Learned Safety and Antidepressants

A new animal study, published in Neuron, may provide a good model system for testing cellular and molecular interactions between antidepressants and behavioral treatments for depression.

Organisms have developed mechanisms for both instinctive and learned fear that help them survive. But in humans, sometimes learned fear can lead to anxiety disorders, stress and depression.

In earlier studies conducted by the some of same researchers, mice were taught to associate a specific noise with protection from an adverse event. Over time, the mice were taught to take advantage of sources of safety in their environment. The authors called this conditioned behavior learned safety.

In this latest study, lead authors Eric R. Kandel and Daniela D. Pollak set out to characterize some of the behavioral consequences of learned safety, and aimed to learn more about the phenomenon at the molecular level. The authors used specific sounds to condition mice to feel safe or fearful. To stimulate fear, a sound was paired with a mild shock to the mouse's foot. To stimulate safety, another sound was played without a shock.

Then the authors performed a stress test in all of the mice. They were placed in a pool of water, forcing the mice to swim. This type of test is commonly used to measure the affects of antidepressant medications on mice. The authors found that the mice that were conditioned to feel safe showed less signs of behavioral despair than those trained to feel fearful. Learned safety was shown to reduce anxiety as effectively as antidepressants such as Prozac®.

Next, the researchers tested how learned safety affected the development of newborn cells in the dentate gyrus, a structure located in part of the brain called the hippocampus. The dentate gyrus generates new nerve cells (neurons). The authors found that mice that were trained to feel safe had more newborn cells in the dentate gyrus compared to those that were trained to feel fearful.

The researchers also discovered that using radiation on the dentate gyrus both slowed safety learning and stunted the antidepressant effects of learned safety.

They also noted that safety learning increased the expression of brain-derived neurotrophic factor (BDNF) in the dentate gyrus. BDNF is a growth factor that promotes the growth and differentiation of new neurons and their connections.

Genetic analyses were also performed in the brain's fear center called the amygdale. Learned safety did not influence serotonin, the brain chemical that most antidepressant drugs target. Instead, learned safety was shown to influence levels of dopamine and neuropeptide brain chemicals. Both systems are thought to influence learning, mood, and cognition.

According to the authors, learning more about the cellular and molecular effects of behavioral conditioning may lead to new drugs for depression and anxiety disorders.

For more information about anxiety disorders, please visit Natural Standard’s Medical Conditions database. 

Comments

[Tim]

It is interesting that serotonin was not the main target for the mechanism of learned safety. Research on depression and drugs for depression have heavily focused on the role of serotonin. This research seems to indicate that another focus point may be available. Hopefully, this perspective will help bring about a new stream of antidepressant research.

[linda]

I have always been a believer in therapy that involves multidisciplinary approaches. Antidepressants, I believe, do have effects on depression; however, it works on a chemical level. There are many other factors besides brain chemicals that affect depression and that is why I strongly believe in psychotherapy in addition to the pharmacotherapy. Learned safety is an example of behavioral therapy that is most needed, and pharmacotherapy should be used adjunctively. I hope that people will soon realize that psychotherapy is the primary mode and that there are different types of therapy available to help cope with one’s illness from different aspects and different approaches.

[Chase]

I think the idea of learned safety promoting more neuronal growth is pretty amazing! Does anyone know whether antidepressants out on the market today have detrimental or inhibitory effects on neuron generation?

[Dani]

Behavioral treatments have never really come to my mind as a treatment option for depression, but this is great news! I bet there are many people out there who would prefer to seek behavioral treatment rather than drugs if it could be equally effective. I also feel as though behavioral treatments will be a better choice in the long-term since effectiveness and relief will not be dependent on the use of antidepressants.

[PK]

Since the dentate gyrus is thought to play a critical role in the development of new memories, it is not surprising that mice with damage to the area would have trouble with learned safety. Considering that neuropathways are not stand-alone structures in the body, I do not understand why anyone would think that only one neurotransmitter could be responsible for something as complex as mood. Perhaps more should be done to look at the linkages between the various neurotransmitters and areas in the CNS to get a better picture.

[mai]

I know that depression and anxiety treatment include both pharmacotherapy and psychotherapy. It would be so great that learned safety can be used in the treatment only without any antidepressant medications. As we all know how much side effects associated with antidepressants. Don’t we have enough pills (for everything) already? I don’t think we need another drug (targets behavioral) to treat depression and anxiety.

[M.K.]

I have heard of cognitive behavioral therapy for the treatment of depression, but learned safety sounds promising. Since this research studied the effects on the cellular and molecular level, one can see how neuronal changes are taking place with this mode of behavior. Hopefully, research will be able to expand on this.

[Jane Marie]

I feel that leaning toward behavioral therapies is a better option for depression treatment. Changing the behavior and feelings that are precursors to depression seems more effective and long lasting than only taking antidepressants. But than again, antidepressants might be more efficient if a chemical imbalance is the sole etiology for depression in certain patients.

[Kristen]

I think it is interesting that this research showed the generation of new neurons. Doesn't this indicate that learned safety is making effective changes in the brain? I have always associated the generation of neuronal connections to be an indicator that the brain is sort of rewiring itself. Maybe these new neurons are showing the progression of the mice out of a depressive state?

[michelle]

I'm interested to see how they would teach this "learned safety" to humans. It is easy to see how it would work in this particular experiment, but I'm not sure the sound of a bell or some other kind of noise would be helpful in teaching this concept to humans. Without this noise trigger continuously present, how would we know to go into "learned safety mode" instead of fear mode? This is a promising concept, but I think it needs a lot of research before it can be applied to humans.

[jacqi]

Michelle brings up a good point; it is not clear from this study how exactly this would be applied in humans. Using a technique like this in the treatment of depression is certainly warranted and would be an alternative to the use of prescription drugs. However, a lot more research needs to be done first so that a technique can be developed that patients would want to use.

[Loa]

If there is “learned” fear, then there is “learned” safety. We can condition ourselves to react differently to something that once emitted a negative reaction. It takes a lot of training. For example, if you have a boss who isn’t very tactful with words, your reaction is negative. You can either take his/her words personally or just toss them aside, and realize that the person is under stress or doesn’t mean to personally be insulting. It’s hard to do but can be done. Just imagine how happy and peaceful you would be if you could learn to change your reactions to the little things that annoy you.

[Tamara.S]

It is interesting to find that learned safety did not influence serotonin, the neurotransmitter typically targeted by antidepressant drugs. Learned safety appears to influence levels of both dopamine and neuropeptide neurotransmitters. This information provides interesting insight to a number of potential targets for new drugs. Perhaps new agents will influence the dopamine and neuropeptide pathways.

[SUMA]

Research has shown that depressive illnesses are disorders of the brain and that neurotransmitters appear to be out of balance. One of the most commonly accepted theories suggests that two naturally occurring substances, serotonin and norepinephrine, are believed to affect core mood and pain symptoms of depression. I agree with the authors that it is interesting that learned safety did not influence serotonin, as this is what is usually targeted by antidepressant drugs.

Other antidepressant drugs target dopamine. This study demonstrated that learned safety appeared to influence dopamine. Due to the fact that depression affects about 121 million people worldwide, any insights and research into developing and/or improving the current medications prescribed for depression is worth pursuing. Even more exciting would be confirming that behavior modification, without the use of drugs, could work.

[iris]

The new study is noteworthy because it reveals in detail how behavioral conditioning can affect the brain. Knowing how behavioral intervention works at the molecular and cellular levels may prove to be an interesting route to identify new ways to treat depression and anxiety disorders. The brain is awesome.

[lisa]

Depression is a disease that affects millions, and many who don’t even know what they’re feeling is considered depression. I have to say that some things are easier said than done. We have to keep in mind that while yes, we can train our minds to do anything we want it to, it will be a difficult course, a very difficult one. I’d like to remind readers that depression causes people to no longer have the same amount of interest in their hobbies. For many, it’s hard even to get up out of bed, literally. It could be that I cannot fully appreciate learned safety since this study was done in rats, as someone else as pointed out. What is learned safety, and how will it be employed in humans? Is it simply behavioral therapy, or will humans listen to noise triggers to learn safety?

[liz]

Depending on the type/severity of depression, either psychotherapy or pharmacotherapy could be an effective treatment for some, while for others require a combination of these therapies. It will be interesting to see how this learned safety could be acquired in humans or lead to the development of antidepressant drugs.

[Ann]

Learned safety seems to be a promising new treatment option. If applied in combination with cognitive behavioral therapy, which is usually the first line of therapy, the use of pharmaceutical drugs can be delayed even further or perhaps introduced at even lower starting doses. This is always an exciting option because few drugs equals few adverse effects.

However, more research on this subject is necessary. Is a learned safety a viable, long-term treatment option?

[dan]

It’s surprising that serotonin was not affected in this study. With so many side effects and adverse reactions associated with current SSRI therapy for depression, this study on learned safety may yield new alternative medications for depression. However, developing new medications based on this study may take many years. The modeling system for testing cellular and molecular interactions in this study seems very preliminary.

[PK]

From my understanding, the concept behind learned safety is the same as cognitive behavioral therapy. The idea is to change our associations with things/sounds/situations so we react in a more productive manner and realize that we can control how we feel about a situation. The major difference is that people are expected to play a more active role in changing their behavior than the mice were in this study. We cannot always remove the upsetting events in our lives (the shock), but we can adjust how we react and remove the anxiety we previously associated with them.

[lynn]

PK,

I agree with your comment that learned safety is the same as cognitive behavior therapy and that we can learn to adjust our reactions to the upsetting events in order to not feel anxious or to remove the anxiety. I think this approach to anxiety treatment is much safer, especially in young adults because they do not have to suffer the side effects of antidepressants anti-anxiety drugs.

[tim]

This is an interesting study. I think this therapy should definitely be studied more and expanded to be used in humans. It seems that it would be very helpful in patients with inappropriate responses to anxious situations. Perhaps it could even be expanded to be used in other types of psychiatric disorders?

[Jessica]

Tim, I think you bring up an excellent point! I too am curious whether learned safety could be used or applied to other psychiatric disorders. Music therapy and meditation are occasionally recommended in these patients. I think if psychiatric patients can train themselves to meditate, then they can train themselves to learn safety and learn how to deal with their anxiety.

[john]

According to a study published in Clinical Nutrition, it is estimated that 121 million people worldwide suffer from depression, which has many complex etiologies. That being said, it’s important that new ways to test drugs continue to be researched and developed. This new modeling system shows promise in developing new treatment for a very burdensome condition.

[K. Kelley]

This study is right on! Far too much of the population today has been diagnosed with anxiety or depression, yet we don’t know why this came about or how they may have learned their fear. I can’t help but wonder if exposure to television or videos or even video games at a young ages might not contribute inadvertently to this learned fear. I applaud learning more about the cellular and molecular effects of behavioral conditioning but would hope it could be corrected with therapy rather than new drugs.