minocycline for negative symptoms in...

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Minocycline for Negative Symptoms in Schizophrenia

Heather Murphy, PharmD PGY-2 Psychiatric Pharmacy Resident

Central Texas Veterans Health Care System Objectives -Review the diagnostic criteria, epidemiology, pathophysiology, and current treatments of schizophrenia -Describe the mechanism of action of minocycline in schizophrenia -Evaluate the current evidence of minocycline in schizophrenia -Formulate an evidence-based conclusion for minocycline use in schizophrenia

http://www.savagechickens.com/2009/04/schizophrenia.html

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I. Epidemiology of Schizophrenia1,2,3,4

a. Schizophrenia affects < 1% of the population b. Sex ratio differs across samples and populations c. Age of onset of first episode varies among men and women

i. Women: late 20s ii. Men: early to mid 20s

d. Life expectancy: expected to be 20-30 years shorter predominately due to suicide and cardiovascular disease

e. Direct and indirect costs estimated to be 10s of billions of dollars every year in the US alone

i. In US over 20% of all social security benefits are used for the care of patients with schizophrenia

Table 1: Risk Factors for schizophrenia2

Environmental Risks Neurodegenerative Theories

-prenatal exposure to virus -prenatal poor nutrition -perinatal hypoxia -psychotropic drug use -psychological stress -advanced paternal age -birth order -season of birth

-progressive loss of neuronal function -loss of dendrites -destruction of neuronal synapses -neuronal cell death

II. Diagnostic and Statistical Manual (DSM) Diagnostic Criteria3,4

a. DSM-IV-TR and DSM-V are largely the same with the exception of DSM-V increasing the number of symptoms required for a diagnosis and eliminating subtypes

b. Symptoms (sx) of schizophrenia include positive, negative, cognitive, aggressive, and affective

i. Positive and negative symptoms are included in diagnostic criteria whereas cognitive, aggressive, and affective are not

c. Changes from DSM-IV-TR to DSM-V criteria unlikely to influence study results, conclusions, and external validity

What is Schizophrenia?

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Table 2: DSM-IV-TR Diagnostic Criteria3,4

Schizophrenia a. One or more of the following (two or more in DSM-V) present for a

significant portion of the time during a 1 month period: i. Delusions

ii. Hallucinations iii. Disorganized speech iv. Disorganized or catatonic behavior v. Negative symptoms

b. Social and occupational dysfunction c. Signs and symptoms persist for at least 6 months d. Schizoaffective disorder and mood disorder with psychotic features

have been ruled out e. Symptoms are not attributable to a general medical condition or

substance use

Table 3: Symptoms of schizophrenia2

Positive Delusions, hallucinations, distortions/exaggerations in language and communication, disorganized speech, catatonic behavior, agitation

Negative Blunted affect, emotional withdrawal, poor rapport, passivity, apathetic, alogia, anhendonia, avolition, difficulty with abstract thinking, lack of spontaneity

Cognitive Difficulty: representing and maintaining goals, focusing/sustaining attention, information processing, prioritizing, problem solving

Affective Depressed or anxious mood, guilt, tension, irritability, worry Aggressive Overt hostility, self-injurious behavior, impulsivity

III. Pathophysiology of schizophrenia a. Dopamine (DA)2

i. Nigrostriatal Pathway: decreased DA extrapyramidal symptoms (EPS) and tardive dyskinesia

ii. Mesolimbic Pathway: increased DA positive sx and possibly aggressive sx

iii. Mesocortical Pathway: decreased DA negative, cognitive, affective sx

iv. Tuberoinfandibular Pathway: decreased DA hyperprolactinemia

b. Glutamate2 i. Decreased glutamate can have downstream effects causing DA

hyperactivity in the mesolimbic pathway and hypoactivity in the mesocortical pathway

c. Inflammatory Pathway5 i. Microglia have been shown to be more activated in

schizophrenia

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1. Microglia: macrophage cells of the central nervous system that regulate immune reactivity

a. Regulate cellular repair, and recruit immune cells into the brain for clearance of infection or cellular debris

b. Chronic or exaggerated microglial activation excessive secretion of pro-inflammatory factors

ii. Increase in pro-inflammatory factors 1. Interleukin-6, interleukin-1β, tumor necrosis factor-α,

free radicals, nitric oxide

IV. Current treatment options6-9 a. The selection of an antipsychotic medication is frequently guided by

the patient’s previous experience with antipsychotics, including the degree of symptom response, past experience of side effects, and preferred route of medication administration

i. First generation antipsychotics (FGAs) 1. Primarily antagonize D2 receptors positive sx

ii. Second generation antipsychotics (SGAs) 1. Have affinity for multiple receptors positive and

negative sx b. There are no guideline recommendations for the treatment of

negative symptoms Table 4: Antipsychotic Agents First Generation Antipsychotics Second Generation Antipsychotics Thorazine® Chlorpromazine Solian® Amisulpride* Prolixin® Fluphenazine Abilify® Aripiprazole Haldol® Haloperidol Saphris® Asenapine Trilafon® Perphenazine Clozaril® Clozapine Mellaril® Thioridazine Fanapt® Iloperidone Stelazine® Trifluoperazine Latuda® Lurasidone Zyprexa® Olanzapine Invega® Paliperidone

Lullan® Perospirone* Seroquel® Quetiapine Risperdal® Risperidone Geodon® Ziprasidone

*Not approved in the United States

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Table 5: Antipsychotic Guideline/Algorithm Recommendations APA6 TMAP7 IPAP8 PORT9

1st Episode SGA SGA SGA SGA (other than clozapine and olanzapine) or FGA

2nd Episode SGA, FGA, Clozapine

SGA, FGA SGA SGA, FGA

3rd Episode Clozapine Clozapine Clozapine Clozapine 6American Psychiatric Association, 7Texas Medication Algorithm Project, 8International psychopharmacology Algorithm Project, 9Patient Outcomes Research Team Table 6: Minocycline10-14

Description Broad spectrum, second generation, lipophilic, tetracycline antibiotic FDA indications

Acne, chlamydia, gonorrhea, meningitis, prosthetic joint infection, syphilis

Unlabeled uses Rheumatoid arthritis, cellulitis Research Huntington’s disease, Parkinson’s disease, schizophrenia, amyotrophic

lateral sclerosis Mechanism of action

Inhibits 30s ribosomal protein synthesis in susceptible bacteria

Adult Dose 100-200mg/day depending on indication Max dose=400mg/day

Absorption Well absorbed orally Protein binding 70-75% Metabolism Hepatic to inactive metabolites Half-life Oral ranges from 11-22 hours Excretion Urine, feces Renal impairment

CrCl <80 ml/min dose not to exceed 200mg/day

Hepatic impairment

Use with caution- no specific dose recommendations

Pregnancy category

D

Safety Tooth discoloration, hepatic effects, autoimmune syndromes, CNS effects, tissue hyperpigmentation, hypersensitivity reactions

V. Minocycline’s role in schizophrenia15-17 a. Glutamate effects

i. Pathway: damaged glutamate NMDA receptors impaired glutamate transmission hypoglutamatergic states

ii. Minocycline: enhances NMDA receptor activation

Why Minocycline?

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b. Microglia activation i. Pathway: increased microglia activation increase in pro-

inflammatory factors ii. Minocycline: inhibits microglia activation

c. Apoptotic effects i. Pathway: vulnerability of apoptosis increased in schizophrenia

ii. Minocycline: reduces apoptosis in neuronal cells d. Antioxidant properties and free radical scavenger

i. Pathway: Oxidative stress increases in reactive species cellular dysfunction decreased antioxidant levels

ii. Minocycline: prevent increases in production of reactive species

Possible Antipsychotic Effects of Minocycline in Schizophrenia Miyoaka T et al. Progress in Neuro-psychopharmacol and Bio Psych (2007)18

Intervention: Minocycline 150mg/day added to current therapy 23 year old male with catatonic schizophrenia Treatment: haloperidol 4-20mg/day

Presentation: Auditory hallucinations, delusions, psychomotor excitement, catatonic stupor, and deterioration in the level of social functioning

First 2 weeks: -PANSS total score: 40 10 (75% Δ) 1 week no minocycline -PANSS total score: 10 38 (74% Δ) Minocycline added back -PANSS total score: 38 10 (66% Δ)

60 year old male with schizophrenia Treatment: risperidone 2mg/day and haloperidol 10mg/day

Presentation: Psychomotor excitement, catatonic stupor, and negativism

First 2 weeks: -PANSS total score: 30 10 (75% Δ) 1 week no minocycline -PANSS total score: 10 40 (75% Δ) Minocycline added back -PANSS total score: 40 7 (83% Δ)

Literature Review

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Adjunctive Minocycline to Clozapine Treated Patients with Persistent Schizophrenia Symptoms

Kelly DL et al. Schizophrenia Research (2011)19

Intervention: Minocycline 100mg BID added to clozapine 36 year old male with catatonic schizophrenia Treatment: clozapine

Presentation: Delusional thinking, socially withdrawn, flat affect, poor concentration

First month: gradual and notable improvements in delusions and positive symptoms First 10 weeks: -BPRS total score: 56 52 (7% Δ) -SANS total score: 76 62 (18% Δ) After 4 years pt is discharged and doing well in the community

26 year old male with schizophrenia Treatment: clozapine

Presentation: Auditory and visual hallucinations, severely distressing feelings of external control and thought broadcasting, delusions, and moderately severe emotional withdrawal, affective blunting, and poverty of speech.

First 16 weeks -BRPS total score: 68 57 (17% Δ) Improvements in positive, negative, and depressive symptoms -SANS total score: 54 44 (19% Δ) -Calgary Depression Scale total score : 11 4 (64% Δ)

Successful use of Add-on Minocycline for Treatment of Persistent Negative Symptoms in Schizophrenia

Jhamnani K et al. J Neurophschiatry Clin Neuro Sci (2013)20

Intervention: Minocycline 100mg/day added to current treatment 25 year old male with undifferentiated schizophrenia Treatment: clozapine, amisulpride

Presentation: Occupational dysfunction, persistent negative sx: amotivation, alogia, anhedonia, apathy, affective blunting, and attention deficits

3 months -SANS: 89 62 (30% Δ) -Improvement in occupational functionality

23 year old female with paranoid schizophrenia Treatment: aripiprazole

Presentation: Attention/concentration difficulties, asociality x 1 year Positive sx in remission

2 months • SANS: 26 21 (19% Δ) • Improvement in attention,

concentration, social interaction

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Minocycline as Adjunctive Therapy for Schizophrenia: An Open-Label Study

Miyaoka T, et al. Clin Neuropharmacol (2008) 31: 287-292.21

Study Goal To examine the adjuvant therapeutic effect of minocycline added to stable regimens of antipsychotic medication

Design Open-label trial with patients arbitrarily picked for inclusion Inclusion Criteria DSM-IV diagnosis of schizophrenia

Treatment resistant patients or patients not responding adequately to current therapy Exclusion Criteria None reported Patient Enrollment 22 patients were included Treatment Minocycline treatment was initiated and titrated: 100 mg orally BID for the first week, and

150 mg orally TID from weeks 2 through 4. Primary Outcome Change in PANSS score Statistical Analysis Analysis of variance with post hoc Bonferroni protected least significant difference was

used to test for differences in PANSS scores Level of statistical significance was p<0.05

Results Table 7: Baseline Demographics Patient Characteristics (n=22)

Male 14 Age (years) 31.2 ± 5.5 Duration of illness (years) 3.4 ± 2.3 Antipsychotic Risperidone Quetiapine Perospirone Olanzapine

10 8 2 2

PANSS Positive Negative General

37.8 ± 7.0 32.6 ± 9.7 56.3 ± 16

Primary Outcome PANSS positive symptoms subscale score was reduced at 4 weeks and 8 weeks

o 4 weeks: mean score=14.5 ± 5.0 (p<0.0001) 61.6% change from baseline


PANSS negative symptoms subscale score was reduced at 4 weeks and 8 weeks o 4 weeks: mean score=14.4 ± 5.3 (p<0.0001)

55.8% change from baseline o 8 weeks: mean score=14.1 ± 4.9 (p<0.0001)

57.2% change from baseline PANSS general subscale score was reduced at 4 weeks and 8 weeks


o 8 weeks: mean score=25.6± 9.4 (p<0.0001) 54.5% change from baseline

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Author’s Conclusion

Adjunctive minocycline treatment of schizophrenia showed improvement in all PANSS subscales and presented preliminary evidence that minocycline may have a potential role in the treatment of schizophrenia

Reviewer’s Conclusion

Strengths of the study include PANSS scoring and IRB approval Limitations of the study include open-label study design, lack on control group, short

trial duration, and lack of external validity

A Double-Blind, Randomized Study of Minocycline for the Treatment of Negative and Cognitive Symptoms in Early-Phase Schizophrenia

Levkovitz Y, et al. J Clin Psychiatry. (2010) 71:138-149.22

Study Goal To examine the efficacy of minocycline added to stable regimens of antipsychotic medication for alleviating negative and cognitive symptoms in early phase schizophrenia

Design Longitudinal, double-blind, randomized, placebo-controlled, intention-to-treat trial Inclusion Criteria

Age 18-35 years DSM- IV diagnosis of schizophrenia <5 years of neuroleptic tx No AP tx within past 6 months of current sx exacerbation PANSS baseline >60 Initiated on AP <14 days prior to study entry Comprehension of study procedure and aims

Exclusion Criteria

Acute, unstable, significant, or untreated medical illness other than schizophrenia Pregnant or breastfeeding DSM-IV diagnosis of substance abuse or dependency Known contraindication to minocycline Had received treatment with minocycline or β-lactam <6 months prior to study entry Under compulsory hospitalization

Patient Enrollment

Treatment Minocycline 200mg/day added to antipsychotic therapy Primary Outcome

Change in SANS

Statistical Analysis

Baseline demographic were evaluated using chi-square or t-test ANOVA was used for between-subjects factors of treatment

Assessed for eligibility (n=137

Did not meet inclusion criteria

(n=67)

Participation in 2 week lead-in phase (n=70)

Drop out

(n=16)

Randomization

(n=54)

Placebo (n=18)

Minocycline (n=36)

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Results Table 8: Baseline Demographics

Measure Minocycline Placebo

Study Total

(n=36)

Completers

(n=13)

Study Total (n=18) Completers

(n=8)

Age 25.1 ± 4.77 24.8 ± 4.01 24.7 ± 4.24 25.5 ± 4.06

Male 25 (69%) 10 (76.9%) 15 (83%) 7 (87.5%)

Age at 1st

episode 21.4 ± 4.3 21.1 ± 3.5 20.9 ± 4.54 22.6 ± 5

Antipsychotic

Olanzapine

Quetiapine

Risperidone

Clozapine

16 (45.7%)

2 (5.7%)

9 (25.7%)

7 (19.4%)

4 (30.8%)

0

4 (30.8%)

4 (30.8%)

5 (27.8%)

1 (5.6%)

11 (61.1%)

1 (5.6%)

3 (37.5%)

0

3 (37.5%)

1 (12.5%)

Minocycline SANS= 32.6 ± 19.6 (p<0.0001)

o 23% change from baseline Placebo SANS=41.6 ± 17.9

o 4% change from baseline Safety Outcome

No patients discontinued medication in placebo group Mild pigmentation was observed in one patient in minocycline group


Minocycline treatment was associated with improvement in negative symptoms and executive function


Strengths of the study include study design, intention to treat, IRB approved Limitations of the study include small sample size, high dropout rate, and lack of external

validity

Minocycline Benefits Negative Symptoms in Early Schizophrenia: A Randomized Double-Blind Placebo Controlled Trial in Patients on Standard Treatment

Chaudhry IB, et al. J Psychopharmacol. 2012;26:1185–1193.23

Study Goal To determine whether the addition of minocycline to treatment as usual (TAU): 1. Prevents the accumulation of negative symptoms 2. Prevents cognitive decline following a first episode of non-affective psychosis 3. Stabilizes the efficacy of antipsychotics

Design Multicenter, double-blind, randomized, placebo-controlled, intention-to-treat trial Inclusion Criteria

In patients and out patients aged 18–65 years DSM-IV diagnosis of schizophrenia, schizoaffective disorder, psychosis not otherwise specified

or schizophreniform disorder within first 5 years of diagnosis Competent and willing to give informed consent Stable on medication 4 weeks prior to baseline and able to take oral medication If female, willing to use adequate contraceptive precautions and to have monthly pregnancy

tests

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Exclusion Criteria

Relevant medical illness (renal, hepatic, cardiac, serious dermatological disorders such as exfoliative dermatitis, systemic lupus erythematosis)

Prior history of intolerance to any of the tetracyclines Concomitant penicillin therapy, anticoagulant therapy, VPA therapy Presence of a seizure disorder, not including clozapine-induced seizures Any change of psychotropic medications within the previous 6 weeks Diagnosis of substance abuse (except nicotine or caffeine) or dependence within the last 3

months according to DSM-IV criteria Pregnant/breast-feeding

Patient Enrollment

Treatment Minocycline or matching placebo was administered in 50 mg increments over an 8-week period up to a total dose of 200 mg daily, taken as a single dose to encourage compliance

Primary Outcome

Change in PANSS score

Secondary Outcomes

Clinical Outcomes: change in CGI score, GAF score, and AIMS Cognitive outcomes: IQ sub-tests, tests of executive function, learning and memory tasks, and five tests from the CANTAB


A sample size of 40 in each group would have 85% power to detect a difference in means of 4.0 using a two-group t-test with a 0.05 two-sided significance level

Results Table 9: Baseline Demographics

Measure Pakistan Brazil Both

Minocycline

(n=56)

Placebo

(n=58)

Minocycline

(n=15)

Placebo

(n=15)

Minocycline

(n= 71)

Placebo

(n=73)

Male Not Reported 41 (57.7%) 45 (61.6%)

Age Not Reported 25.9 ± 7.1 26.6 ± 8.3

PANSS

Negative

Positive

General

Total

22.3 ± 8.1

19 ± 7.3

41 ± 9.6

82.2 ± 21.5

22.5 ± 6.5

19 ± 5.5

42.4 ± 12

83.8 ± 20.6

23.1 ± 8.6

11.4 ± 4.7

28.5 ± 7.2

63 ± 17.2

17.8 ± 6.5

11.9 ± 4.8

28.3 ± 8

57.9 ± 13

Not

Reported

Not Reported

Assessed for eligibility (n=198)

Did not meet inclusion criteria

(n=54)

Randomization (n=144)

Minocycline

(n=71)

Drop out

(n=27)

Analyzed

(n=46)

Placebo

(n=73)

Drop out

(n=27)

Analyzed

(n=48)

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Table 10: Primary Outcome Results

PANSS Pakistan Brazil

Minocycline Placebo Minocycline Placebo

6 Months

Negative

Positive

General

Total

(n=30)

16.5 ± 5.2

13.6 ± 4.1

31.5 ± 10.1

61.7 ± 17.6

(n=34)

18.5 ± 5.8

15 ± 5.8

33.6 ± 11

67.4 ± 21.1

(n=13)

16.5 ± 5.6

8.5 ± 2.5

21.8 ± 4.6

46.7 ± 10.3

(n=11)

18.1 ± 7.5

13.6 ± 7.4

28.8 ± 8.46

60.5 ± 20.1

12 Months

Negative

Positive

General

Total

(n=33)

15.5 ± 9.2

12.7 ± 6.3

29.4 ± 12.5

57.7 ± 26.5

(n=37)

16.5 ± 5.2

13.6 ± 4.1

31.5 ± 10.1

61.7 ± 17.6

(n=13)

13.8 ± 6.5

8 ± 1.9

19.7 ± 4

41.5 ± 10.8

(n=11)

18.5 ± 7.2

12.9 ± 5.5

31.2 ± 8.5

62.6 ± 18.1

Mean improvement in negative symptoms: Minocycline=9.2 versus placebo= 4.7 Adjusted difference of 3.53±1.01 95% CI: 1.55-5.51 Secondary Outcome Results Clinical outcomes: statistically significant difference in AIMS scores favoring minocycline

therapy adjusted difference of 0.9±0.41 95% CI: 0.09-1.71 Cognitive outcomes: no statistically significant differences

Safety Outcome

Table 11: Safety Results Minocycline (n=71) Placebo (n=73) Nausea/Vomiting/Anorexia 28 16 Headache 9 17 Dizziness 4 14 Skin/Tooth discoloration 3 3 EPS 0 2


The addition of minocycline to treatment as usual in the early course of schizophrenia predominately improves negative symptoms


Strengths of the study include study design, intention to treat, and meeting power Limitations of the study include small sample size, antipsychotic treatment not reported or

controlled, reporting data separate for each country, power analysis did not include clinically significant change in PANSS score

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A Randomized Trial Administering Aspirin, Minocycline or Pramipexole vs Placebo as Add-on to Antipsychotics in Patients with Schizophrenia or Schizoeffective Disorder.

Weiser M, et al. Abstract. 2012.24 Study Goal To test the inflammatory process and elaborate on the dopamine hypothesis in schizophrenia Design Multicenter, randomized, placebo control trial Inclusion Criteria

CGI-S score >4 PANSS negative sx score >18

Exclusion Criteria

Not reported

Patient Enrollment/ Treatment

400 patients were included to be randomized to one treatment arm: Aspirin 1000mg/day + pantoprazole 40mg/day Minocycline 200mg/day Pramipexole 1.5mg Placebo

Primary Outcomes

Mean change in PANSS

Secondary Outcomes

Change in PANSS subscores and CGI


ANOVA for overall change in symptoms

Results ANOVA for overall change in PANSS total score for comparison of 3 drugs and placebo o p= 0.03

Placebo versus aspirin o Effect size= 0.26, p= 0.056

Placebo versus minocycline o Effect size= -0.14, p= 0.328

Placebo versus prampexole o Effect size= 0.01, p=0.952

Table 12: Secondary Outcome Results

Placebo vs: PANSS Positive Symptoms

PANSS Negative Symptoms

PANSS General Symptoms

CGI Score

Aspirin ES= 0.24 p= 0.079

ES= 0.07 p= 0.586

ES= 0.31 p= 0.04

ES= 0.23 p= 0.102

Minocycline ES= 0.04 p=0.771

ES= -0.93 p=0.095

ES= -0.16 p=0.307

ES= -0.24 p=0.107

Pramipexole ES= -0.11 p=0.451

ES= 0.06 p=0.451

ES= -0.05 p=0.717

ES= 0.04 p=0.799

Overall p= 0.0842 p= 0.0995 p= 0.0214 p= 0.0140 ES= effect size Bold= statistically significant


The overall ANOVA for PANSS total was significant, however post-hoc analyses were only significant at a trend level for aspirin, uncorrected for multiple comparisons

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Efficacy of Anti-Inflammatory Agents to Improve Symptoms in Patients with Schizophrenia: An Update

Schizophr Bull. 2013 [Epub ahead of print]25

Study Goal To provide an update of the efficacy of different types of anti-inflammatory agents, given in augmentation to standard treatment, to improve symptom severity in patients with schizophrenia

Design Meta-analysis Inclusion Criteria

Randomized, double-blind, placebo-controlled studies regarding augmentation of antipsychotic medication with an anti-inflammatory agent

Patients included had a diagnosis of a schizophrenia spectrum disorders (schizophrenia, schizophreniform disorder, or schizoaffective disorder), according to the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders (DSM-III, DSMIII-R, DSM-IV, and DSM-IV-TR or International Classification of Diseases, 9th or 10th Revision).

Studies reported sufficient information to compute common effect size statistics of change scores

Exclusion Criteria

Studies providing only posttreatment data Crossover studies

Literature Search

Electronic search using PubMed, Embase, the National Institutes of Health web site http://www.clinicaltrials.gov, Cochrane Schizophrenia Group entries in PsiTri, and the Cochrane Database of Systematic Reviews

Treatment Anti-inflammatory agents included: aspirin, celecoxib, cytostatics, davunetide, estrogens, fatty acids, leptin, macrolides/tetracyclines, melatonin, minocycline, monoclonal antibodies, n-acetylcystine, corticosteroids, transplantation adjuncts

Primary Outcome

Mean change in PANSS or BPRS


Standardized differences were calculated from the mean differences (placebo vs augmentation) of the change score (end of treatment minus baseline) means and SDs

Hedges’s g was used to quantify the mean standardized differences of combined studies using a random model

I2 was calculated to test whether the studies could be taken together to share a common population effect size

Mean standardized differences with a p<0.05 were considered significant Results Minocycline

3 studies were included: All used a relatively high dose of 200 mg and long duration of treatment, ranging from 4-12

months Levkovitz et al and Chaudhry et al included only first episode psychosis Chaudhry et al study consisted of 2 smaller trials performed in Pakistan and Brazil presented

separately Weiser et al is not published yet, data are used from an abstract Combined in meta-analysis: Mean weighted effect was 0.22 (95% CI: −0.39 to 0.82) I2 = 83%


Minocycline did not show efficacy on symptom severity of schizophrenia, however further trials are needed


I2 >50% limiting a reliable interpretation of the results

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Schizophrenia is a complex disease state with many potential pathophysiological causes

Current treatments are more effective at reducing positive symptoms compared to negative symptoms

Preliminary evidence suggests minocycline may have a role in the treatment of schizophrenia

Further research is needed to determine minocycline’s place in therapy

Content Critique: Lisa Mican, PharmD

Style Critique: TBD

Primary Reviewer: Mina Mehvar, PharmD

Addition Reviewers: Emily Czeck, PharmD Katerine Getchell, PharmD

Conclusions

Acknowledgments

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32. Robbins TW, James M, Owen AM, et al. A study of performance on tests from the CANTAB battery sensitive to frontal lobe dysfunction in a large sample of normal volunteers: Implications for theories of executive functioning and cognitive aging. Journal of the International Neuropsychological Society 1998;4: 474-490.

33. Goldman HH, Skodol AE, Lave TR. Revising Axis X for DSM-IV: A review of measures of social functioning. American Journal of Psychiatry. 1992; 149: 1148-1156.

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Scale for Assessment of Negative Symptoms (SANS)26 o Used to measure negative symptoms in schizophrenia split into 5

domains, and within each domain separate symptoms are rated from 0 (absent) to 5 (severe)

o Response is variable however a percentage improvement has not been consistently used in the literature to define a response

Positive and Negative Syndrome Scale (PANSS)27 o Validated 30-item clinician administered rating scale used to assess the

effects of drug treatment in schizophrenia o Assess positive, negative, and general psychopathology symptoms rated

on a scale of 1 to 7: “not present” to “extremely severe” o Response is variable: generally 20-30% reduction

Clinical Global Impression (CGI)27 o Provides an overall clinician-determined summary measure that takes

into account all available information, including a knowledge of the patient's history, psychosocial circumstances, symptoms, behavior, and the impact of the symptoms on the patient's ability to function.

o Response is variable but generally much improved to very much improved indicates response

Brief Psychiatric Rating Scale (BPRS)28 o One of the oldest, widely used clinician administered scales to measure

psychotic symptoms rated on a scale of 1 to 7: “not present” to “most severe”

o Response is variable: generally 20-40% reduction Global Assessment of Functioning (GAF)29

o Clinician rated, functional assessment scale rated 1 (most impaired) to 100 (healthiest)

o Response is variable Calgary Depression Scale for Schizophrenia30

o Clinician rated assessment scale for depressive symptoms o Assesses depressive symptoms in schizophrenia separate from that

related to positive, negative, and EPS o Score above 6 has an 82% specificity and 85% sensitivity for predicting

presence of major depressive episode Abnormal Involuntary Movement Scale (AIMS)31

o Clinician rated scale used to assess for dyskinesias such as tardive dyskinesia

o Not a diagnostic tool but provides ratings that can be used in diagnostic criteria

o 12 item scale rated on a continuum of 0 (none) to 4 (severe) o Response is not defined

Appendix A- Rating Scales

Murphy 19

Cambridge Neuropsychological Test Automated Battery (CANTAB)32 o Computer-based cognitive assessment system consisting of a battery of

neuropsychological tests, administered to subjects using a touch screen computer.

o Consists of 22 tests that examine various areas of cognitive function including:

General memory and learning Working memory and executive function Visual memory Attention and reaction time Semantic/verbal memory Decision making and response control

o Response is variable Social and Occupational Functioning Assessment Scale (SOFAS)33

o Clinician rated scale that considers social and occupational functioning on a continuum from excellent functioning to grossly impaired functioning

o Includes impairments in functioning due to physical limitations, as well as those due to mental impairments

o Impairment must be a direct consequence of mental and physical health problems

o Response is variable

AIMS= Abnormal Involuntary Movement Scale AP=antipsychotic APA= American Psychiatric Association CGI=Clinical Global Impression Scale DA=dopamine DSM=Diagnostic and Statistical Manual EPS=extrapyramidal symptoms ES=effect size FGA=first generation antipsychotic GAF=Global Assessment of Functioning I2=homogeneity statistic IPAP= International psychopharmacology Algorithm Project PANSS=Positive and Negative Syndrome Scale PORT=Patient Outcomes Research Team SANS=Scale for Assessment of Negative Symptoms SGA=second generation antipsychotic SOFAS= Social and Occupational Functioning Assessment Scale Sx=symptoms TAU=treatment as usual TMAP=Texas Medication Algorithm Project

Appendix B- Abbreviations

minocycline for negative symptoms in...

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