – September 2006 Patient Population Inclusion Exclusion

§ Ages 18–65 years old § Psychiatric Inpatients § Bipolar I disorder with current

episode manic with or without psychotic features by the DSM-IV

§ Primary treatment: Lithium § ³ 22 on the YMRS at baseline

§ Substance abuse/dependence within 5 weeks of study

§ Taken any psychopharmacologic treatment 4 weeks before admission

§ Detectable blood lithium levels when enrolled § Rapid cycling in the past 12 months § Current mixed episode § Previous refractoriness to lithium § Current Axis I disorder other than BP § Clinically significant abnormal labs

Intervention

§ Randomized 1:1:1 to receive allopurinol, dipyridamole, or placebo in addition to lithium § Given 300mg BID of allopurinol or 200mg BID of dipyridamole; if pts were unable to tolerate the

former doses, they were terminated from the study § Lithium was dosed 600mg/day and after 7 days increased to 900mg/day, then flexible dosing to

achieve target level of 0.6 -1.2 mmol/L

12 | D O N A T

Intervention § Lithium levels were drawn at 7, 14, and 21 days § Concomitant as needed diazepam (max 20mg/day) was used for agitation except for 12- hours

prior to the application of rating scales § Outcomes were assessed at 7, 14, 21, and 28 days

Outcomes Primary Secondary § D YMRS § D CGI

Statistical Analysis § Intention-to-treat analysis § Difference between groups detected by one-way ANOVA with LOCF § Duncan post-hoc tests were used

Results Baseline

Characteristics

§ No significant difference in baseline characteristics were noted between groups

Table 12. Baseline Characteristics Variable Allopurinol

N=45 Dipyridamole

N=50 Placebo

N=46 Gender, female, n (%) 24 (53) 28 (56) 29 (63) Age, yrs; mean (SD) 26.9 (8.3) 29.3 (9.8) 29.3 (8.5) Duration of illness, yrs; mean (SD) 6.1 (5.3) 7.9 (8.2) 7.9 (7.5) No. of previous manic episodes, mean (SD) 4.0 (3.0) 3.0 (2.6) 3.1 (2.5) No. of hospitalizations, mean (SD) 3.6 (3.6) 3.2 (3.1) 3.1 (2.5) Psychosis, n (%) 21 (47) 22 (44) 21 (46)

Outcomes

Table 14. Secondary Outcomes

Outcome Allopurinol Dipyridamole Placebo P- value CGI Score, mean (SE) Baseline 5.4 (0.2) 5.2 (0.2) 5.1 (0.2) 0.84 Week 4 1.4 (0.2) 2.0 (0.2) 2.4 (0.2) <0.001 Uric Acid level, mean (SE) Baseline 4.8 (0.2) 4.7 (0.2) 4.7 (0.2) 0.89 Week 4 3.3 (0.2) 4.7 (0.2) 4.4 (0.2) <0.001 Serum Lithium Level, mean (SD) Week 4 0.98 (0.2) 0.99 (0.19) 0.95 (0.2) 0.61 Response rate, n (%) Week 3 36 (90) 30 (70) 22 (55) 0.002 Week 4 35 (92) 30 (73) 23 (74) 0.07 End (intent to treat- ITT) 37 (82) 31 (62) 29 (63) 0.06 Remission (YMRS score £ 12), n (%) Week 3 32 (80) 28 (65) 15 (38) 0.0004 Week 4 34 (90) 27 (66) 20 (65) 0.02 End (ITT) 37 (82) 28 (56) 25 (54) 0.008

Table 13. Primary Outcome Outcome Allopurinol Dipyridamole Placebo P value

YMRS, mean (SE- standard error) Baseline 34.2 (1.4) 34.2 (1.3) 33.8 (1.4) 0.96 Week 1 22.8 (1.4) 24.7 (1.3) 21.6 (1.4) 0.25 Week 2 15.1 (1.4) 17.7 (1.3) 17.5 (1.4) 0.34 Week 3 9.3 (1.4) 13.3 (1.4) 16.4 (1.4) 0.003 Week 4 6.3 (1.5) 11.7 (1.4) 12.8 (1.6) 0.005

13 | D O N A T

Outcomes Remission (YMRS score £ 7), n (%) Week 3 21 (53) 14 (33) 9 (23) 0.02 Week 4 27 (71) 21 (51) 14 (45) 0.07 End (ITT) 29 (64) 21 (42) 18 (39) 0.03

§ NNT: o End of study response rate: 5.2 o End of study remission rate (YMRS £ 12): 3.6 o End of study remission rate (YMRS £ 7): 4.0

§ Side effects: Most common were dizziness and diarrhea; not significantly different between groups

Discussion Author’s

Conclusion Allopurinol was shown to be an efficacious and well-tolerated antimanic agent when combined with lithium

Critique Strengths: § Multi-center, randomized, double-

blind, placebo-controlled, parallel- group inpatient clinical trial

§ 4-week follow-up § Obtained lithium and uric acid levels § Patients were treated with lithium,

which theoretically may have synergistic effect with allopurinol

Limitations: § Excluded pts with substance abuse § Excluded pts with another Axis I disorder § Excluded pts who have taken lithium and any other

psychotropic medication prior to the study § Unclear how lithium was managed based on levels § Not specified how often BZDs were utilized in each

group § Did not assess caffeine use

Table 15. Weiser M, Burshtein S, Gershon AA, et al. Allopurinol for mania: A randomized trial of allopurinol versus placebo as add-on treatment to mood stabilizers and/or antipsychotic agents in manic patients with bipolar disorder. Bipolar Disorders. 2014;16(4): 441- 447.37

Objectives To examine the efficacy of allopurinol as add-on treatment to mood stabilizers and/or antipsychotic agents in manic patients with bipolar disorder

Methods Design Six-week, randomized, double-blind, placebo-controlled clinical trial

§ Multi-center trial in Romania and Israel Patient Population Inclusion Exclusion

§ Ages 18- 65 years old § Psychiatric inpatients and outpatients § Diagnosis of bipolar I in a manic or mixed

episode by the DSM-IV § Treated with mood stabilizer +/-

antipsychotic for at least 3 days and up to 2 weeks

§ YMRS baseline score >17

§ Pregnant/ breast-feeding § Unstable medical conditions § Taking warfarin, amoxicillin, ampicillin,

theophylline, and mycophenolate mofetil § Allergy to allopurinol § Significant risk of suicide § Substance use disorder

Intervention § Randomized to receive either allopurinol 150 mg BID or identical cellulose capsule for 42 days and mood stabilizer +/- antipsychotic

§ Outcomes were assessed at baseline and at the end of the study

Outcomes Primary Secondary § D YMRS

§ D Clinical Global Impression for Bipolar Disorder (CGI-BP) § D Positive and Negative Syndrome Scale (PANSS) – see

appendix C

14 | D O N A T

Statistical Analysis § Sample size of 180 participants was needed to achieve 90% power with an effect size of 0.6 with an estimated 30% dropout rate

§ Intention to treat analysis § Within group changes over time were assessed using two-tailed paired t-tests § Between group changes were assessed using two-sample t-tests § Difference in change in score from baseline to last observation carried forward- LOCF endpoint § Secondary analysis from baseline to LOCF endpoint was assessed with mixed model linear

regression Results

Baseline Characteristics

§ No significant difference in baseline characteristics were noted between groups

Table 16. Baseline Characteristics Variable Allopurinol grp

N=90 Placebo grp

N=90 Gender, male, n (%) 29 (32.2) 30 (33.3)

Age, yrs; mean (SD) 47.6 (12.5) 45.8 (11.2)

Race, Caucasian, n (%) 90 (100) 90 (100) Lifetime alcohol abuse/dependence, n (%)

20 (22.7) 18 (20.2)

Lifetime drug abuse/dependence, n (%)

3 (3.33) 0 (0)

Outcomes

Table 18. Secondary Outcomes

Outcome Baseline mean (SD)

End of study mean (SD)

P-value Effect Size

CGI-BP overall Allopurinol 4.0 (1.1) 2.83 (1.21) 0.57 0.042 Placebo 4.0 (1.0) 2.93 (1.18) CGI-BP mania Allopurinol 4.2 (0.9) 2.95 (1.27) 0.5 0.049 Placebo 4.1 (0.8) 2.97 (1.19) CGI-BP depression Allopurinol 1.4 (0.9) 1.32 (0.53) 0.55 -0.048

Placebo 1.3 (0.8) 1.17 (0.50) Outcome Baseline End of study P-value Effect Size

PANSS Total Allopurinol 56.2 (17.0) 44.5 (10.45) 0.74 -0.025 Placebo 57.3 (14.7) 45.10 (9.94)

§ No difference in percentage of responders (³ 50% improvement in YMRS) o 37.8% in allopurinol group and 38.6% in placebo group

§ Side effects: Most common side effects were dizziness, anxiety, and nausea; not significantly different between groups

Table 17. Primary Outcome Outcome Baseline

mean (SD) End of study mean (SD)

P-value Effect Size

YMRS Allopurinol 25 (5.2) 14.40 (8.65) 0.78 0.023 Placebo 24.6 (5.6) 14.00 (8.56)

15 | D O N A T

Discussion Author’s

Conclusion The findings do not support a clinical role for allopurinol, at the dose tested, and as an add-on treatment for acute mania.

Critique Strengths: § Multi-center randomized,

double-blind, placebo-controlled clinical trial

§ Treated with mood stabilizers +/- antipsychotics

§ Adequately powered § 6-week follow-up

Limitations: § Did not specify which mood stabilizers or antipsychotics

used, doses used, or the break down between groups § No information on how the above medications were

monitored § Lower dose of allopurinol used § Did not assess uric acid levels – unknown if patients were

compliant § Excluded patients who took lithium § Excluded patients with substance abuse § Baseline YRMS scores were not as high as previous studies § Did not separate results into outpatient vs. inpatient § Did not assess caffeine use

Table 19. Summary of a Meta-analysis Chen A, Malmstrom T, Nasrallah H. Allopurinol augmentation in acute mania. A meta-analysis of placebo-controlled trials. Journal of Affective Disorders. 2018:226;245-250.40

Studies Included Sample Size (n) Allopurinol Dose Effect Size for Reduction in YMRS Score (Cohen’s d)

Weiser, et al. (2014)* 180 150mg BID 0.023 Jahangard, et al. (2012)* 57 300mg BID 0.742

Fan ,et al. (2012) 23 150mg BID then 300mg BID 0.250 Macho-Viera, et al. (2008)* 91 300mg BID 0.320 Akhondzadeh, et al. (2006) 75 150mg BID 0.561

Total -- -- 0.294 Other Conclusions § Uncontrolled caffeine usage may contribute to non-significant findings § Patients with older mean age were correlated with less efficacy, and there may be a possible threshold beyond which

allopurinol efficacy as adjunct may diminish o Older age may reflect longer duration of illness and/or increased number of lifetime episodes

§ Primary treatment may be associated with allopurinol efficacy o Studies using LI and VPA as primary treatment resulted in larger effect sizes, which may act through similar

mechanisms of action, and lead to synergistic effects § Choice of allopurinol dose used did not appear to influence the efficacy

*Studies included in this presentation

16 | D O N A T

Summary 1. Bipolar disorder is a recurrent, cyclic mental disorder characterized by fluctuations in mood

episodes, including mania 2. Although the pathophysiology behind mania is unknown, one proposed mechanism is the

dysregulation in the purinergic system 3. Uric acid is a byproduct of purine breakdown and leads to decreased adenosine, which may

contribute to bipolar mania symptoms through the purinergic system 4. Allopurinol is a xanthine oxidase inhibitor decreasing the production of uric acid levels, and its

use has been theorized to have a positive impact on bipolar mania outcomes when used in combination with other antimanic agents

Conclusions

1. Evidence suggests that allopurinol can be safely used as an adjunct to VPA or LI in acute bipolar mania although quality of evidence is somewhat low

2. Many limitations exist in the trials reviewed that limit generalizability to the United States (U.S.) population

a. All of the studies occurred outside of the U.S. b. Methods were heterogenous across all studies c. Mean ages were younger than 50 years old d. Exclusion criteria was strict

3. Negative study – Weiser, et al. a. Primary treatment used is seen more in clinical practice, but it was not well-defined

which medications were used in the trial and how they were managed b. Had many limitations that made it difficult to generalize to the U.S. population c. Highlights that allopurinol should be used as adjunctive to LI or VPA monotherapy in the

inpatient setting only 4. Overall, trials had high remission rates, low NNT, low to moderate effect sizes, and low side

effects – safe to use

Recommendations 1. No clinical reason to check baseline uric acid levels of everyone admitted for bipolar mania 2. May consider allopurinol adjunctive treatment in the following:

a. Inpatients meeting criteria for bipolar mania b. Age < 35 years old c. Primary treatment of LI or VPA d. Adequate response is not achieved after optimizing other recommended treatments

3. If adjunct allopurinol is used: a. Initiate at 150mg BID and may increase to 300mg BID after 1 week b. Duration of 4-6 weeks c. Monitor uric acid levels weekly

17 | D O N A T

References 1. Grande I, Berk M, Birmaher B, et al. Bipolar disorder. The Lancet. 2016;387(10027):1561-1572. 2. NIMH Bipolar Disorder [Internet]. Nimh.nih.gov. 2017 [cited 2018 Sep 24]. Available from:

https://www.nimh.nih.gov/health/statistics/bipolar-disorder.shtml 3. Hirschfeld R, Vornik L. Bipolar disorder [Internet]. AJMC. 2005 [cited 2018 Sep 24]. Available

from: https://www.ajmc.com/journals/supplement/2005/2005-06-vol11-n3suppl/jun05-2074ps85-s90

4. Bipolar disorder statistics [Internet]. Depression and Bipolar Support Alliance. Undated [cited 2018 Sep 24]. Available from: https://secure2.convio.net/dabsa/site/SPageServer/?pagename=education_statistics_bipolar_disorder

5. Belmaker R. Bipolar disorder. New England Journal of Medicine. 2004;351(5):476-486. 6. Plomin R, DeFries JC, McClearn GE, et al. Behavioral genetics. 3rd ed. New York, NY: W.H.

Freeman, 1997. 7. Craddock N, Sklar P. Genetics of bipolar disorder. The Lancet. 2013;381(9878):1654-1662. 8. Berk M, Dodd S, Callaly P, et al. History of illness prior to a diagnosis of bipolar disorder or

schizoaffective disorder. Journal of Affective Disorders. 2007;103(1-3):181-186. 9. Moreno C, Laje G, Blanco C, et al. National Trends in the Outpatient Diagnosis and Treatment of

Bipolar Disorder in Youth. Archives of General Psychiatry. 2007;64(9):1032. 10. Calabrese J, Vieta E, El-Mallakh R, et al. Mood state at study entry as predictor of the polarity of

relapse in bipolar disorder. Biological Psychiatry. 2004;56(12):957-963. 11. Tondo L, Vazquez G, Baldessarini R. Depression and mania in bipolar disorder. Current

Neuropharmacology. 2017;15(3):353-358. 12. Coryell W, Endicott J, Keller M. Outcome of patients with chronic affective disorder: A five-year

follow- up. American Journal of Psychiatry. 1990;147(12):1627-1633. 13. Solomon D, Leon A, Endoicott J, et al. Longitudinal course of bipolar I disorder. Archives of

General Psychiatry. 2010;67(4):339. 14. Pompili M, Gonda X, Serafini G, et al. Epidemiology of suicide in bipolar disorders: a systematic

review of the literature. Bipolar Disorders. 2013;15(5):457-490. 15. Gibbons R, Hur K, Brown C, et al. Relationship between antiepileptic drugs and suicide attempts

in patients with bipolar disorder. Archives of General Psychiatry. 2009;66(12):1354. 16. Schaffer A, Isometsa E, Tondo L, et al. International Society for Bipolar Disorders Task Force on

Suicide: meta-analyses and meta-regression of correlates of suicide attempts and suicide deaths in bipolar disorder. Bipolar Disorders. 2014;17(1):1-16.

17. American Psychiatric Association. Diagnostic and statistical manual of mental disorders (5th ed.). Arlington, VA: American Psychiatric Publishing; 2008.

18. 2018-2019 Psychiatric Pharmacotherapy Review. Lincoln, NE: College of Psychiatric and Neurologic Pharmacists; 2018.

19. Young R, Biggs J, Ziegler V, et al. A rating scale for mania: Reliability, validity and sensitivity. The British Journal of Psychiatry. 1978;133(5):429-435.

20. Spearing M, Post R, Leverich G, et al. Modification of the clinical global impressions (CGI) scale for use in bipolar illness (BP): The CGI-BP. Psychiatry Research. 1997;73(3):159-171.

21. Miklowitz D, Johnson S. The psychopathology and treatment of bipolar disorder. Annual Review of Clinical Psychology. 2006;2(1):199-235.

22. Krüger S, Seminowicz D, Goldapple K, et al. State and trait influences on mood regulation in bipolar disorder: Blood flow differences with an acute mood challenge. Biological Psychiatry. 2003;54(11):1274-1283.

23. Phillips M, Drevets W, Rauch S, et al. Neurobiology of emotion perception II: Implications for major psychiatric disorders. Biological Psychiatry. 2003;54(5):515-528.

18 | D O N A T

24. Mayberg H, Keightley M, Mahurin S, et al. Neuropsychiatric aspects of mood and affective disorders. Essentials of Neuropsychiatry and Clinical Neurosciences. Washington, DC: American Psychiatry Association; 2004. p. 489-517.

25. Knutson B, Adams C, Fong G, et al. Anticipation of increasing monetary reward selectively recruits nucleus accumbens. The Journal of Neuroscience. 2001;21(16):RC159-RC159.

26. Stockmeier C. Involvement of serotonin in depression: evidence from postmortem and imaging studies of serotonin receptors and the serotonin transporter. Journal of Psychiatric Research. 2003;37(5):357-373.

27. Naranjo C, Tremblay L, Busto U. The role of the brain reward system in depression. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2001;25(4):781-823.

28. Strakowski S, Sax K, Setters M, et al. Enhanced response to repeated d-amphetamine challenge: Evidence for behavioral sensitization in humans. Biological Psychiatry. 1996;40(9):872-880.

29. Dwivedi Y. Adenylyl cyclase-cyclic AMP signaling in mood disorders: Role of the crucial phosphorylating enzyme protein kinase A. Neuropsychiatric Disease and Treatment. 2008; 4(1):161-176.

30. Yatham L, Kennedy S, Parikh S, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disorders. 2018;20(2):97-170.

31. Bipolar disorder: Assessment and management [Internet]. National Institute for Health and Care Excellence (NICE). 2016 [cited 2018 Oct 10]. Available from: https://www.nice.org.uk/guidance/cg185

32. Goodwin G, Haddad P, Ferrier I, et al. Evidence-based guidelines for treating bipolar disorder: Revised third edition recommendations from the British Association for Psychopharmacology. Journal of Psychopharmacology. 2016;30(6):495-553.

33. Yildiz A, Vieta E, Leucht S, et al. Efficacy of antimanic treatments: Meta-analysis of randomized, controlled trials. Neuropsychopharmacology. 2010;36(2):375-389.

34. Offermanns S, Rosenthal W. Encyclopedia of Molecular Pharmacology. Berlin, Heidelberg: Springer Berlin Heidelberg; 2008.

35. Cheffer A, Castillo A, Corrêa-Velloso J, Gonçalves M, et al. Purinergic system in psychiatric diseases. Molecular Psychiatry. 2017;23(1):94-106.

36. Jahangard L, Soroush S, Haghighi M, et al. In a double-blind, randomized and placebo-controlled trial, adjuvant allopurinol improved symptoms of mania in in-patients suffering from bipolar disorder. European Neuropsychopharmacology. 2014;24(8):1210-1221.

37. Zyloprimâ [package insert]. Vaughn, Ontario: AA Pharma, Inc.; 2010. 38. Weiser M, Burshtein S, Gershon A, et al. Allopurinol for mania: A randomized trial of allopurinol

versus placebo as add-on treatment to mood stabilizers and/or antipsychotic agents in manic patients with bipolar disorder. Bipolar Disorders. 2014;16(4):441-447.

39. Machado-Vieira R, Soares J, Lara D, et al. A Double-Blind, Randomized, Placebo-Controlled 4-Week Study on the Efficacy and Safety of the Purinergic Agents Allopurinol and Dipyridamole Adjunctive to Lithium in Acute Bipolar Mania. The Journal of Clinical Psychiatry. 2008;69(8):1237-1245.

40. Chen A, Malmstrom T, Nasrallah H. Allopurinol augmentation in acute mania: A meta-analysis of placebo-controlled trials. Journal of Affective Disorders. 2018;226(9):245-25.

19 | D O N A T

Appendix A: Other Pathophysiologic Theories for Bipolar Disorder

Table 20. Other Major Theories of Bipolar Disorder Pathophysiology18,29

Type of Theory Overview Brain derived neurotrophic factor (BDNF) § Associated with promotion of neuronal growth and

synaptic plasticity § Regulates glutamate, GABA, DA, and 5-HT release § Polymorphisms are associated with greater disease

severity § Lithium & VPA enhances BDNF activity

Protein kinase C (PKC) § Excessive PKC lead to increase in impulsivity and altered judgment

§ Mood stabilizers attenuate PKC activity Calcium § Plays a critical role in modulation of neurotransmitters

and neuronal excitability § Calcium is involved in the phosphoinositide cycle,

lithium’s site of action § Lithium blocks calcium entry leading to normalized

neurotransmitter signaling Mitochondrial dysfunction

§ A number of genes implicated in the etiology of bipolar disorder also code for mitochondrial proteins

§ A reduction in these genes seen in bipolar disorder § Mitochondrial dysfunction can negatively impact

neuronal plasticity and promote apoptosis Appendix B: Mood Stabilizer Medication Monitoring

Table 21. Dosing and Monitoring for Mood Stabilizers18

Medication Dosing Monitoring Lithium Immediate Release (IR)

Initial: 300mg BID – TID Goal range: 1200 – 1800mg in 3 divided doses

Extended Release (ER) Initial: 450 – 600mg qHS Goal: 1200 – 1800mg in 2 divided doses

Serum level = 12 hours post dose Maintenance: 0.6 – 1.0 mEq/L Acute mania: 0.8 – 1.2 mEq/L

Valproic acid (IR)/ divalproex sodium (DR- delayed release and ER)

Initial: 20mg/kg/day may increase by 250mg based on serum level and response

Serum level = IR/DR: prior to the next dose ER: 12 hours post dose Target: 50 – 125 mcg/mL

20 | D O N A T

Appendix C: Positive and Negative Syndrome Scale (PANSS)

Table 22. Positive and Negative Syndrome Scale (PANSS)18 Description Values Interpretation

Clinician rated assessment to measure symptoms of psychosis during a 15- 30-minute interview

Each item on 7-point scale with 1= not present and 7=most severe Symptoms measured by clinician: tension, emotional withdrawal, posturing, motor retardation, excitement, disorientation, and uncooperativeness Symptoms measured through verbal report: conceptual disorganization, unusual thought content, anxiety, guilt, grandiosity, depressive mood, hostility, somatic concern, hallucinatory behavior, suspiciousness, and blunted affect

Scoring: ³ ~53= markedly ill ~32-52= moderately ill £ ~31= mildly ill Response= variable, generally 20-40% reduction in symptoms Remission= score of 3 or less for at least 6 months