Treatment-Emergent Mania Is A Myth

Let's say that you're at your buddy's house. You're watching a crappy prime-time network program (the episode where Jack Bauer goes down on Madam President). Suddenly, your friend stands up, goes to the fridge, and takes out a diet-coke in a black can (d-bags call it Coke Zero). Before opening the can, he methodically taps his index and middle fingers on top of the can.

When you hear the tapping, you casually turn your head toward your friend and ask, "Are you retarded?"

"No," says your soon to be former friend, "I'm knocking loose the bubbles from the bottom of the can so they float to the top, so it won't foam when opened."

If you haven't tried this technique, you have certainly seen someone do it, despite the fact that it doesn't work (1). It's simply just not true, yet people all over the world perform this little trick and proudly profess their discovery to others, who then spread this good news to even more people. After enough time, a myth is transformed into a fact.

Another myth that has been accepted as fact is antidepressant induced mania, which is the topic of study in this pointless investigation (2). The study is titled, "Correlates of Treatment-Emergent Mania Associated With Antidepressant Treatment in Bipolar Depression." The stated goal of the study is to examine "the correlates associated with treatment-emergent mania in patients receiving adjunctive antidepressant treatment for bipolar depression."

Hidden beneath these words is the assumption that antidepressant induced mania is a real phenomenon with legitimate scientific backing. Moreover, it means the authors (all 13 of them) cited research studies that support this assumption.

"While antidepressants may be effective in some individuals with bipolar disorder, they can precipitate a rapid mood switch from depression to mania (8, 14, 15), a phenomenon also known as treatment-emergent mania." (2). According to this sentence, studies 8, 14, 15 are studies that utilize the scientific method to provide nearly conclusive evidences that "treatment-emergent mania" is a real phenomenon.

Reference 8 is a letter to the editor (3). It's in reference to a study published in 2005, in which antidepressants were found not to induce mania. I'll repeat that, because it sounds mildly important. The study found that antidepressants did not induce mania, yet, this letter was referenced as evidence in support of antidepressant induced mania. Drater spelled backwards is what?

Reference 14 is titled, "A placebo-controlled evaluation of adjunctive modafinil in the treatment of bipolar depression" (4). First, modafinil is an arousal promoting agent (that's pharma speak for stimulant), not an antidepressant*. Secondly, the study found this, "there was no difference between groups in treatment-emergent hypomania or mania." They're 0 for 2.

Reference 15 is here (5). This study actually looked at the phenomenon of treatment emergent mania; however, it was a meta-analysis that found this, "In bipolar depressives, manic switch occurs substantially more often with TCAs (11.2%) than with SSRIs (3.7%) or placebo (4.2%)". The SSRI rate was lower than the placebo rate. Since this study (2) looked at the antidepressants sertraline, venlafaxine, and bupropion (SSRI, SNRI, & DNRI) and not TCAs**, that's strike three.

I vaguely recall myself complaining about not reading references before citing them (6, 7). What exactly to peer reviewers do anyway?

I had to re-read this study. When I found out that the authors cited 3 studies in support of their assertion that countered their assertion, I blacked out, only to wake-up 7 days later in Butte, Montana digging for copper in a pair of crotchless panties.

However, I should have stayed in Butte. When I picked-up where I left off, I read this, "more than 40% of patients enrolled in STEP-BD self-reported manic or hypomanic switch associated with antidepressant use." Self-reported? Parents self-reported that vaccines caused autism in their children. I'm suppose to accept patient self-reports as proof when patients cannot remember if they were hospitalized for a mood episode (8, I know the book has 1,200 pages; I'm too lazy to find the reference, but trust me it's in there, somewhere, I think..., don't quote me on that).

Here is where the researchers exhibit that special kind of stupid that I mentioned briefly in this post (9). The study found "that minimal manic symptoms at baseline coexisting with otherwise full syndromal bipolar depression are associated with antidepressant treatment-emergent mania or hypomania." Some could argue that the switch (as evidence by minimal manic symptoms) was already in progress, before the antidepressant was on board. Bipolar disorder is, after all, a highly recurrent disorder.

I could say more about this study, but my head hurts. I may have just popped an aneurysm. You can read more about this study and still learn nothing by going here (10).

You can read more about antidepressant induced mania here (11).

* Technically, "antidepressant" is a meaningless term. The FDA regulates what drug companies can advertise their drugs as treating. There are many classes of drugs (e.g., TCA, SSRI, NASSA), all of which have different mechanisms of action and are all equal in efficacy (roughly). A drug can have antidepressant properties and not be labeled as an antidepressant. Just because one subclass of antidepressant might increase switch rates does not mean all antidepressants increase switch rates. Modafinil works by stimulating the tuberomammillary nucleus of the hypothalamus, thus increasing arousal (in case you cared to know).

** Although the proposed mechanism of action for TCAs is through serotonin-norepinephrine re-uptake (SNRI), they are dirty drugs. They also block histamine receptors, muscarine receptors, and alpha adrenergic receptors. Those additional properties might explain the differences between TCA and SSRI in that one study.



M. A. Frye, G. Helleman, S. L. McElroy, L. L. Altshuler, D. O. Black, P. E. Keck, W. A. Nolen, R. Kupka, G. S. Leverich, H. Grunze, J. Mintz, R. M. Post, T. Suppes (2009). Correlates of Treatment-Emergent Mania Associated With Antidepressant Treatment in Bipolar Depression American Journal of Psychiatry, 166 (2), 164-172 DOI: 10.1176/appi.ajp.2008.08030322

I Need a Pill to Erase Stupid People

**WARNING: SCIENTIFIC CONTENT**

In this month's issue of Nature Neuroscience (1), there is an article titled "Beyond extinction: erasing human fear responses and preventing the return of fear." Anyone who has taken a general psych course knows that the term "extinction" refers to the process of unpairing a conditioned response from a conditioned stimulus. It's a component of classical conditioning.

"I'm bored." Wait, it gets better...

It works like this: You have an - unconditioned response-UR (e.g., hardened nipples), which is evoked reflexibly by the unconditioned stimulus-US (ice cubes). When you pair the US with a neutral stimulus that does not cause hardened nipples (e.g., Jonas Brothers), this is called the conditioned stimulus-CS. After the US, which leads to the UR, has been paired repeatedly with the CS, then the CS alone will elicit the same response, this is called the conditioned response-CR. Finally, when the CS is presented in the absence of the US repeatedly, the CR frequency is reduced, thus rendering the Jonas Brother incapable of hardening nipples; this is referred to as extinction.

This study (1) used a paradigm known as fear conditioning. It's identical to the process-above, except the CS is usually a noxious stimulus (e.g., Fall Out Boys). This form of memory is a type of implicit (i.e., unconscious) memory and primarily involves a subcortical structure called the amygdala. Take note of the word unconscious, because it will reveal how big an idiot you are, if you work for a print media outlet.

The study found "that oral administration of the beta-adrenergic receptor antagonist propranolol before memory reactivation in humans erased the behavioral expression of the fear memory 24h later and prevented the return of fear. Disrupting reconsolidation of fear memory opens up new avenues for providing a long-term cure for patients with emotional disorders." (1).

In response to these findings, which are not new (2), the following headlines were generated: "Beta-Blocker Erases Bad Memories" (3), "Pill Could Erase Bad Memories" (4), and my favorite, "Pill to erase bad memories: Ethical furore over drugs 'that threaten human identity'"(5). In that last article, an expert in "biological" ethics (the ethics caused by a chemical imbalance) opines, "It is obviously up to the individual whether or not she wishes to risk the possible effects, including psychological discontinuity, of erasing unpleasant memories. An interesting complexity is the possibility that victims, say of violence, might wish to erase the painful memory and with it their ability to give evidence against assailants. Similarly criminals and witnesses to crime may, under the guise of erasing a painful memory, render themselves unable to give evidence." Wow, he's a special kind of stupid.

The type of memory this cognitively retarded individual is discussing is called declarative memory, the knowledge to which we have conscious access (e.g., events and facts). Implicit memory, in contrast, is the knowledge to which we typically have no conscious access (e.g., motor skills, fear responses). Typically, I'd go easy on someone who lacks neuroscience training; however, if you read the damn article, it says, in black-and-white print, that propranolol (which suppresses the activity of the sympathetic nervous system) reduced the conditioned fear response, while leaving the "declarative memory for the acquired contingency between the conditioned and unconditioned stimulus intact" (1).

First, the authors should not have used the word "erased." Media types jump all over stuff that evokes images (a conditioned response) of 1930's science-fiction movies. Secondly, blink-rate was the behavior measured. No other behavioral measure of fear was studied. Thus, it is inconclusive that the fear response was completely erased. Moreover, in the body of the article, the authors state, "...that the fear memory may either be erased (storage theory) or may be unavailable as a result of retrieval failure (retrieval theory). Note that no behavioral procedure is currently available that differentiates between these two views of amnesia." They don't even know which process it is, or if it's either process. Personally, I throw my support behind a connectionist model of memory.

"What's that?"

Look! Midgets! (6).

Just like all other researchers who lack clinical experience and want to make their results seem more important than they are, they threw in this whopper, "disrupting the reconsolidation of fear memory opens up new avenues for providing a long-term cure for patients with emotional disorders." The disorder they specifically mention is post-traumatic stress disorder (PTSD).

The specific memory process they are trying to disrupt is called "reconsolidation," the process by which a memory (either declarative or implicit), after encoding and consolidation, is strengthened when recalled. This is actually a more efficient way of learning than through repetition alone (that's why flashcards are better than reading notes, 7). Their hypothesis is that the administration of a drug that partially suppresses the sympathetic nervous system (SNS) when a conditioned fear response is cued (i.e., recalled) supposedly disrupts reconsolidation, and the fear response is dampened (i.e., not strengthened).

The reason why this won't be a "long-term cure" for emotional disorders, especially PTSD, is due to the fact that "bad" memories are both declarative (i.e., hippocampus-dependent) and implicit (i.e., amygdala-dependent). The two memory systems are separate (known as double dissociation) and can function independently. This is the reason why the fear response was suppressed, but the memory for the conditioning events were intact. At the same time, this does not mean that one system cannot influence the other.

For example, amygdala activity (e.g., fear) has been shown to strengthen the consolidation (as opposed to reconsolidation) of memories. This happens through enhancement of hippocampal functioning (8). Moreover, amygdala activity can interact directly with the hippocampus during the initial encoding phase of an experience, which also positively affects long-term consolidation.
In other words, amydala activity can modulate declarative memory at multiple stages (encoding, consolidation, and reconsolidation) leading to a net effect of enhanced retention. IMPORTANT POINT: the more intense the stimulus (e.g., severe trauma), the better consolidated the memories will be (both declarative and implicit).

People (such as soldiers) who experience severe trauma, have very vivid declarative memories and intense emotional memories of their trauma. Both unconscious and conscious stimuli can provoke intense emotional and cognitive reactions (e.g., autonomic arousal, flashbacks). A soldier, who was a patient where I work, reported that s/he witnessed 19 of his/her fellow soldiers being killed (2 by suicide). That's a little more intense than a gentle electric shock or pictures of spiders. Do you think propranolol (half life of 3.4-6 hrs) will "erase" his/her fear response? I don't.

Cognitive-behavioral therapists will tell you that in addition to emotions leading to certain thoughts, thoughts can lead to experiencing emotions. Since the emotional memory process (amygdala-dependent) can enhance declarative memories during encoding, consolidation, and reconsolidation; administration of a beta-blocker before the reconsolidation phase (which was done in this study) could be too late. To truly help these people, you would have to prevent initial consolidation. This means people would have to be treated prophylatically (i.e., give people the drug before the trauma). The problem for a soldier is that propranolol reduces reaction times, something that could mean life or death for a soldier (plus there is no evidence that it prevents fear conditioning).

As it relates to memory reconsolidation, propranolol produces results similar to sedatives (i.e., benzodiazepines, 9, 10), which are commonly prescribed to people with PTSD and only manage anxiety (i.e., not a cure). I'm failing to see the scientific breakthrough here. If you really want to help our veterans, be sure to blow smoke in faces of the children they hardly ever see (11).



Merel Kindt, Marieke Soeter, Bram Vervliet (2009). Beyond extinction: erasing human fear responses and preventing the return of fear Nature Neuroscience DOI: 10.1038/nn.2271

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Smokers Give Their Partners Dementia

Adding to the exhaustive list of societal ills supposedly caused by smokers (e.g., heart disease, diabetes, J. Geils Band), is this article published in the British Medical Journal (1).

To be quite honest, as far as studies of second hand smoke (SHS) go, this is quite good. But then again, Hillary Clinton looks good next to a bloated and naked Alan Schatzberg.

One thing this study included that most studies of SHS didn't was an actual objective measure of nicotine exposure (cotinine). Typically, study participants are given questionnaires in which they are asked to remember past exposure to SHS during the earlier decades of life. That's not what I would call "scientific."

First the results: "Participants who did not smoke, use nicotine products, or have salivary cotinine concentrations of 14.1 ng/ml or more were divided into four equal size groups on the basis of cotinine concentrations. Compared with the lowest fourth of cotinine concentration (0.0-0.1 ng/ml) the odds ratios (95% confidence intervals) for cognitive impairment in the second (0.2-0.3 ng/ml), third (0.4-0.7 ng/ml), and highest fourths (0.8-13.5 ng/ml) were 1.08 (0.78 to 1.48), 1.13 (0.81 to 1.56), and 1.44 (1.07 to 1.94; P for trend 0.02), after adjustment for a wide range of established risk factors for cognitive impairment."

While the authors did control for known risk factors for cognitive impairment, they didn't control for known factors associated with elevated cotinine (other than SHS).

Once nicotine is in the body, between 70-80% is converted to the metabolite cotinine by the P450 liver enzyme CYP2A6. The remainder is converted into nicotine-N-oxide, nornicotine, and norcotinite. All of which are excreted in urine. Cotinine usually sticks around in your system for 20-25 hours after exposure to nicotine. What its presence does not indicate, is how one came in contact with nicotine.

Therefore, "Cotinine is a marker of exposure to many risk factors other than tobacco smoke. These correlations could confound studies of the health effects of smoking, especially passive smoking." (2).

Here are some of the known factors that are associated with increased levels of cotinine in nonsmokers: low education, low SES, high alcohol consumption, low fruit or vegetable consumption, high fried food consumption, and low breakfast cereal consumption. These are just the factors significant at the p<0.001 level and doesn't include factors at levels 0.01 and 0.05.

Lastly, some people, due to genetic variation, have low CYP2A6 activity, which reduces the rate of nicotine metabolism. These people are more likely to be nonsmokers (3).

Since none of the above-mentioned factors were taken into consideration, what the BMJ study is actually examining is the association between cotinine level and cognitive impairment, not SHS exposure per se.

I'm still not convinced by this apparent association either. The highest level of cotinine was 13.5ng/ml. In this study (2), the amount of cotinine is actual smokers ranged from 80.9ng/ml to 389.4 ng/ml, while nonsmokes ranged from 0.6 ng/ml to 0.8 ng/ml.

If nicotine exposure in small amounts can lead to cognitive impairments (as the study suggests), then smokers should be developing dementia at rates similar to people with Down syndrome (4). Since less than a quarter of the population are smokers (5, there are more ex-smokers than smokers now), a decline in the rate of dementia should be on the horizon.

That's about as likely to happen as electing an Arab US president (Obama doesn't count, he's only half Arab).

I know people love to hate smokers and like to pretend SHS exposes people to nearly equal amounts of toxic chemicals and increased health risks as actual smokers (read this idiot's rant, 6), but that's just not the reality of the situation (7, 8).

Besides, SHS is so 1990's. Today, we are faced with a new threat to our health: Third-Hand Smoke (9). I shit you not. Go ahead, read the article while I have a smoke...

Did you read it? Are you afraid for your child's health and safety? Well, I hope you are, because that was the entire point. I'm actually feeling guilty for blowing smoke in the faces of all those babies at that Romanian orphanage. Excuse me while light-up another one...



David J Llewellyn, Iain A Lang, Kenneth M Langa, Felix Naughton, & Fiona E Matthews (2009). Exposure to secondhand smoke and cognitive impairment in non-smokers: national cross sectional study with cotinine measurement BMJ

Good News for Rat Psychiatry

"Nicotine Exposure During Adolescence Induces a Depression-like State in Adulthood" is the title of a study published by Bolanos et al (the fruity looking guy to the right, 1).

The summary over at Sciencedaily is titled "Teen Smoking Could Lead To Adult Depression, Study Says" (2).

As you can see in the picture, Ms..err..Mr. Bolanos is pictured with a group of rats and not with Jonas Brothers. However, the title of his study, plus the conclusions he and his colleagues draw, lead you to believe that they are referring to actual people.

"Carlos Bolanos and a team of researchers found that nicotine given to adolescent rats induced a depression-like state characterized by a lack of pleasure and heightened sensitivity to stress in their adult lives. The findings suggest that the same may be true for humans." Actually, nothing in this study suggests that same may be true for humans.

Why is that? Because they studied rats.

You mean Harry Reid and Nancy Pelosi?

No, I mean members of the genus Rattus; Reid and Pelosi are members of Desmodus rotundus (3).

The rats were injected with "either nicotine or saline for 15 days. After the treatment period ended, they subjected the rats to several experiments designed to find out how they would react to stressful situations as well as how they would respond to the offering of rewards."

The said stressful situations included: running in an open field, running in a maze, and forced swimming. The reward paradigm was the administration of sucrose. Clearly, this screams ecological validity.

"The rats that were exposed to nicotine engaged in behaviors symptomatic of depression and anxiety."

Adding, "the researchers were able to alleviate the rats' symptoms with antidepressant drugs or, ironically, more nicotine." Okay, that last sentence was just plain stupid. Perhaps these people need a primer on the neurobiology of nicotine.

The average cigarette contains approximately 6-11mg of nicotine. However, when smoked, only 1-3mg reaches the circulation (the rats were given .32mg/kg twice-a-day, which seems excessive for an animal that weighs 250g. Studies I have read usually dose rats with 10 μg/kg). The half-life (amount of time it takes for half of the drug to be excreted) is typically around 2 hours. Because of the short-half life, a characteristic withdrawal syndrome (e.g., anxiety) begins rather quickly.

Here's the rub, when nicotine is re-administered, those symptoms disappear. There is nothing ironic about it. Secondly, the antidepressnat used in the study (bupropion) is a dopamine (DA) reuptake inhibitor. As fate would have it, nicotine leads to a transient increase in DA. I think these researchers were treating withdrawal, not a "depression-like state."

I know the withdrawal syndrome can be characterized as a "depression-like state," but they are passing this off as if its actual depression, which it's not.

Why isn't it? Two words: animal model.

Here's the problem with animal models of depression (or any other psychiatric disorder). Whereas many diseases can be considered at a molecular level, mental illnesses lack such pathophysiological understanding and are reliant upon lame and nonspecific syndromal classifications (e.g., DSM-IV-TR), which renders animal models as less valid.

For those not in the know, construct validity (as it relates to animal models) is "the accuracy with which the model replicates the key abnormalities or phenomena under study within the clinical condition" (4). Another important aspect of depression animal models is its predictive validity, the "given model's ability to correctly identify effective antidepressant treatments, usually drugs." Clearly, that hasn't happened yet (4, 5, 6).

As it relates to our good ol' friend agent 296.3 ( AKA Major Depressive Disorder), "there are no symptoms, nor any other clinical features, that are pathognomonic for depression. Assumed 'core' psychopathological phenomena such as a blunting, or absence of the capacity to experience pleasure (anhedonia), can also present as a common clinical feature in substance misuse and schizophrenia" (4).

Here is what the "depression-like state" in those rats looked like, "repetitive grooming, decreased consumption of rewards offered in the form of sugary drinks (supposedly an analogue to anhedonia), and becoming immobile in stressful situations instead of engaging in typical escape-like behaviors."

It's very similar to human depression as you can see. Also, the authors admitted that "the effect size of nicotine on sucrose preference (the anhedonia analogue), though statistically significant, is small, and that nicotine did not influence total sucrose intake" (1).

As should be obvious, many of the symptoms of depression are quite difficult to model in animals (e.g., suicidal ideation). What is suppose to be science is actually an exercise in logic, "arguments for the validity of animal models rely on Causal Analogical Models (CAMs)" (4).

What!?

"These CAMs are underpinned by Casual Analogical Reasoning."

WTF!?

I have no idea either; but I think I made my point.

The reasoning goes like this: 1) Animal A is similar to animal B, with regards to properties 1, 2, and 3; 2) Animal A has property 4; 3) Therefore, animal B has property 4.

As it relates to depression, part 1 assumes that rats and humans are identical, which we are not, therefore assumptions 2 and 3 don't hold.

So why did Ms. Bolanos conclude his interview with this, "The message to young people of course is don't smoke and don't even try it, if they do smoke, they need to be aware of the potentially long-term effects that recreational or even occasional cigarette smoking can have on their systems."

Answer: He's an idiot.

By "long-term", he means one month, which is apparently how long it takes an adolescent rat to become an adult rat? (not my area of expertise). What I do know is this: Smoking cigarettes actually acts as an inhibitor monoamine oxidase A and B (7). This effect is not produced by the administration of pure nicotine, it's caused by other compounds in cigarette smoke. This means that cigarettes are actually MAOI's, which can be used to treat depression. If nicotine causes a "depression-like state," then cigarettes can counteract that "depression-like state."

So my message to young people of course is do smoke or at least try it. And while you're at it, blow smoke in a baby's face (8).



Sergio D Iñiguez, Brandon L Warren, Eric M Parise, Lyonna F Alcantara, Brittney Schuh, Melissa L Maffeo, Zarko Manojlovic, Carlos A Bolaños-Guzmán (2008). Nicotine Exposure During Adolescence Induces a Depression-Like State in Adulthood Neuropsychopharmacology DOI: 10.1038/npp.2008.220