Suicidal Ideation/Medication Side Effects

From Nontrivial Neuropsychiatric Nourishment from Noble Notable Nabobs, presented by the University of Wisconsin School of Medicine and Public Health and the Madison Institute of Medicine

Educational Objectives

The goal of this program is to improve the clinician’s recognition of factors contributing to treatment-emergent sui­cidal ideation and to improve prevention of possible side effects and drug interactions of psychotropic medications. After hearing and assimilating this program, the clinician will be better able to:

1.   List the factors associated with treatment-emergent suicidal ideation in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study.

2.   Explain the role of antidepressants in the development of treatment-emergent suicidal ideation.

3.   Briefly discuss the genetic factors that correlate with suicidal ideation.

4.   Describe the mechanisms and management of selected side effects of psychotropic medications.

5.   Discuss the symptoms and management of selected drug interactions of psychotropic drugs.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the plan­ning committee to disclose relevant financial relationships within the past 12 months that might create any personal con­flicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Zisook receives research support from Aspect and PAMLAB and is a speaker for AstraZeneca and GlaxoSmithKline. Dr. Jefferson re­ceives grant/research support from Bristol-Myers Squibb, GlaxoSmithKline, Lilly, Novartis, Pfizer, and Wyeth; is a consultant for GlaxoSmithKline; receives lecture honoraria from Bristol-Myers Squibb, GlaxoSmithKline, Lilly, and Wyeth; is a share­holder in Bristol-Myers Squibb, GlaxoSmithKline, and SciClone; and is a principal of Healthcare Technology Systems. Dr. Jefferson presents information in his lecture that is related to off-label or investigational use of a therapy, product, or device. The planning committee reported nothing to disclose.

Acknowledgements

Drs. Zisook and Jefferson were recorded at Nontrivial Neuropsychiatric Nourishment from Noble Notable Nabobs, held April 3-4, 2009, in Madison, WI, and sponsored by the University of Wisconsin School of Medicine and Public Health and the Madison Institute of Medicine. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

Factors Associated with Suicidal Ideation in Star*D

Sidney Zisook, MD, Professor and Director of Psychiatry Residency Training Program, University of California, San Di­ego, School of Medicine

Introduction: depression common (more common than coronary heart disease and cancer combined); depression chronic and recurring, disabling, painful (both physically and mentally); possibly progressive; potentially fatal; treatable, but diagnosis often missed and treatment not provided or inadequately provided

Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study: funded by National Institute of Men­tal Health (NIMH); multicenter trial of >4000 participants with diagnosis of major depressive disorder (MDD); only exclusions psychotic depression, bipolar disorder, or need for inpatient  treatment (investigators wanted popu­lation as similar to community patients as possible); all patients initially started on citalopram (level 1); if no im­provement by 12 to 14 wk, subjects assigned randomly to one of several alternative treatment arms; speaker’s remarks focus on level 1 and on 1) patients with suicidal ideation at baseline; 2) those who had no suicidal ideation at baseline but did at 2-wk follow-up visit; 3) those who had no suicidal ideation at baseline or 2-wk follow-up, but developed it later in study

Suicidal ideation at baseline: 4041 enrolled in study; looked at those with suicide item postbaseline (n = 3630); of these, 1909 (53%) had suicidal ideation at baseline (research focused on which risk factors worsened suicidal ide­ation), and 1721 (47%) did not (research focused on what proportion had emergent suicidality); 12.6% of men and 18.9% of women had past suicide attempts; 42% of men and women “felt life was empty”; 23% of men and 17.7% of women had frequent thoughts about killing themselves; 2% had plans for suicide; non-risk factors for suicidal ideation at baseline  —  age; race; family history of suicide; number of general medical problems; anxious features; atypical features; risk factors for suicidal ideation at baseline  —  sex (male); unemployment; never married, di­vorced, separated, or widowed; preadult onset of first major depressive episode; recurrent MDD; past suicide at­tempts; alcohol and/or drug abuse; chronic depression; severe depression (Quick Inventory of Depressive Symptomology [QIDS] score ³20); psychiatric care delivery setting (less suicidal ideation in patients treated in pri­mary care setting compared to those in psychiatric setting)

Suicidal ideation by first treatment visit: first visit usually 2 wk after antidepressant started; no suicidal ideation at baseline  —  93% continued to have no suicidal ideation; of 7% that developed suicidality, “vast majority” had pas­sive suicidal ideation (eg, “life is empty”), 1% had frequent thoughts of suicide, and 0.1% had plans or had made at­tempts; no suicidal ideation at baseline or at 2-wk follow-up visit  —  only 67 patients had suicidal ideation at final (4-16-wk) treatment visit; 197 did not return after first visit, so their outcomes unknown; >1000 had no suicidal ideation at final visit (resolved with continued treatment); speaker concludes that suicidal ideation not present at first follow-up but present later probably not drug-related; no suicidal ideation at baseline but present at first fol­low-up visit  —  of 115 patients, 37% continued to have suicidal ideation, and >60% did not; however, in most of these patients, suicidal ideation resolved by end of treatment

Emergent suicidal ideation at first treatment visit: non-risk factors  —  age; sex; employment history; marital status; recurrent depression; past suicide attempts; family history of MDD; number of medical problems; chronic depres­sion; anxious features; atypical features; treatment setting; risk factors  —  drug abuse; severity of depression

Emergent suicidal ideation after first treatment visit: risk factors  —  drug and/or alcohol abuse; severity of depres­sion; black ethnicity; preadult onset of MDD; speaker opines that emergent suicidal ideation at this stage not driven by antidepressants; patients who had good response to treatment, especially those who remitted, less likely to de­velop emergent suicidal ideation; speaker recommends treating aggressively and to remission

Outcomes of other subpopulations: suicidal ideation at baseline  —  5% worse at 2 wk than at start of study, 95% same or improved; worse at 2 wk than at baseline  —  68% improved by end of treatment; same or better at 2 wk  —  3% worsened over time, suggesting waxing and waning nature of depression

Worsening of suicidal ideation: risk factors at first treatment visit  —  sex (male); melancholic features; care deliv­ered in psychiatric specialty setting; risk factors at last treatment visit  —  no predictors found

Suicidality at level 1: no definitive suicides during study (1 patient fell from roof, but unclear whether accident or suicide); 19 patients made suicide attempts (52% of those had previous attempts); 32% of patients who made at­tempts had no suicidal ideation at baseline; none of these cases was attributed to antidepressants by investigator

Genetic factors in suicidal ideation: studied genes related to dopamine receptors, serotonin receptors and transport­ers, and norepinephrine receptors; glutamate receptor (GR) genes only ones found to predict suicidal ideation; indi­viduals without alleles of GRIK2 or GRIA3 genes associated with suicidal ideation (58% of STAR*D subjects) had <5% chance of developing emergent suicidal ideation; of those with 1 copy of GRIA3 gene, 5% to 35% developed suicidal ideation during treatment; risk highest in those with 2 copies of GRIK2 gene; however, 40% of those who had emergent suicidal ideation during STAR*D had neither of those genes

Conclusions: tentative because study not controlled and not randomized at level 1; suicidality “clearly” core feature of major depression, which waxes and wanes before, during, and possibly after treatment; emergent suicidality early and later in course of treatment important concern for small minority of treated patients; risk factors include drug and/or alcohol abuse, severe depression, black ethnicity, preadult onset of first major depressive episode, and lack of response or remission; in patients who experience treatment-emergent suicidal ideation, improvement seen in 63%, usually within 4 wk; when emergent suicidality occurs, medication not considered sole or principal cause; findings underscore importance of understanding risk factors for emergent suicidal ideation, maintaining careful surveillance, and treating as vigorously as necessary to achieve remission; “it’s depression that kills; it’s treatment of depression that is the best way we currently know to prevent suicide”

Side Effects and Drug Interactions

James W. Jefferson, MD, Clinical Professor of Psychiatry, University of Wisconsin School of Medicine and Public Health; Distinguished Senior Scientist, Madison Institute of Medicine

Introduction: determine if side effects present before treatment began; no drug without side effects; tailor side-effect profile to patient; “when in doubt, leave it out”; listen to patients (sometimes develop subtle side effects that lead to noncompliance); not all side effects represent adverse events

Anticholinergic side effects: include dry mouth, blurred vision, constipation, urinary retention, increased heart rate, and cognitive impairment; amitriptyline most anticholinergic drug, followed by imipramine, paroxetine, nortrip­tyline, sertraline, fluoxetine, and bupropion; venlafaxine has no anticholinergic activity

Dry mouth: in placebo-controlled trials, least offensive drug escitalopram, most offensive nefazodone (not direct comparative studies); some drugs that do not have anticholinergic effects still cause dry mouth for unknown rea­sons (eg, venlafaxine); management of dry mouth  —  requires attention to oral hygiene (probably good idea to visit dentist more often than every 6 mo) and hydration; recognize dry mouth as long-term problem; dry mouth can be minimized or maximized by choice of appropriate drug and dose; several over-the-counter products avail­able to increase salivation

Drooling (wet mouth): complaint heard most frequently with clozapine (30% of patients on clozapine report excess saliva); unclear if due to overproduction of saliva or inability to clear it (2 studies found no increase in flow rate); management  —  attempts include anticholinergic medications, a₂ agonists, a₁ blocker, and intrasalivary injection of botulinum toxin; no treatment consistently effective; overtreatment may convert wet mouth to dry mouth

Excessive sweating: common side effect of antidepressants; human body has set point for temperature; sweating trig­gered when temperature rises above that point; cholinergic and adrenergic agonists cause false perception of over­heating; least offensive drug nefazodone, most offensive venlafaxine; management  —  no placebo-controlled trials; treatment attempts include a₂ agonists, a₁ blockers, anticholinergics, b-blockers, serotonin antagonists, and sero­tonin-norepinephrine; again, no treatment consistently effective; in small trial, 11 of 16 patients had good response to terazosin (Hytrin); speaker recommends switching medication

Insufficient sweating: rare; possibly side effect of topiramate or zonisamide; occurs mostly in children, with devel­opment of oligohidrosis and hyperthermia (potentially lethal); mechanism unknown; warn patient and parents of possibility “and keep your fingers crossed”

Hyponatremia: the lower the sodium level, the more serious the condition; symptoms nonspecific and vary with ra­pidity of onset and sodium level; symptoms of milder hyponatremia include headache, decreased concentration, cramps, confusion, weakness, dysgeusia, and nausea; symptoms of more serious hyponatremia include delirium, seizures, coma, decerebrate posture, and death; possible association with syndrome of inappropriate antidiuretic hormone secretion (SIADH); all selective serotonin reuptake inhibitors (SSRIs) implicated, plus venlafaxine, du­loxetine, bupropion, and mirtazapine; tends to occur early in course of treatment; risk factors include older age, taking diuretic, smoking, sex (women at higher risk); management  —  stop drug; restrict fluids; controversial whether to measure sodium levels in all older patients, especially those with other risk factors

Anticonvulsants: carbamazepine and oxcarbazepine can cause hyponatremia, but through mechanism different from drugs above; rare with carbamazepine, but epilepsy trials show 2.5% of patients taking oxcarbazepine had sodium levels <125 mEq/L; some reports of substantial drop in sodium levels in patients switched from carbam­azepine to oxcarbazepine; risk factors include low baseline sodium, older age, higher dose of drug, taking other drugs, and smoking; management  —  stop drug; restrict fluids; severe chronic (defined as >48 hr) hyponatremia may require administration of intravenous sodium chloride, but rate of administration important (too slow or too fast results in neurologic problems); best to consult primary care

Eye problems: topiramate can cause acute myopia and secondary angle-closure glaucoma; described across age spectrum; most commonly reported with low doses £50 mg/day); fewer reports with higher doses (>100 mg/day); onset rapid, so patients should be cautioned to stop drug immediately and consult primary care physi­cian or ophthalmologist if red, painful eye, severe headache, or blurred vision develops

Papilledema: in rare cases, lithium has caused pseudotumor cerebri; suspicion raised if patient complains of head­ache and/or blurred vision; stop drug immediately (reversible with prompt discontinuation)

Skin: dangerous or fatal skin reactions more common in people with HLA-B*1502 allele who take carbamazepine;  carried almost exclusively by people with ancestry across broad bands of Asia; highest risk (10%-15%) in people of Chinese, Thai, Malaysian, Filipino, or Taiwanese ancestry; very low risk (<1%) in people of Japanese or Korean ancestry; skin reactions also seen with phenytoin and fosphen-ytoin; almost no data available about lamotrigine (re­port of 1 Han Chinese with HLA-B*1502 allele who developed toxic epidermal necrolysis while taking lamotrig­ine)

Drug interactions: poor metabolizers (PMs) have 2 “bad genes” for particular cytochrome P₄₅₀ enzyme, slow metab­olizers (IMs) have 1 good gene and 1 bad gene, normal metabolizers (EMs) have 2 good genes, and ultra-rapid metabolizers (UMs) have duplicates of affected genes; UM not necessarily advantageous because drugs may me­tabolize too rapidly to achieve therapeutic levels; many drug-metabolizing enzyme polymorphisms across ethnic­ities; some antidepressants (eg, bupropion, fluoxetine, paroxetine, possibly duloxetine) can convert EM to PM or IM phenotype; example  —  if perphenazine combined with CYP2D6 inhibitor (eg, paroxetine), perphenazine blood levels increase 2- to 13-fold

AmpliChip: cleared by Food and Drug Administration for genotyping CYP2D6 and CYP2C19; requires sample of whole blood; does not consider nongenetic factors; costs hundreds of dollars (not necessarily covered by insur­ance); unclear whether cost-effective

Lamotrigine: blood levels decrease in pregnancy and continue to decrease as pregnancy progresses; reports exist of women who developed breakthrough seizures because lamotrigine dose not adjusted upward as pregnancy pro­gressed; after delivery, lamotrigine levels must be readjusted

Oral contraceptives: carbamazepine, oxcarbazepine, and topiramate lower blood levels of oral contraceptives; oral contraceptives lower blood levels of lamotrigine (which rise again during pill-free week); to avoid yo-yo effect, avoid lamotrigine

Conclusions: all drugs have side effects; all drugs can have interactions; education of physicians and patients about potential drug issues recommended

Suggested Reading

Cheshire WP, Fealey RD: Drug-induced hyperhidrosis and hypohidrosis: incidence, prevention and management. Drug Saf 31:109, 2008; Ellison DH, Berl T: Clinical practice. The syndrome of inappropriate antidiuresis. N Engl J Med 356:2064, 2007; Fava M et al: Background and rationale for the sequenced treatment alternatives to relieve depression (STAR*D) study. Psychiatr Clin North Am 26:457, 2003; Fraunfelder FW et al: Topiramate-associated acute, bilateral, secondary angle-clo­sure glaucoma. Ophthalmology 111:109, 2004; Kessler RC et al: National Comorbidity Survey Replication. The epidemiol­ogy of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA 289:3095, 2003; Kraus JE et al: Clinical features of patients with treatment-emergent suicidal behavior following initiation of paroxetine ther­apy. J Affect Disord  [Epub ahead of print], 2009; Laje G et al: Genetic markers of suicidal ideation emerging during citalo­pram treatment of major depression. Am J Psychiatry 164:1530, 2007; Mago R, Monti D: Antiadrenergic treatment of antidepressant-induced excessive sweating in 3 patients. J Clin Psychiatry 68:639, 2007; Man CB et al: Association between HLA-B*1502 allele and antiepileptic drug-induced cutaneous reactions in Han Chinese. Epilepsia 48:1015, 2007; Roxanas M et al: Venlafaxine hyponatraemia: incidence, mechanism and management. Aust N Z J Psychiatry 41:411, 2007; Rush AJ et al: STAR*D Investigators Group. Sequenced treatment alternatives to relieve depression (STAR*D): rationale and design. Control Clin Trials 25:119, 2004; Sockalingam S et al: Clozapine-induced hypersalivation: a review of treatment strategies. Can J Psychiatry 52:377, 2007; Zisook S et al: Clinical correlates of the worsening or emergence of suicidal ideation during SSRI treatment of depression: An examination of citalopram in the STAR*D study. J Affect Disord [Epub ahead of print], 2009; Zisook S et al: Preadult onset vs. adult onset of major depressive disorder: a replication study. Acta Psychiatr Scand 115:196, 2007.