Background

Development of Anxiety Among Depressed Veterans After Antidepressant UsageZhiguo Li, Paul Pfeiffer, Katherine Hoggatt, Kara Zivin, Karen Downing and Marcia Valenstein

SMITREC, Department of Veteran Affairs and University of Michigan, Ann Arbor, MI

Suicide is the 11th leading cause of death in USA, which is recognized as a key public health problem that needs a national strategy for prevention.

Suicide is a complex, multi-determined phenomenon, with biological and physiological contributors, as well as social, environmental and economical factors.

People with psychiatric disorders, especially depressive disorders, are at higher risks for suicide.

Although antidepressant medications reduce depressive symptoms, concerns have re-emerged that antidepressant treatment might increase rather than decrease suicide risks, particularly during treatment initiation or dosage change.

Previous studies also show that people with anxiety disorders are also at higher risks for suicide.

It is important to determine risk factors for anxiety development among depressed patients after antidepressant initiation.

Purpose of the study

Examine antidepressant (specific agents) as risk factors of anxiety development among depressed veterans after antidepressant initiation.

Antidepressants of interest: four of the most commonly prescribed agents within the SSRI (selective serotonin reuptake inhibitors) class: fluoxetine, citalopram, paroxetine, sertraline, three of the most commonly prescribed alternative antidepressants: bupropion, mirtazapine and venlafaxine.

Other potential risk factors: age, gender, race, ethnicity, comorbid psychiatric disorders --- personality disorder, substance abuse, PTSD (post traumatic stress disorder), and etc.

Study Population

All subjects come from the VA’s National Registry for Depression (NARDEP), which includes detailed services and pharmacy data for over 1,500,000 patients diagnosed with depressive disorders in VA facilities nationwide from fiscal year 1997 forward.

Inclusion criteria: patients who had received at least two clinical diagnoses of depression or one diagnosis followed by an antidepressant fill during the study period, between April 1, 1999 and September 30, 2004 patients who had a new start of one of the following seven antidepressant agents: citalopram, fluoxetine, paroxetine, sertraline (SSRIs), venlafaxine, bupropion or mirtazapineA new start of an agent was defined as a prescription after a six month clean period with no antidepressant prescriptions.

Exclusion criteria: Patients with a diagnosis of bipolar I disorder, schizophrenia, or schizoaffective disorder Patients with any anxiety disorder diagnosis except post-traumatic stress disorder (PTSD) at baseline (in the one-year period prior to the first antidepressant use)Patients who were given an antianxiety drug (buspirone or a benzodiazepine) in the 6-month period prior to the new start date

MethodsCox proportional hazards model: dependent variable: (1) time from antidepressant start to development of anxiety (may be censored) (2) time from antidepressant start to development of anxiety before 12 weeks (censored at 12 weeks) --- to be consistent with other studies in the literature

covariates: antidepressant, demographic variables (age, gender, race, etc.), comorbid psychiatric disorders (personality disorder, substance abuse, etc., # of inpatient psychiatric stays, # of psychotropic medicines in last 12 months)

follow up period: from start of antidepressant to end of drug or development of anxiety (or 12 weeks)

anxiety is indicated by: anxiety diagnosis or antianxiety medication

372,573 subjects were included: 22,755 (6.1%) patients developed anxiety13,792 (3.7%) had a prescription of anti-anxiety medication, 10,027 (2.7%) had an anxiety diagnosis, and 1064 (0.3%) had both

Agent bupropion citalopram fluoxetine mirtazapine paroxetine sertraline venlafaxine

frequency 42,336 97,206 54,955 14,091 45,544 103,190 15,392

% 11.4 26.1 14.8 3.8 12.2 27.7 4.0

variable N %

Major depression 73041 19.6

Medicare usage 107976 29.0

Personality disorder 6751 1.8

Total inpatient psych stays

0

1

>1

348672

18069

5973

93.6

4.9

1.5

number of psychotropic medicines

0

1

>1

303794

55580

13340

81.5

14.9

3.6

variable N %

Male 341535 91.6

Age group:

<44

45-64

>64

63702

182828

126184

17.1

49.1

33.8

Race:

White

Black

Other

274081

52143

46490

73.5

14.0

12.5

Hispanic 17054 4.6

Substance abuse 53807 14.4

PTSD 43826 11.8

Service connection 113915 30.6

Charlson score

0

1

2

3

205484

103211

41125

22894

51.1

27.7

11.0

6.1

Unadjusted Adjusted

Variable Hazard ratio 95% CI Hazard ratio 95% CI

Antidepressant:BupropionFluoxetineCitalopramMirtazapinParoxetineVenlafaxineSertraline

1.129**1.0341.092**1.448**1.238**1.257**1

(1.074, 1.186)(0.990, 1.079)(1.054, 1.132)(1.352, 1.551)(1.186, 1.292)(1.178, 1.342)1

0.9910.9441.058*1.265**1.227**1.127**1

(0.943, 1.042)(0.944, 1.028)(1.020, 1.096)(1.180, 1.355)(1.176, 1.281)(1.055, 1.203)1

PTSD (yes) 1.614** (1.556, 1.673) 1.336** (1.285, 1.389)

Age group:<4545-64>64

10.921**0.585**

1(0.889, 0.955)(0.562, 0.608)

10.943*0.656**

(0.908, 0.980)(0.622, 0.691)

Hispanic (no) 0.759** (0.714, 0.807) 0.855** (0.804, 0.909)

Service connection (no) 1.126** (1.095, 1.158) 0.999 (0.970, 1.029)

ResultsSummary statistics:

*: Service connection indicating some VA-recognized disability stemming from injuries or conditions that occurred or exacerbated during military service in the past 3 year.

Frequencies of antidepressant usage:

Results of fitting Cox model: anxiety indicated by either diagnosis or antianxiety medicine

Unadjusted Adjusted

Variable Hazard ratio 95% CI Hazard ratio 95% CI

Charlson score category:0123

11.196**1.183**1.183**

1(1.160, 1.233)(1.133, 1.236)(1.133, 1.236)

11.0101.050*1.095**

1(0.953, 1.071)(1.004, 1.099)(1.060, 1.130)

Major depression 1.553** (1.507, 1.600) 1.328** (1.288, 1.370)

Medicare (no) 1.421** (1.379, 1.465) 1.061* (1.020, 1.105)

Personality disorder (yes) 1.562** (1.432, 1.703) 1.072 (0.980, 1.173)

Total inpatient psychiatric stay (last 12 months):01>1

11.654**1.579**

1(1.569, 1.743)(1.463, 1.744)

11.298**1.273**

1(1.219, 1.381)(1.142, 1.418)

# psychotropic medicine (last 12 months):01>1

11.294**1.574**

1(1.251, 1.339)(1.481, 1.672)

11.228**1.386**

1(1.186, 1.272)(1.303, 1.474)

Female 1.284** (1.229, 1.341) 1.187** (1.134, 1.243)

Race:WhiteBlackOther

10.904**0.908**

1(0.864, 0.945)(0.870, 0.947)

10.736**0.770**

1(0.703, 0.771)(0.737, 0.805)

Similar results are found when:

• Anxiety is indicated by diagnosis only

• Anxiety is indicated by antianxiety medicine only

• Look at anxiety developed in the first 12 weeks after antidepressant start

• fluoxetine, sertraline and bupropion are associated with lower risks of anxiety development than citalopram, mirtazapine, paroxetine and venlafaxine.

•Younger patients, females, whites and Hispanic patients are at higher risks than older patients, males, other races and non-Hispanic patients.

•Major depression and PTSD increase the risks, and those with more severe psychiatric disorders are at higher risks of anxiety development after anti-depressant initiation.

Conclusions

• A meta-analysis in an FDA memorandum in November 2006 pointed out that younger age is associated with higher risks of antidepressant induced suicide.

Our finding that younger age is associated with higher risks of anxiety development after antidepressant initiation coincides and helps to explain this.

• A previous study on depressed veterans with anti-depressant use found that patients receiving bupropion, fluoxetine or sertraline had lower risks for suicide than for patients prescribed citalopram, mirtazapine, paroxetine or venlafaxine.

This also coincides with our finding that bupropion, fluoxetine and sertraline are associated with lower risks for anxiety development.

Discussion

• Confounding by indication: Prescribers may have been more likely to prescribe mirtazapine to anxious patients.

Likewise, prescribers may have been more likely to prescribe bupropion to those who were less anxious.

• Our measure of medication use was from administrative data, and patients may not have ingested medications they filled.

• Our study population is from VA patients with depression and antidepressant use, so the study findings may not generalize to other populations.

Limitations

*: 0.001< p value <0.05, **: p value <0.001