|
QUEST -
Mood
AUTHOR:
|
|
|
Risk of HAM-D Remission |
RR of HAM-D Remission |
Risk of QIDS-SR Remission |
RR of QIDS-SR Remission |
Risk of QIDS-SR Response |
RR of QIDS-SR Response |
|
Ven. + Mirt. |
7/51 = 0.137 |
.137/.069=1.99 |
8/51 = 0.157 |
.157/.138=1.14 |
12/51 = 0.235 |
.235/.121=1.94 |
|
Tranylcypro. |
4/58 = 0.069 |
|
8/58 = 0.138 |
|
7/58 = 0.121 |
|
Comments: This 12-week study found no differences between groups of pts with tx-refractory MDD treated with tranylcypromine or venlafaxine + mirtazapine in rates of remission (HAM-D < 7 or QIDS-SR < 5) or response (>50% reduction from baseline QIDS-SR score). A significantly larger proportion of subjects treated with tranylcypromine dropped out of the study 2/2 inability to tolerate tx. Strengths: study directly compares two interventions; important study given relative paucity of research data in populations with tx-refractory depression. Weaknesses: open-label design; between group differences at baseline could potentially effect results (e.g. larger proportion of pts in V+M group were treated with mirtazapine in step 3); amount of time in tx was different between groups (larger proportion of subjects in T group were in tx < 4 weeks, including 2 week washout period)—did this bias results to show less improvement from baseline?; mean dose of tranylcypromine (36.9 mg/day) did not approach higher doses (70-120 mg/day) shown to be more effective.
Bottom Line: In a 12-week randomized, open-label trial of 109 subjects with MDD, who did not experience remission or were unable to tolerate 3 preceding medications trials, treated with tranylcypromine or venlafaxine+mirtazapine, there were no differences between groups in rates of remission (HAM-D < 7 or QIDS-SR < 5) or response (>50% reduction from baseline QIDS-SR score). The proportion of subjects treated with tranylcypromine who withdrew from the study 2/2 tx intolerability was significantly higher than that of the venlafaxine+mirtazapine group.
AUTHOR:
Carolina Aponte
Urdaneta
Carbamazepine Capsules as Monotherapy for Acute Mania in Bipolar Disorder
Chairman’s Rounds, September 9, 2006
Citation: Weisler, RH et al. ‘Extended-Release Carbamazepine Capsules as Monotherapy for Acute Mania in Bipolar Disorder: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial’. J Clin Psychiatry 2005; 66:323-330.
Clinical Question: What is the efficacy and safety of monotherapy with extended-release carbamazepine in patients with bipolar I disorder experiencing manic or mixed episodes?
Background Info: Carbamazepine has been long used in the treatment of bipolar disorder, however its efficacy was proven only recently in a well conducted study. Due to the limitations in response and tolerability of the available agents to treat bipolar disorder, the availability of additional options is likely to improve outcomes.
Question Type: Therapy
Validity Criteria for Appropriate Question Type:
Follow-up: 144 patients (60.3%) completed the study. All but 4 patients who entered the trial were properly accounted for and attributed at its conclusion. Randomization: Randomized. Intention to treat: from the 239 patients, 235 were included in the intention to treat sample. Similar groups: There were no important differences between groups. Blinding: Double blinded. Equal treatment: There was equal treatment aside from the intervention. Non intervention treatment: Lorazepam prn was the only additional medication allowed.
Study Design Type: Randomized Controlled Trial
Relevant Criteria for Appropriate Design:
Allocation: Randomized (no comments on how randomization was achieved).
Blinding: Double blind (no comments on how blinding was achieved).
Follow up period: 21 days, following a 5 day single-blind placebo lead in period.
Setting: 25 study sites (19 US and 6 in India). There is no comment on what kind of study sites these were - university, community, public, or private.
Patients/Population: n= 239. >18 y/o. DSM-IV criteria for bipolar disorder most current episode manic or mixed, with a prior manic or mixed episode, with YMRS score of > 20. Information was not given on how these patients were recruited.
Intervention/ exposure: Extended Release Carbamazepine (beaded capsules) up to 1600 mg daily (started at 200 mg and titrated by 200 mg daily).
Outcomes: Primary outcome was change in YMRS total score. Secondary outcomes included: responder rate (defined as decrease> 50% in YMRS score), change in CGI and HAM-D scores and time to outpatient status.
Patient Follow Up: 144 completed the study. 95 terminated prematurely: 4 lost to follow up, 17 adverse effects, 35 lack of efficacy, 13 protocol violations, 4 other.
Main Results: Primary outcome: Treatment group with statistically significant decreases in YMRS scores at day 7, 14 and 21 compared to placebo (Last observation carried forward analysis in ITT sample p <.0001 at all points) Figure 1. Secondary outcomes: ERC-CBZ patients had significantly higher response rates on all measured days (p<0.0001), with by my calculations a relative risk of 2.1 at the end point. CGI-S and CGI-I scales scores were significantly improved in the treatment group (p<.0001), as were HAM-D scores (p<.01). 48.3% in ERC-CBZ group vs. 34.8% in the placebo group were discharged from the hospital during double-blind treatment period (P>.05). Cohen’s effect size was 0.85 (large effect). Significantly more subjects in the placebo group discontinued because of lack of efficacy (23.1% vs. 6.6% p <.001). ERC-CBZ group had significantly higher adverse events (91.8% vs. 56.4%).
Conclusions: Overall, this was a well designed study. The validity criteria for appropriate question type were met, also the sample was big enough. However, the period of follow up was short, the participants seemed to be less sick than the usual manic population we handle, and because the study provides little information on study sites and recruitment it could be difficult to extrapolate results to our own patients. Monotherapy treatment with extended release carbamazepine was statistically significantly more efficacious than placebo in the treatment of manic or mixed episode in the first 21 days of treatment in this RCT. Although the treatment group had a significantly higher incidence of adverse events, this does not fully account for the drop outs in the treatment group, from which the authors conclude that the medication is safe and well tolerated.
Two Teaching Points:
1. Intention to treat analysis, which is analysis of outcomes based on the treatment arm to which patients are randomized, preserves the value of randomization. Analyses restricted to patients who adhered to assigned treatment can provide misleading estimate of impact.
2. The intention to treat principle is violated by excluding patients who did not begin the treatment to which they were allocated.
Two Questions for Discussion: 1. Why is carbamazepine less used if efficacy has been proven? 2. At what point would you consider carbamazepine monotherapy in your manic (or mixed episode) patients?
Author:
Jane Gagliardi 10/30/00
TEGRETOL AND MANIA
Post et al. review carbamazepine (CBZ), valproic acid (VPA) and the newer anticonvulsants in the treatment of bipolar affective disorder. They have gathered information from a large number of trials in bipolar disorder and have included those trials in which the methods included some kind of controlled design. As part of the introduction, they note that lithium (Li) is thought of as the standard therapy, but that the largest controlled trial of Li in acute mania indicates only 50% of patients demonstrated 50% improvement after three weeks of therapy in the acute setting. Poor response to Li was associated with rapid cycling, negative family history, increasing number of episodes prior to initiation of Li therapy, and comorbid substance abuse.
CBZ
in acute mania:
there were 19 controlled studies included in the paper, comprising 203 patients.
123 of the 203 patients with acute mania showed a marked to excellent
response to CBZ. (61% response rate
in acute mania).
CBZ in acute depression: there were
fewer studies; the authors included one of their own pilot studies and said that
only 17 of 57 acutely depressed patients (30%) had a moderate to marked effect
with CBZ monotherapy. In
uncontrolled studies, there was a reported 73% treatment effect.
CBZ in prophylaxis: there were 14 “partly controlled” / controlled studies included in the analysis of prophylaxis. In these studies, 63% of patients given CBZ showed a moderate to excellent prophylactic response, which compared to 63% response to Li. In a trial comparing Li to CBZ in which patients were crossed over to the other treatment group after a year of therapy, 31% of the patients on Li and 37% of the patients on CBZ dropped out because of inadequate response to the medication.
-
Additional observations about CBZ:
-No real target blood reference range identified across subjects; there does seem to be some relevance of blood levels for individual patients -
-Theory that activity in the mesial temporal structures (preliminary PET data) may predict response to CBZ
-
-Rapid cycling seems to be a poor prognostic factor for CBZ as well as for Li therapy
-
-Patients with negative family history may respond better to CBZ
-
-Mechanism of action: 1996 demonstration of CBZ blocking the Ca influx through NMDA receptors
-
-Cytochrome P450 3A4 inducer; decreases its own levels as well as those of OCP’s
-
-Potential adverse effect of agranulocytosis
Small et al. performed a longitudinal, prospective study of newly hospitalized patients with bipolar disorder, mixed or manic episodes. Patients were excluded if they had a history of other axis I disorders, significant medical problems, substance abuse or physical illness, or other contraindications to Li or CBZ. Dropout rate was high; by eight weeks, 2/3 of patients were excluded because of lack of efficacy or refusal to continue. Patients who were evaluated were assessed based on the GAS, MRS, BPRS, CGI, and SDMS-M subscale. Both Li and CBZ were found to be “modestly effective” in the short-term treatment of acute mania. In this study, 52 subjects were initially included. In the CBZ group, one had decreased granulocyte count and had to be dropped from the study. Rate of recurrent mania and depression were similar; rate of noncompliance was slightly higher in the lithium group. Overall, dropout rate was similar but dropouts occurred earlier in the CBZ group than in the Li group.
Dilsaver et al. performed an evaluation of CBZ vs. chlorpromazine in the treatment of 36 inpatients with bipolar disorder (depressed). They found that CBZ treatment was about as effective as chlorpromazine in improving mood, sleep, headache, and mood fluctuations (there were some trends on physician global improvement scale favoring CBZ, but these were not significant). In this study, one patient had blurry vision and another had rash and fever as reasons for withdrawal from the CBZ group.
Bottom Line: According to the data reviewed in these articles, CBZ appears to be about equally effective as Li in the treatment of acute mania and in prophylaxis of bipolar disorder. Depending on the patient and the potential tolerability of CBZ, it could be a viable option for the treatment of acute mania as well as for prophylaxis in bipolar disorder. Importantly, the authors of these articles take care to point out that response to one agent does NOT predict response to another, and it may be necessary to switch or add medications for adequate treatment of patients with bipolar disorder.
References:
Post
RM; Ketter TA; Denicoff K et al. The place of anticonvulsant therapy in bipolar
illness. Psychopharmacology(1996)
128: 115-129.
Dilsaver SC; Swann SC; Chen y et al. Treatment of bipolar depression with carbamazepine: Results of an open study. Biological Psychiatry(1996) 40: 935-937.
Small JC; Klapper MH; Milstein V et al. Carbamazepine compared with lithium in the treatment of mania. Archives of General Psychiatry (1991) 48: 915-921.
Author:
Jane Gagliardi - Chairman's Rounds 11/27/00
TREATING PATIENTS WITH BIPOLAR DISORDER IN PREGNANCY
Question: what are the issues in treating patients with bipolar disorder in pregnancy? Specifically, what are the risks involved in continuing mood stabilization with Depakote or Tegretol during pregnancy?
Finnerty et al (1996) report on a woman who was hospitalized at 26 weeks of pregnancy, 4 weeks after she and her psychiatrist decided in the outpatient setting to d/c her Depakote because she informed him that she was 5 months pregnant. The patient immediately de compensated, becoming hostile at home and ceasing to control her diabetes. She was admitted to the hospital for stabilization and was tried on haldol and benzodiazepines, which even at high doses (40 haldol, 14 ativan) was not effective. She eventually underwent ECT; however, at 29th week of pregnancy, on ECT, she experienced premature rupture of the membranes and required C section. Post-partum, she deteriorated and required psychiatric hospitalization and stabilization—tried on VPA, ativan and haldol, finally required ECT.
The article brings up a number of interesting issues about the problems inherent in bipolar disorder and pregnancy:
Patients need to be informed of the risk of possible problems in pregnancy in the presence of mood stabilizing medications;
A manic patient is not exercising good judgment and is more likely to have an unplanned pregnancy;
The same patient is also likely not to receive good prenatal care;
Medical illness in the same patient will not be well controlled, which can cause problems for the developing fetus (e.g., diabetes);
Most exposure to medications/drugs happens early in the pregnancy, before the physician is aware of pregnancy;
Bioavailability of medications during pregnancy is altered and drug levels may be irrelevant due to different ratios of protein binding and altered distribution;
The post-partum period is a high-risk period for relapse into depression or mania;
ECT is thought by psychiatrists to be safe in pregnancy, although there are some reports of premature rupture of the membranes in ECT which are questionably attributable to ECT;
The legalities of committing a woman based solely on the potential for harm to her fetus are questionable (most states do not allow commitment for this reason).
Eller et al. (1997) examined the implications of anticonvulsant therapy during pregnancy by conducting a review of the literature available through ~1996. Since the 1980’s, there have been reports in the literature about specific patterns of malformations in children born to women receiving depakote (VPA) and tegretol (CBZ).
Notably, all the women studied in the literature for these data have taken these medications for the treatment of seizure disorder, in which there is a recognized increased risk of birth defects in uncontrolled seizure disorder; there is also the question of whether or not any of these abnormalities were inherited rather than acquired because of the medications.
Recommendations have been to treat women who take VPA or CBZ as if they have had children with neural tube defects in the past—e.g., folic acid 4 mg PO qD (usual prenatal dose 400 mcg). There is some possibility, however, that this dose of folic acid might induce CP450 enzymes and alter metabolism of the medications, requiring close monitoring. Further, there is no good evidence that this intervention would work (it is extrapolated from other, widely known data about the efficacy of folic acid in preventing neural tube defects). There are a number of theories about why VPA and CBZ are associated with neural tube defects, which seem to boil down to glutathione and SAM metabolism (animal studies).
There are also recommendations that women taking VPA or CBZ should take vitamin K 10 mg PO qD for the last 1-2 months of pregnancy, and the infant should receive a 1 mg injection of vitamin K at birth in order to address the increased risk of intracranial hemorrhage.
Finn et al. (2000) conducted a prospective study of neonates born to mothers who had been taking valproic acid with the goal of determining the incidence of withdrawal symptoms and hypoglycemia.
Objective: To define the risk of hypoglycemia in term infants exposed to valproic acid, and to describe the withdrawal symptoms.
Design: Prospective study in Denmark on a case-control basis.
Cases: 22 infants selected from 24,500 infants born in the North Jutland County in Denmark between 7/93 and 2/97 whose mothers were taking valproate during pregnancy. Exclusion criteria were preterm (<37 weeks), or the second twin. 19 of the mothers had primary generalized epilepsy, and three had complex partial epilepsy. 20 were taking VPA alone and 2 were taking VPA + CBZ.
Controls: 233 infants born at term to mothers not taking VPA or having epilepsy during the same time period provided one blood sample each (at either 1,2,4,6,12,24,48,72 or 96 hours post-partum) for glucose measurements; 22 additional infants from this hospital (term, normal pregnancies, no epilepsy in mothers) had their cord blood analyzed for glucose, insulin, proinsulin and C peptide.
Method: Women with epilepsy taking VPA were seen monthly by a neurologist during pregnancy and had blood levels of VPA monitored. All patients had U/S; 11 had amniocentesis, and one had a chorionic villus biopsy. The women either abstained from EtOH or drank small amounts.
Glucose was measured at birth (cord blood), then at 1,2,4,6,12,18,24 hours
and then every 8 hours till the 5th day of life.
Insulin, proinsulin, and C peptide were determined, as well as LFT’s.
The infant’s VPA level was determined at days 2 and 4 of life.
Infants were observed with q8-hourly records of withdrawal symptoms
(irritability, jitteriness, hypertonia, seizures, and vomiting).
Measures: Hypoglycemia was defined as <1.8mMol/L (32 mg/dL) based on previous studies by this same group.
Results: 14 boys, 8 girls. 13 of 22 infants in the case group had episodes of hypoglycemia. 7 occurred at 1 hour, 3 occurred at 2 hours, 1 occurred at 4 hours, one at 12 hours, and one at 67 hours. All infants developing hypoglycemia were placed on glucose drips and all were asymptomatic. One infant had 8 episodes; one had three, two had two, and nine had one episode of hypoglycemia. At one hour, the case infants had significantly lower average glucose (2.1) than the control infants (2.9), p<0.01. At two hours, there was a trend (p=0.06). A logistical regression showed that the mother’s VPA level in the third trimester was significantly and inversely correlated with infants’ plasma glucose concentrations (p<0.01).
10 of 22 infants in the case group demonstrated w/d symptoms beginning at 12-24 hours and lasting until 2-7 days. There was one infant who had a seizure. One infant had an elevated AST, but had also suffered asphyxia; the rest of them had normal LFT’s. A proportion of the infants required formula supplementation of breast mild because of w/d symptoms.
There were no major malformations among the case infants; four infants did have minor abnormalities, including one infant who met criteria for fetal VPA syndrome.
Moore
et al. (2000) reviewed 57 children with fetal anticonvulsant syndromes
(mostly VPA) in order to further understand the clinical and behavioral
phenotype of fetal anticonvulsant syndromes.
Cases: 52 children located
through a parents’ support group (National Fetal Anticonvulsant
Syndrome Association) and 5 others found in a clinic.
Method: Retrospective analysis via medical and family history questionnaire at a clinic.
Measures: Questionnaire; karyotypes (51 cases); DNA testing for Fragile X (48 cases); review of photos by two experts who rated the children on whether or not they had FACS; ophthalmologic exams (46 cases)
Results: 46 of the 59 mothers were taking VPA (34 VPA alone, 12 in combination); 4 were taking CBZ, 4 were taking phenytoin. There were 15 women taking more than one medication.
11 (19%) had experienced neonatal w/d—4 required NGT, 3 were floppy, 6 were jittery, 2 had seizures (and one of these were found to be hypoglycemic in nature).
No cleft palates were reported.
Myopia (16/46), astigmatism (11/46) and strabismus (8/46) were prevalent in this group of children.
44 (77%) had developmental delays or learning difficulties; 28 of 38 school-aged children (74%) were in special schools or receiving special education in mainstream schools. 10 of 38 school aged children (26%) were in normal mainstream education; three of these were in their first year. 41 of 53 children older than 2 (77%) needed to have speech therapy. 32 of the children (56%) had gross motor delays (13 severe enough to require OT).
46 (81%) had aberrant behavior; a formal diagnosis of behavior d/o was made in 9 (16%) cases. 22 (39%) were rated as hyperactive; 4 as autistic; 2 as having Asperger’s syndrome. Only four children had neither developmental delays nor behavior problems.
Disadvantages: Selection bias! The children included were those whose parents had sought a support group for their abnormalities. Retrospective. Self-report (questionnaires). Possibility that the children’s anomalies were inherited but, because of maternal anticonvulsant use, were being attributed to the medications.
Summary of the findings about the risk of VPA and CBZ in pregnancy from the four references below.
|
VPA |
CBZ |
|
11.1% risk of malformation |
5.7% risk of malformation |
|
Neural tube defects 1-2% (lumbosacral) |
Neural tube defects 1% (lumbosacral) |
|
Fetal VPA syndrome—brachycephaly, high forehead, shallow orbits, ocular hypertelorism, small nose and muth, low-set, posteriorly rotated ears, long overlapping fingers and toes, hyperconvex fingernails (Eller et al) Epicanthic folds, infraorbital groove, medial deficiency of eyebrows, flat nasal bridge, short nose with anteverted nares, smooth/shallow philtrum, long thin upper lip, thick lower lip, small and downturned mouth (Moore et al) |
Cranial facial defects, fingernail hypoplasia, developmental delay (Eller et al) Epicanthic folds, short nose, long philtrum, upward slanting palpebral fissures, hypoplastic nails (Moore et al) |
|
Risk of hemorrhage b/c impaired vitamin K dependent clotting factors |
Risk of hemorrhage b/c impaired vitamin K dependent clotting factors |
|
Risk of acute liver failure in the infant |
Risk of transient neonatal hepatic dysfunction |
|
Risk of developmental delay and behavioral problems (Moore et al) |
|
References
Eller DP, Patterson CA, Webb GW.
Prescribing in pregnancy: Maternal and fetal implications of
anticonvulsive therapy during pregnancy.
Obstetrics and Gynecology
Clinis 24(3): 523-532, September 1997.
Finn E, Joergensen A, Hoseth E, et al. Neonatal hypoglycemia and withdrawal symptoms after exposure in utero to valproate. Archives of Disease in Childhood Fetal and Neonatal Edition 83(2): F124-F129, September 2000.
Moore SJ, Turnpenny P, Quinn A, et al. A clinical study of 57 children with fetal anticonvulsant syndromes. Journal of Medical Genetics 37(7): 489-497, July 2000.
Finnerty M, Levin Z, Miller LJ. Acute manic episodes in pregnancy. American Journal of Psychiatry 153(2): 261-263, February 1996.
Author:
Chris Aiken, M.D.
Topiramate for Bipolar Disorders
Question:
What is the evidence that topiramte treats bipolar disorders?
Five open label, naturalistic case series’ of topiramate published:
|
Study |
Type /Dose (M=Mean) |
N |
M:F Age |
Subjects |
Wks |
Measure* |
Response |
|
McElroy |
adjunctive 50-500mg/d |
54
|
3:7 42y |
Outpatients, treatment refractory. Bipolar I (43), II (11), schizoaff (2). Divided by episode = manic (30), depressed (11), euthymic (13). |
4, 10, & last eval. (~30) |
Change in CGI, YMRS, or IDS |
Manic improved (YMRS 9.9 --> 5.3 --> 6.9, p 0.004). Depressives unchanged. Euthymics slightly more depressed (p 0.025). |
|
Marcotte |
adjunctive with a few monotherapy m 200mg/d |
58
|
3:5 45y |
Treatment refractory, inpatients (30%), outpatients (70%), bipolar (59%), cyclothym (17%) schizoaff (16%), numerous comorbidities. |
16 mean |
Qualitative: mood, sleep, appetite, con-centration. |
62% "marked/moderate improvement" |
|
Calabrese |
monotherapy m 614mg/d |
11 |
? |
Hospitalized, severe treatment refractory acute mania |
4 |
>50% YMRS |
27% improved |
|
Kusumaker |
adjunctive ? mg/d |
19 |
0:1 |
Out-patients, female, rapid cycling bipolar with psychotropic-induced wt gain. |
? |
? |
52% improved |
|
Chengappa |
adjunctive 1-300mg/d |
20 |
? |
Bipolar (18), schizoaff (2), manic episodes. |
12 |
>50% on YMRS & CGI |
60% improved |
References:
McElroy et al. Open-label adjunctive topiramate in the treatment of
bipolar disorders. Biol Psychiatry 47: 1025-33, 2000.
Marcotte D. Use of topiramate, a new antiepileptic as a mood stabilizer. J Affect Disorder 50: 245-51, 1998.
Calabrese et al. Topiramate in severe treatment-refractory mania.
Abstract, APA Toronto 6/1998.
Kusumaker et al. Topiramate in rapid cycling bipolar women. Abstract
APA-Washington DC, 1999.
Chengappa et al. Topiramate as add-on treatment for patients with
bipolar
mania. Bipolar Disorder 1: 42-53, 1999.
*Abbreviations:
CGI (clinical global impression for mania), YMRS (Young mania rating scale), IDS (Inventory of depressive symptoms).
McElroy, Specific Strengths :
• Reported improvements maintained on 2 standard rating scales at
3 measurements.
• Subjects separated by mood at baseline.
McElroy, Specific Weaknesses:
• High drop out rate (35% @10wk, 52% total); these results were
not counted except in the "last evaluation" category. Another
13% were not counted because additional psychotropics were added when
their mood worsened.
• Initial YMRS was relatively low (9.9). Subsets with higher YMRS were
also analyzed (similar results found).
Marcotte, Specific Strengths:
• None
Marcotte, Specific Weaknesses:
• Qualitative measures done in clinical, not research setting.
Bias/placebo-effect is evident in his statement that "majority of
responders showed improvement within 72 hours at dose of 50mg/d."
In comparison, McElroy found a "slow response" with similar
dosages.
• Chart review. Drop-outs not applicable (though 10% discontinued due
to SE).
• Subjects had high mix of conditions, which led to much categorizing
(data-fishing) with unimpressive results.
Generalizations:
• Five case series were found for topiramte in bipolar disorders,
all except one were for adjunctive therapy.
• Of the two larger studies, one had severe methodologic limitations (Marcotte);
the other (McElroy) more rigorous study showed good results for mania
but was limited by a high drop out rate.
• No studies could control for clinician/patient bias, placebo effect,
natural course of illness, and effect of other drugs.
• Most studies used refractory patients
• No studies had clean exclusion/inclusion criteria.
Reviewer:
Joseph Sharpe
MANIA IN LATE LIFE:
FOCUS ON AGE AT ONSET
Source:
American Journal of Psychiatry 149:7, July 1992
Authors: Robert Young, M.D. and Gerald Klerman, M.D.
Category: Review
Summary: The authors review diagnosis and classification of Bipolar disorder including incidence and prevalence of mania in the elderly. This paper emphasizes the limited number of systematic studies available, however they do explore the existing literature and discuss several aspects of psychopathology and how each relates to age and age-onset. Included in there analysis of Bipolar disorder are manic affective features, dysphoria and mixed states, delusions/psychotic features, and cognitive dysfunction. This paper focuses on late-onset bipolar noting trends and/or studies that are appropriate to this target group.
Diagnosis/classification/prevalence/incidence:
Types of bipolar include
-
Type I: hospitalized at least once for mania plus history of depression
Type II: not-hospitalized due to hypomania plus history of depression
Type III:' cyclothymia' fluctuations in mood without mania or severe depression
Type IV: Mania is associated with illnesses or medications
Type V: Major depression with strong family hx of bipolar Type VI: Hx of mania but no depression 'uni polar mania'
Incidence: Limited data. Conflicting reports. Both sexes show the association with age was weaker for mania than for depression.
Etiology: Probands with late onset bipolar disorder have a lower rate of affective disorder among their relatives than do probands with early onset. Drugs of abuse have been associated with cases of mania in which age of onset is greater than 40 years. Manic patients aged greater than or equal to 60 with onset of first manic episode after age 58 had antidepressant pharmicotherapy associated with their index episode more often than elderly manic patients with onset at an earlier age. Manic symptoms can occur with cerebrovascular disease, as well as other focal brain lesions. Right-side lesions have been particularly implicated in the pathogenesis of mania.
- Manic affective features: Slater and Roth have stated that many cases of mania in the elderly are 'milder' than in younger patients. Although this is only from clinical impressions. Older patients tended to have lower GAFs when symptomatic.
- Dysphoria and mixed states: Post has suggested that older manic patients exhibit concomitant depressive features more often than younger patients.
- Delusions and other psychotic features: Post has stated that compared to younger patients, geriatric manic patients more often have persecutory delusions that are not mood-congruent. Again though this is only a clinical observation. Rosen et al. Has reported a negative association between psychotic symptoms and late onset bipolar pt.s.
- Cognitive Dysfunction: Broadhead and Jacoby have stated that a greater proportion of elderly than of young manic patients performed in the demented range on the Kendrick neuropsychological battery. In a retrospective study, those who were older than 58 yrs. at the time of the first manic episode more often showed evidence of cognitive dysfunction in routine clinical evaluations when they were acutely symptomatic than did patients with earlier onset.
- Resolution of Acute Episode: Some studies have suggested an association between greater age at onset and greater duration of episode and/or chronicity. However these studies do not differentiate between age at onset and age alone.
- Relapse: MacDonald has noted an association between greater age and shorter intervals between episodes in pt.s with bipolar. Stone has reported an increase in frequency of readmission, over 1-month to 10-yr follow up, for those with histories of previous affective episodes than for those without such history.
- Mortality: Observed mortality rate for elderly bipolar pt.s appears to be greater than the base rate for this age group in the community. Neither Dhingra and Rabins nor Shulman et al. detected a difference in mortality between geriatric patients with late onset of illness and patients of the same age with early onset of illness.
- Cognitive Dysfunction/Dementia: Dhingra and Rabins could not detect differences in cognitive impairment, as assesses by MMSE score, between patients with late-onset mania and geriatric patients with early-onset mania at 5 and 7 yr follow ups.
- Treatment: Differences in treatment in regards of age have not been explored however consideration must be given to factors that influence drug pharmokinetics and pharmacodynamics.
- Pharmacokinetics: Reduced lithium clearance can be associated with increased age. The volume of distribution, because of increased fat/lean body mass ratio, may also be reduced. Lower doses of lithium might be needed to achieve equivalent plasma levels.
- Efficacy of Acute Pharmacotherapy: Schaffer and Garvey suggest that lithium levels below 1.0 meq/liter can be effective in some elderly patients. Broadhead and Jacoby did not note differences in therapeutic response in relation to age at onset.
IN
PATIENTS WITH POSTPARTUM ONSET OF MANIC
SYMPTOMS IS THE INITIAL PRESENTATION AND RECURRENCE OF MANIA
ATTRIBUTED OR IMPACTED BY THE POSTPARTUM STATE
Reference:
Videbech P, Gouliaev G, First
admission with puerperal psychosis: 4-14 years of follow-up
Methods:
Design:
Retrospective Cohort study
Setting:
The study took place in Denmark
where women were admitted to psychiatric hospitals for the first time
with postpartum psychosis were identified by using the national personal
identification number to link data from the Danish Psychiatric Central
Register with the Danish Medical Birth register.
Inclusion
Criteria:
first admission to a psychiatric department in the years 1973
to 1980;
admission within 12 months
after a parturition;
diagnosis at discharge was psychosis (ICD-8 290 to
299)
and all admissions
took place at the psychiatric departments in Arhus County, Arhus
psychiatric hospital or the psychiatric
wards in the cities of Silkeborg or Randers with a well-defined
catchment of approximately 600,000 inhabitants.
Control
Group: every proband had two
controls with inclusion criteria of 1) they delivered at the same
maternity ward in the same year and 2) they had same parity and
approximately the same age.
Outcomes:
Primary: Evaluate women who had
first time diagnoses and admissions to psychiatric hospitals following
delivery of the first child and compare certain demographical variables
with those of the background
population and to investigate whether obstetrical factors could
contribute to the development of the disorder.
Description
of Prognosis factors considered: Mental disorder, hospitalizations,
medications and social functioning.
Validity
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Was the patient sample clearly defined, representative of clinical practice, and captured in a similar point in disease progression? Yes
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Was the duration of follow-up sufficient? Yes. Were all patients accounted for? Yes
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Were outcome criteria objective and unbiased relative to prognostic factors? Yes
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Was their adjustment for linked prognostic factors? No
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Were pts in study treated similarly? Yes
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Ds the study population describe my patient? Yes, somewhat
Results