Table of Contents

Volume 1, Issue 2                                                                                      February, 2015


Special article: 

Antipsychotics (dopamine blockers) in bipolar depression 

There's more to it than FDA indications


FDA-indicated medications for acute bipolar depression are quetiapine (Serquel), olanzapine- fluoxetine combination (Symbyax, also called OFC), and most recently lurasidone (Latuda).  PL holds the view that two medications which do not have FDA indications, ziprasidone (Geodon) and aripiprazole (Abilify), also have a scientific rationale for efficacy in bipolar depression.

Of these agents, quetiapine and OFC have, by far, the worst risks, especially if used long-term (given that they worsen metabolic syndrome and cardiovascular risks).  Thus, PL recommends lurasidone, aripiprazole, and ziprasidone - not quetiapine or OFC -  as the primary dopamine blocker treatments for bipolar depression.  The rest of this article will explain this recommendation.  

“PL recommends lurasidone, aripiprazole, and ziprasidone - not quetiapine or OFC -  as the primary dopamine blocker treatments for bipolar depression.” 

Dopamine blockers, not “antipsychotics”

It's  illogical to speak of “antipsychotics” for bipolar depression.   Most cases of bipolar depression don't involve psychotic symptoms (delusions or hallucinations).  So why do we speak of “antipsychotics” for non-psychotic bipolar depression?   The drug companies will tell you:  Well, there are “antidepressant effects” to antipsychotics; or, worse: “antipsychotics” are also “antidepressants.”

Readers of George Orwell will know that his dystopic vision of a “Newspeak” that abuses  language for nefarious purposes has come into existence.  This is not just PL's opinion.  The  European College of Neuropsychopharmacology (ECNP) and the American College of Neuropsychopharmacology (ACNP) recently completed task forces on psychiatric drug nomenclature where they make the same statement:  the names we use for our drugs are scientifically incorrect and clinically misleading.  Orwell said it long ago:  Thought is constrained by language. If we use false terms, we’ll have false thoughts.

So let's stop using the phrase “antipsychotic” (or “antidepressant”, for that matter; PL will address that topic in a future issue).  “Antipsychotics” are not just effective for psychotic symptoms; they have many other non-psychotic uses:  for depressive symptoms, for anxiety, sleep, agitation in dementia or delirium, even for physical states like emesis.  The ECNP/ACNP task forces recommend using clinically neutral terms based on biological mechanisms. PL recommends the general term “dopamine blocker” for this class of agent. (Biological definitions have their own limitations, we realize: drugs have more than one mechanism, and they differ on potencies for any mechanism; but, in agreement with ECNP/ACNP, we think this terminology is less false than any other).  

By changing our language, we'll immediately realize that these agents aren't limited to “psychotic” conditions.  Hence their use in (non-psychotic) bipolar depression. 

Acute bipolar depression

Dopamine blocker studies exist mainly for acute bipolar depression, meaning a current severe clinical depressive episode that usually lasts 2-6 months.  The usual duration of treatment, in standard FDA studies, is 6-8 weeks.  

Thus, to the extent there is scientific evidence of efficacy of dopamine blockers in bipolar depression, that evidence exists for about 2 months of treatment. That’s it.  Not 2 years.  And certainly not 20 years. 

In other words, this research evidence, if valid, would instruct you to treat bipolar depression with dopamine blockers for two months, and then stop those agents.  To say that dopamine blockers should be continued, we would need evidence of maintenance efficacy of these agents.  You might say we have such evidence for some of these agents. The PL viewpoint is that the efficacy of those agents is not well-proven in scientifically valid maintenance designs in bipolar illness. 

It is worth pointing out that there are no data on OFC for maintenance treatment (olanzapine is not the same), and that the aripiprazole maintenance study found that it was not effective in prevention of bipolar depressive episodes (efficacy was present only in prevention of manic episodes).  Thus, long-term preventive efficacy cannot be assumed from acute efficacy data.  

Olanzapine-fluoxetine combination (Symbyax)

The  Study of the Month dissects the data behind OFC. As described there, that study proved that olanzapine did not work for treating bipolar depression, and, the amount of data supportive of OFC is rather small in size and less definitive than you might believe. 

Quetiapine (Seroquel)

Acute bipolar depression studies with quetiapine are, superficially, more straightforward than with OFC.  Astra Zeneca planned two large 8 week trials of quetiapine alone versus placebo, and the drug worked in both cases, with large effect sizes of benefit that included core mood symptoms (like anhedonia, low energy, and sad mood). The FDA provided the requisite indications. 

As clinicians and patients know, quetiapine is an extremely sedating drug.  It has potent antihistaminic, antiadenergic, and anticholinergic effects, as discussed in the Drug of the Month below.  One would tend to notice taking it. Some  academic leaders involved in the quetiapine studies acknowledge that it's likely that those RCTs weren't truly blinded: Patients could tell when they took quetiapine, and when they didn't (received placebo).  Unblinded studies tend to increase treatment effect sizes, hence the quetiapine studies likely overestimate  its benefits.  

In sum, quetiapine showed benefit; but is it  as big of a clinical benefit as it seems, or an inflated effect of a highly sedating drug?

Lurasidone (Latuda)

The newest FDA-indicated agent, was shown effective in two 6-week RCTs of bipolar depression. It isn't sedating, and other  aspects of study design seem valid.   In short, of the three agents with FDA indications, this one seems to have the most valid scientific proof.  

Aripiprazole (Abilify)

Now we come to  agents without FDA approval for bipolar depression. Let’s begin with aripiprazole.  Bristol Myers Squibb did two 8 week trials of this agent for bipolar depression. In both cases, repeatedly, the drug was better than placebo from weeks 1 through 6, but at week 8, placebo showed a benefit which reduced the overall effect size and led to a p-value above 0.05 (not statistically significant).

See figures, MADRS= Montgomery Asberg Depression Rating Scale:

FDA indication wasn't given since the study was designed with the a priori outcome of improvement at 8 weeks.  

The PL viewpoint is that aripiprazole was effective in bipolar depression, because the benefits seen at 4 and 6 weeks are more meaningful scientifically than the final 8 week endpoint.  

This is why:  The duration of a study should be adjusted to the duration of an illness. There is no general rule that a study should be long, or that the longer the study, the better it is.  Mania RCTs are only 3 weeks in duration, because manic episodes are short, lasting 2-4 months untreated according to some studies.  Unipolar depression studies are 8 weeks long because unipolar depressive episodes are long, lasting 6-12 months untreated.  But bipolar depressive episodes, though longer than mania, are shorter than unipolar depressive episodes. According to a century of natural history data dating back to Kraepelin, bipolar depressive episodes tend to last 2-6 months, less in those with rapid-cycling course (about one-quarter of bipolar subjects).  So, if you conduct a trial that is 8 weeks long, in a condition where a substantial minority of patients are improved by 2-3 months, you will have a “placebo” rate of improvement, due to natural remission, that is high.  This makes it difficult to show drug benefit.  Thus 6 weeks is more scientifically valid than 8 weeks for the duration of a  bipolar depression trial.  The PL editor made this point to Bristol Myers Squibb when it planned the original bipolar depression study.  That mistake has confused some clinicians into thinking the drug has no benefit for a condition in which it showed benefit.  

This is why the lurasidone studies were 6 weeks long. And this why the aripiprazole study’s effect at 4 and 6 weeks shouldn't be ignored. 

If aripiprazole improves depressive symptoms, it isn't surprising that other studies found it to be effective in unipolar depression, leading to FDA indication as augmentation of antidepressants. 

Lastly, although PL strongly believes that biological rationale should not be the primary factor in treatment decisions, biological mechanisms are relevant for interpreting clinical trial data.  Aripiprazole is a moderate dopamine agonist.  Dopamine agonists (like amphetamines and bupropion) tend to improve depressive symptoms. In contrast, olanzapine and quetiapine have little monoamine agonist effects (minor effects were shown retrospectively in some animal studies later conducted by their companies), and certainly not as much as aripiprazole (or ziprasidone).  

Ziprasidone (Geodon)

Based on biological mechanism, if any dopamine blocker is going to be effective for depressive symptoms, it should be ziprasidone.  It's the only modern dopamine blocker that also is a serotonin reputake inhibitor (SRI) and a norepinephrine reuptake inhibitor (NRI).  Its effects are about equally as potent as standard SRI and tricyclic antidepressants.   The trouble is that Pfizer conducted two RCTs of ziprasidone versus placebo in acute bipolar depression, and it didn't work.  Unlike aripiprazole, there wasn't benefit at some weeks but not others. There just wasn't benefit.  

This should seem odd: Drugs without strong monoamine agonism, like quetiapine, are supposedly "antidepressant" in their effects, while drugs with strong classic antidepressant mechanisms are not "antidepressant" in their effects.  How can this be?

Perhaps it comes back to clinical concepts.  "Bipolar depression" just means a current "major" depressive episode in someone with past mania/hypomania.  As with "major" depressive episodes in unipolar depression, it may represent multiple different depressive subtypes, as discussed in the PL website.  One relevant subtype is "mixed depression", i.e., depression mixed with manic symptoms (discussed here). It could be that the apparent "antidepressant" effect of dopamine blockers has to do partly with dopamine blockade itself, which is effective for mixed manic/depressive states, rather than with mood elevating monoamine agonism effects of classic SRIs/ NRIs.  

This hypothesis could be tested by studying ziprasidone in patients with "mixed depression".  About a decade ago, the PL editor designed and conducted this project and indeed ziprasidone was effective, better than placebo, in an overall sample of 73 subjects. 

This result is similar in size to the OFC study arm (n=78).  In other words, the widespread use of OFC is based on an amount of scientific evidence that is similar to what exists with ziprasidone for mixed depression.  Pfizer never sought FDA indication for mixed depression efficacy because ziprasidone was about to become a generic medication when this study was completed (hence there were no profit to be gained by marketing this use).  If clinicians only went by FDA indications, they would ignore  ziprasidone, not because efficacy data don't exist, but because there weren't economic motivations to obtain FDA indication for them.  

The case of ziprasidone and OFC shows why clinicians should focus on science, not primarily presence or absence of  FDA indications. 

Low doses

William Osler's axiom was that all drugs are toxic; it's only the dose and indication which makes them therapeutic.  In the aripiprazole studies of bipolar depression, secondary analyses found that in those treated wtih lower doses (5-10 mg/d), aripiprazole was more effective than placebo; it was in the higher dose group (>10 mg/d) that placebo seemed similar to aripiprazole. In the lurasidone montherapy studies, the low dose arm (20-60 mg/d; mean dose 32 mg/d) was equivalent in efficacy to the high dose arm (80-120 mg/d; mean dose 85 mg/d). It is the PL clinical experience that a similar principle may apply  with ziprasidone.  At low doses (<80 mg/d), we've seen patients show good improvement for bipolar depression; it could be that higher doses are less effective. This observation seems to contradict common clinical intuitions: we tend to believe that more is better. But this isn't always the case. A biological explanation may be as follows:  At lower doses of all dopamine blockers, there is less dopamine blockade. It's commonly believed that about 80-90% dopamine blockade is needed for full antipsychotic effect.  That's great, but we're not treating psychosis here; we're treating mostly non-psychotic bipolar depression.  It could be that only about 50% or so of dopamine blockade is sufficient to get benefit for the manic aspects of the mixed depressive state in bipolar depression.  Thus, higher doses of dopamine blockers may confer no further mood benefit. Turning to the dopamine agonism of aripiprazaole and the serotonin/norepinephrine reuptake blockade of ziprasidone, these effects are present to the same extent at any dose, including low doses.  

"We tend to believe that more is better."

So it could be that low doses provide a good amount of "antidepressant"-like monoamine agonism, with sufficient dopamine blockade for manic symptoms. While higher doses might just produce more and more dopamine blockade, which might just produce more antimanic effect, moving the mood down, rather than elevating it. 

These biological explanations may or may not be correct, but as we said in issue 1, the PL approach is to emphasize the clinical research evidence, which indicates more benefit in bipolar depression with lower doses of dopamine blockers.  We encourage clinicians to avoid using the high doses shown effective for schizophrenia and mania as their standard for treating bipolar depression.  This rule is especially important, we think, to see the benefits of aripiprazole and ziprasidone.

"Clinicians should avoid using the high doses shown effective for schizophrenia and mania as their standard for treating bipolar depression."

Weighing risks and benefits

Osler's dictum that the art of medicine is the art of balancing probabilities also comes into play.  Clinicians shouldn't just use those drugs which are FDA-indicated, and hence marketed to them.  They should compare the scientific evidence of all drugs, take into account comparisons of side effects among drugs with scientific evidence of efficacy, and then weigh probabilities of benefits versus harms.  As discussed in the drug of month section, quetiapine has notable and long-term metabolic syndrome and harmful cardiovascular effects.  So does olanzapine.  When these known common harms are taken into account, it seems to PL that the benefit/harm calculation tilts in the direction of lurasidone, aripiprazole, and ziprasidone.

These three agents are left mainly with the risk of akathisia (see the PL website for more on akathisia), which can present as worsened agitation and/or suicidality. Akathisia is clinically dangerous and immediate intervention is needed, either by stopping the dopamine blocker, or by lowering its dose and/or adding a counteracting agent.  Among counteracting agents, PL experience and a limited scientific literature suggest that beta-blockers are the most effective, especially propranolol, which crosses the blood-brain barrier more easily than other beta-blockers.  In the US, a generic slow-release formulation, propranolol ER is now available without insurance restrictions. We recommend it to be given at night, since its benefits extend throughout the day.  Doses begin at 60 mg/d.  Pulse should be followed so it doesn't fall below 60 beats/minute.  In healthy middle-aged persons,  propranolol ER dose range for akathisia tends to be 60-120 mg/d.

How to dose

Lurasidone: Give 20 mg at night for 2-3 weeks.  Increase to 40 mg at night if there's no benefit at all. In a minority of cases, consider going to 60 mg/d. Remember: higher doses above 60 mg/d were not more effective in the monotherapy RCTs of bipolar depression, where the mean effective dose was 32 mg/d.  A common mistake is to see higher doses, like 60-120 mg/d, used based on FDA labeling  for schizophrenia studies, not bipolar depression. 

Aripiprazole:  Begin with 2 mg at night for 2-3 weeks.  If there's no effect, increase to 5 mg at night for 2-3 weeks.  If there's no effect, increase to 7.5 mg at night for 2-3 weeks. If there's no effect, increase to 10 mg at night.  Higher doses than 10 mg/d are proven less effective for bipolar depression than lower than 10 mg/d. Thus there is no reason to use more than 10 mg/d. Again, a common mistake is to go up to 20-30 mg/d based on FDA labeling for schizophrenia or mania, not bipolar depression.

Ziprasidone:   Begin with 20 mg at night for 2-3 weeks.  If there's no effect, increase to 40 mg at night for 2-3 weeks.  If there's no effect, increase to 20 mg in the morning and 40 mg at night for 2-3 weeks. If there's no effect, increase to 40 mg twice daily. In the PL experience, higher than 80 mg/d doesn't tend to produce more efficacy for bipolar deperession. Instead, akathisia increases with higher doses. 

If patients develop akathisia despite having some benefit with one of these agents, we recommend adding propranolol ER 60 mg at night, increasing as needed to 80-120 mg at night.  If there's no or little benefit with one of these agents, and akathisia occurs, we recommend simply stopping the dopamine blocker and trying a different one. 

If akathisia occurs with multiple dopamine blockers, we recommend pre-treatment with propranolol ER 80-120 mg at night before starting a different dopamine blocker trial.  

PL Reflection

We will develop better new drugs but it will be a continual challenge for doctors to learn how to properly use them. Otherwise it would be like giving a driver’s license to someone who can’t drive.

Frank J. Ayd, Jr MD 2005

The PL Bottom Line

  • PL recommended agents for bipolar depression are lurasidone, aripiprazole, and ziprasidone. 
  • Low doses should be used. Akathisia is the main problem with these agents. Propranolol ER can be used to manage that problem in some cases.
  • The benefit of quetiapine is probably overestimated in its studies.  
  • Olanzapine alone is proven ineffective. 
  • Dopamine blockers may mostly help "bipolar" depression when it represents "mixed depression", the combination of severe depression with some manic symptoms.

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