ARIPIPRAZOLE in DEPRESSION and ANXIETY: BUYER BEWARE!

                              ALAN EPPEL MB, FRCPC

Attached to the cover of a recent issue of the Canadian Journal of Psychiatry was an advertisement promoting the use of aripiprazole for the treatment of depression.

The advertisement was addressed to me personally and recommended that aripiprazole be considered early on in the treatment algorithm for depression. The advertisement implied that  adjunctive aripiprazole be considered after 2 to 4 weeks of nonresponse to an antidepressant.

The use of second-generation antipsychotics for the treatment of mood and anxiety disorders has skyrocketed in the past decade. While there is some evidence for efficacy claims are frequently made without a balanced consideration of the risks versus benefits.

SIDE EFFECTS

The main serious side effects antipsychotic medications are 1) metabolic syndrome and 2) extrapyramidal symptoms and tardive dyskinesia. 

Metabolic Syndrome Diagnostic Criteria: International Diabetes Federation Criterion A plus two of other four items.

A.

Waist circumference

men >37 inches; women >31.5 inches 

 B. 

1. Fasting triglycerides >150 mg/dl

 2. High-density lipoprotein Men: <40 mg/dl Women: <50 mg/dl

 3. Systolic blood pressure/diastolic blood pressure >130/85 mmHg, or on antihypertensive medication 

4. Fasting glucose >100 mg/dl, or on insulin or hypoglycemic medication. 

 In a meta-analysis conducted by Spielmans et al. adjunctive aripiprazole had an effect size of only 0.35 considered, small to moderate. 

 Aripiprazole was associated with akathisia with the number needed to harm of NNH=4.  With regard to weight gain NNH= 29. Average weight gain across a number of trials was one kilogram and ranged from 0.42 1.67 kg.

Troublesome methodological deficiencies were identified in these studies. The Federal Drug Administration expressed concern about a number of protocol violations in one of the aripiprazole studies. This concerned the number of participants who used prohibited medications during the trial.

The authors note that at the time of publication there were no trials that directly compared adjunctive atypical antipsychotic medication to other treatment strategies such as such adjunctive lithium, switching the antidepressant, or adding psychotherapy.

In a study of second generation antipsychotics in 342 youth, Carbon et al found that 15.2% developed drug-induced parkinsonism. 

SGA-group drug-induced parkinsonism rates were as follows:

quetiapine = 1.5%, olanzapine = 13.8%,

risperidone = 16.1%, ziprasidone = 20.0%,

and aripiprazole = 27.3%.

Treatment-emergent dyskinesia ranged from 4.5% with aripiprazole, to 15.5% with olanzapine.

Cloud et al in a review  noted tardive dyskinesia prevalence rates of 13 % among patients on SGAs and 32 % among patients on first-generation agents. One included review of 12 trials reported  the annual incidence of TD to be 3.9 % for SGAs and 5.5 % for first-generation drugs

CONCLUSION

Contrary to early hopes, second generation antipsychotics do have significant rates of serious side effects. In the treatment of schizophrenia and related psychoses these risks may be outweighed by the potential benefits.

However the risk benefit equation provides  no justification for the use of SGAs in the  treatment of mood or anxiety as first, second or even third line agents.

References:

1. Spielmans GI et al. Adjunctive atypical antipsychotic treatment for major

depressive  disorder: a meta-analysis of depression, quality of life, and

safety outcomes. PLoS Med. 2013;10(3):e1001403. doi: 10.1371/journal.pmed.1001403.

2. Carbon M  et al. Neuromotor Adverse Effects in 342 Youth During 12 Weeks of Naturalistic Treatment With 5 Second-Generation Antipsychotics.

J Am Acad Child Adolesc Psychiatry. 2015 Sep;54(9):718-727

                    3.Cloud LJ, Zutshi D, Factor SA. Tardive dyskinesia: therapeutic options for 

                    an increasingly common disorder. Neurotherapeutics. 2014 Jan;11(1):166-76.

           

BIPOLAR DISORDER: WHY LITHIUM IS STILL FIRST CHOICE

Journal Abstracts

Nervenarzt. 2014 Sep;85(9):1166-70. doi: 10.1007/s00115-014-4083-x.

[New facts of long-term prophylaxis for bipolar affective disorder].

[Article in German]

Bschor T1, Müller-Oerlinghausen B, Stoppe G, Hiemke C.

              

Lithium and with restrictions, carbamazepine, valproic acid, lamotrigine, olanzapine, aripiprazole and quetiapine, are approved in Germany for maintenance treatment of bipolar disorder. 

 Lithium is the only drug that (I) proved to be effective for the prevention of depressive as well as manic episodes in state-of-the-art studies without an enriched design and that (II) is approved for the maintenance treatment of bipolar disorders without restrictions. It (III) is also the only drug which is recommended for maintenance treatment by the current German S3 guidelines on bipolar disorders with the highest degree of recommendation (A) and (IV) is the only drug with a well proven suicide preventive effect. Hence, lithium is the mood stabilizer of first choice.

No patient should be deprived of lithium without a specific reason. Side effects and risks are manageable if both the physician and the patient are well informed.

For patients who do not respond sufficiently to lithium, have contraindications or non-tolerable side effects, other mood stabilizers should be used. Restrictions in their respective approval as well as specific side effects and risks have to be taken into account. 

Because maintenance treatment is a long-term treatment, particular concern should be paid to drugs with the potential risk of a metabolic syndrome, particularly atypical antipsychotics.

             

  Harv Rev Psychiatry. 2014 Nov-Dec;22(6):353-7. Factors associated

  with lithium efficacy in bipolar disorder.

              

              

 Rybakowski JK.

About one-third of lithium-treated, bipolar patients are excellent lithium responders; that is, lithium monotherapy totally prevents further episodes of bipolar disorder for ten years and more. These patients are clinically characterized by an episodic clinical course with complete remission, a bipolar family history, low psychiatric comorbidity, mania-depression episode sequences, a moderate number of episodes, and a low number of hospitalizations in the pre-lithium period.

 Recently, it has been found that temperamental features of hypomania (a hyperthymic temperament) and a lack of cognitive disorganization predict the best results of lithium prophylaxis.

             

  Lithium exerts a neuroprotective effect, in which increased expression of brain-derived neurotrophic factor (BDNF) and inhibition of the glycogen synthase kinase-3 (GSK-3) play an important role. The response to lithium has been connected with the genotype of the BDNF gene and serum BDNF levels. A better response to lithium is connected with the Met allele of the BDNF Val/Met polymorphism, as is a hyperthymic temperament.

              

  Excellent lithium responders have normal cognitive functions and serum BDNF levels, even after long-term duration of the illness. The preservation of cognitive functions in long-term lithium-treated patients may be connected with the stimulation of the BDNF system, with the resulting prevention of affective episodes exerting deleterious cognitive effects, and possibly also with lithium's antiviral effects.

            

   A number of candidate genes that are related to neurotransmitters, intracellular signaling, neuroprotection, circadian rhythms, and other pathogenic mechanisms of bipolar disorder were found to be associated with the lithium prophylactic response. The Consortium on Lithium Genetics (ConLiGen) has recently performed the first genome-wide association study on the lithium response in bipolar disorder.

BIG PHARMA’S COVERT STRATEGIES AND THE SUBVERSION OF PSYCHIATRIC DIAGNOSIS.

EDITORIAL

Many physicians assume they are immune to the advertising and marketing strategies of  pharmaceutical companies.

Physicians are confident in their own knowledge and judgment and believe that they will not be overly influenced by a presentation sponsored by a pharmaceutical company  promoting a specific medication.

Physicians believe they are resilient enough to see through the ruse of being offered a reasonably good meal in exchange for sitting through a biased presentation.

These beliefs overlook the more subtle aspects of marketing tactics.

Marketing is not  primarily about the manipulation of evidence. Rather Marketing is informed by more basic implicit psychological processes:  leaning theory, cognitive priming, attachment theory.

Advertising connects the  brand name of a drug  with positive  emotional stimuli, pictures of happy patients in pleasing surroundings. 

Marketing strategies engage the physician in a way that promotes positive emotions and  memories that are associated with the drug name. It is done through direct detailing and  the development of positive attachments between the physicians and the drug reps. It is is done by the provision of gits and financial incentives.

But there are less obvious and more intricate strategies that large companies and affiliated physicians may use. For example companies may work to expand the indications for a particular medication. This can be done in two ways:  

i) claim specific mechanisms of action of a drug that target specific symptoms thus creating a niche market.

ii)  broaden diagnostic criteria for a condition by lobbying for changes to DSM.

This may  include the creation of new diagnostic entities and changing diagnostic thresholds.

This is made a lot easier when the pharmacological company itself provides assistance to physicians in making the diagnosis. The company will happily provide  brief diagnostic checklists that allegedly offer a cut off point that implies the prescription of the new medication.

The checklist replaces a comprehensive biopsychosocial assessment.

Some of these strategies have led to quantum increases in the prescription of antipsychotic medications across a range of diagnoses. Antipsychotic medications have been promoted to augment antidepressants in the treatment of depression and anxiety in the early stages of treatment while the risks of metabolic syndrome and tardive dyskinesia are downplayed.

There is even an effort underway to change the name “antipsychotic” to make the use of these medications in a broad range of conditions more palatable to patients and physicians (1). This would also make it less apparent that these medications can cause metabolic syndrome and tardive dyskinesia.

Wakefield has stated:

“A major pressure unique to psychiatric research today,

and one that has detrimentally affected the quality of journal

editing, is the push to publish articles that provide real or

apparent support for proposed changes in the DSM.

Links between DSM diagnosis and reimbursement, research funding,

and approval of pharmacotherapies create non-scientific

motives for justifying additions to DSM and thus for making

claims that stretch or go beyond or against the evidence.” (2,3)

And

“Entire research programmes (e.g. on complicated grief disorder,

or binge eating disorder) are pursued with the goal in mind of justifying

entry into DSM, with researchers interpreting their data and reviewers

evaluating submitted manuscripts through the lens of DSM.

This appears to have occurred with the new and somewhat absurd inclusion in DSM-V of a depressive mixed mood state. In DSM 5 under “specifiers” for depressive disorders there is a category for depression with mixed features which consist of at least three of the following:

elevated, expansive mood

inflated self-esteem or grandiosity

more talkative than usual or pressure to keep talking

flight of ideas or subjective experience that thoughts are racing

increase in energy or goal-directed activity

increased or excessive involvement in activities that have a high potential

for painful consequences such as buying sprees, sexual indiscretions

or bad business decisions

decreased need for sleep while still feeling rested.

But these specifiers are core symptoms of bipolar disorder and that should be the diagnosis!  There appears to be no scientific evidence for or need to invent a new category of mixed depression. This was very puzzling until I attended a presentation promoting the use of the antipsychotic medication Lurasidone for “mixed states”.

References

1. Zohar J, Allgulander C. Antipsychotics in anxiety disorders: An oxymoron or a reflection of   non-adequate nomenclature? European Neuropsychopharmacology, 21, 6, p.427-428, June 2011.

2. Wakefield J.  The editor’s dilemma: how DSM politics are

turning psychiatry into a pseudoscience. Acta Psychiatrica Scandinavica 132,

6  p.415 - 502, December 2015.

3. Rosenheck R. Second generation antipsychotics: evolution of scientific knowledge or uncovering fraud. Epidemiology and Psychiatric Sciences (2013), 22, 235–237.

Alan Eppel