Moving Beyond ‘Chemical Imbalance’ Theory of Depression

Robert Malenka, M.D., Ph.D.
Robert Malenka, M.D., Ph.D.

A ‘bottom up’ approach to understanding the brain leads to crucial new discoveries

From The Quarterly, Fall 2012

What causes depression? Experience tells us that people can become depressed when they are under acute or chronic stress. Or when they are exposed to trauma. It tells us that the period immediately following childbirth often finds new moms in a ‘blue’ mood. We also know that some people who lose a loved one stay ‘down’ even after an extended period of grieving.

But all of these are associations between certain life experiences and depression, not biological causes.

And they tell us nothing about why millions of other people, for no apparent reason at all, experience plunges in mood that leave them incapable of experiencing pleasure, even in rewarding activities and experiences that almost universally produce it.

The first attempts at defining depression as a biologically-based illness hinged on a theory of ‘a chemical imbalance in the brain.’ It was thought that too much or too little of essential signal-transmitting chemicals—neurotransmitters—were present in the brain. Treatments were developed to keep neurotransmitters (such as serotonin) within the tiny gaps called synapses between adjacent nerve cells, where signals are exchanged. By preventing specific neurotransmitters from being reabsorbed into nerve cells, the theory went, the signals between cells would be boosted and mood would be lifted. The most popular antidepressant medications, such as Paxil® and Prozac®, were developed to function in this manner. Unfortunately, the alleviation of depression’s symptoms with these treatments remains elusive; they are ineffective for as many as 50% of patients with depression.

“This idea of chemical imbalance has been useful—that you have a kind of chemical soup in which there may be too much dopamine or too little serotonin,” says Robert C. Malenka, M.D., Ph.D., a Brain & Behavior Research Foundation Scientific Council Member, three-time NARSAD Grantee, and the Pritzker Professor of Psychiatry and Behavioral Sciences at Stanford University School of Medicine.

“But in truth,” Dr. Malenka continues, “the ‘brain soup’ idea is no longer adequate.” It really has reached a dead-end. This is why antidepressants aren’t working for so many people—all the current medications work via these same mechanisms. Therefore, Dr. Malenka reasons, “there’s a great need to understand in greater detail the brain biology that underlies depression’s symptoms” so that novel therapies can be found.

Wanting to understand pleasure leads to a surprising discovery

Earlier this year, Dr. Malenka led a team of researchers conducting a series of experiments involving neurons in a part of the brain known since the 1950s to be associated with the ability to feel pleasure. This area, called the nucleus accumbens, or NAc for short, is part of what is often called ‘the pleasure circuit.’ He and his colleagues were exploring the idea that some malfunction in the NAc has an important connection with clinical depression’s most universal symptom: the inability to feel pleasure, which psychiatrists call anhedonia.

The NAc “has evolved over eons to promote our survival. It is activated during sex; during the pleasurable aspects of feeding. It’s the one that tells you warmth is really good when you’re cold; that water is great when you’re thirsty; that sleep is wonderful when you’re tired,” says Dr. Malenka. It’s the part, when functioning properly that tells us: ‘I should engage in behaviors that increase my chances of experiencing this rewarding event again.’” If this all-important circuit isn’t working properly, anhedonia is the result.

The research team made an unexpected discovery. They found that a hormone known to affect appetite, called melanocortin, turns off the brain’s ability to experience pleasure when an animal is stressed. And it was happening, importantly, in the NAc part of the brain. “A few scattered studies had suggested that chronic stress increased melanocortin levels in the brain, but it wasn’t yet known, whether melanocortin actually affected the nucleus accumbens or how,” said Dr. Malenka. This is the first study to implicate melanocortin in depression. These new findings could lead to an entirely new class of antidepressant medications.

Recognizing the brain as a vast network

Dr. Malenka notes that research performed by others makes strong connections between problems in the NAc and conditions as diverse as addiction, obsessive-compulsive disorder (OCD) and schizophrenia. This curious fact gets at the central problem that has motivated Dr. Malenka’s highly successful 30-year career in neuroscience.

“It turns out that everything in the brain is more complicated than we might imagine. Everything we study involves interactions between different brain areas and therefore different circuits and different modulators of those circuits.”

In moving beyond the comparatively simple ‘chemical imbalance’ model, Dr. Malenka and others don’t mean to imply that neurotransmitters like serotonin or dopamine are unimportant. The problem is that both of these neurotransmitters, and others, “influence circuit activity in many complex ways in many different brain areas and many different circuits. And it’s not as if every one of those circuits is dysfunctional in, for example, depression.”

Dr. Malenka is a leading expert on those tiny gaps called synapses across which nerve cells transmit
signals. There are trillions of synapses in the human brain. The grand challenge of Dr. Malenka’s career has been to understand how these critical signal-junctions operate; and to relate this fine-grained knowledge to what goes wrong in specific circuits to cause the symptoms of illnesses such as depression or OCD or addiction. For his work, he received the Brain & Behavior Research Foundation 2010 Goldman-Rakic Prize for Outstanding Achievement in Cognitive Neuroscience.

Of the support from the Foundation he has received, Dr. Malenka said, “Having been supported with a NARSAD Young Investigator Grant and later with a NARSAD Distinguished Investigator Grant, the Foundation has provided me with valuable financial support to pursue ideas that were ‘outside the box.’ But it also has given me the acknowledgement that the research ideas were worth pursuing.”

“In one part of my work, I’ve studied very basic mechanisms involving, for instance, the molecules involved in synaptic transmission and changes of synaptic strength,” which are associated with learning and memory. Many of these molecules he studies—proteins called neuroligands and neurexins—when they are abnormal have been found to contribute to pathology in disorders like autism and schizophrenia. Many of the genetic studies the public hears about, in which gene mutations are associated with one or another psychiatric illness, often identify defects in genes that instruct cells to manufacture these vital proteins Dr. Malenka has studied at the synapse.

“We can’t study every genetic variant, or every brain region, and certainly not every synapse,” Dr. Malenka reasons. “It’s just impossible. So we have to make educated guesses based on our knowledge that variation in many different genes predisposes to similar disorders.”

This is a hopeful observation. It leads Dr. Malenka and others to proceed on the hypothesis that pathways and circuits, numerous though they may be, seem to converge on disturbances in a finite set of essential brain functions (see sidebar on p. 8).

Targeting malfunctioning circuits may treat symptoms across disorders

His team’s discoveries about the melanocortin circuit’s contribution to anhedonia-like behavior identify a potentially new pathway of intervention in depression, beyond adjusting neurotransmitter levels. It focuses specifically on identifying and correcting the melatonin circuit malfunction that stress appears to cause, which in mice was linked with the inability to engage in pleasurable activity.

There is the prospect that detailed circuit-knowledge of this kind may lead to an entirely new way of treating disorders as different as depression and schizophrenia.

One might for example treat anhedonia, or the inability to be motivated by the prospect of reward, whether this symptom occurs in a person diagnosed with major depression or some other illness. Indeed, many people with schizophrenia are observed clinically to be unable to motivate themselves, or when motivated, find it very hard to convert that thought into action. A future medication that acted on melanocortin receptors to address anhedonia might help such a patient, who would continue to take other medications to control other symptoms seen in schizophrenia but not depression, such as psychosis.

The idea to look at diseases through the lens of malfunctioning circuits and relays in the brain and the symptoms they cause is being explored in Foundation-funded NARSAD Grants to many scientists like Dr. Malenka. This path of research promises to bear a harvest of great value in the years ahead.


Robert C. Malenka, M.D., Ph.D.
Scientific Council Member
1990,1992, 2007 NARSAD Grantee
2010 Goldman-Rakic Prize for Outstanding Achievement in Cognitive Neuroscience
Pritzker Professor in Psychiatry and Behavorial Sciences
Stanford University School of Medicine

Article comments

It is interesting you mention anhedonia and an inability to put things into action. I suffer from both. My diagnosis is chronically depressed, PTSD, ADD, social anxiety etc etc. I am 56 and have been this way ever since I can remember. I was sexually molested at 5. It feels as though I have tried every possible perscription drug cocktail and nothing really seems to make any difference. Matter of fact one time I was so happy (I spent the day with my estranged lil sister) I had to go and get drunk just to bring my emotions down!! Sounds crazy huh? But it really thought I was going to explode from joy!!! I hate feeling this way. It makes sense that there must be something else going on other than a chemical inbalance. When you get ready for ghinny pigs---let me know

My grand daughter is three years old on Christmas Eve. From since I can remember she has always seemed different to other babies/children. Some of the examples are she has to close all the doors upstairs before she will come down. If you try to stop her she will cry and throw herself around. This can go on for 45 mins to an hour. If you try to talk to her she is vacant behind the eyes and you can not connect to her. She will complete a pattern of what looks like self soothing which would appear that she is trying to calm herself. She will stroke her face then her arms and then her legs and continue the pattern. She will throw herself around but she is so strong it is hard to hold her. She is completely distraught and exhausted by the end if it. If I ask her why she has been screaming she says she does not know and that she does not like screaming. She screams in the middle of the night but is still asleep when you go to her. She does other things like undo and redo her shoes before she puts them on. She must clip the pram straps once she is taken out. They appear to be rituals. She will pull clumps of her hair out when she has an episode and does not appear to feel any pain. She has ripped the skin down the side of her fingers until the are bleeding and again shows no sign of discomfort. She is advanced in counting, identifying colours, shapes, writing and she appears to have long conversations with you stringing 10 to 20 words together although some of the words are not clear. So one part of her is far more advanced than other children of her age. But the difficult behaviour side can happened up to twice a day. We have changed her diet and she has nothing with artificial colourings or preservatives along with cutting out milk as she appeared to crave it. This has had limited effect. She can be happy and jolly one day and exceptionally difficult on others. We have involved the health visitor and doctor who are very dismissive that there is anything wrong. My daughter is at her wits end and does not know what to do for the best. I read some of the notes on chemical imbalance and the advances you are making in your research. I would be grateful if you could suggest any ways in which we can help her in this early stage of her life. We can not keep treating her like children who are having a tantrum because I am not sure she can help her behaviour and some how we must find a way to help her engage in the world without treating her like she is a petulant children. I apologise for my lack of ability in the written word. I am myself dyslexic. My email address is I would welcome any advice or suggestions as I do not believe the British health system will identify there is a problem until she is much older and I worry that we shod be making allowances to enable her to cope rather treating her as if it is the terrible two's. Kind regards. Tania

Sounds to me like she could be schizophrenic,it's hard to diagnose this because she is only 3 years old but it is said that the younger it happens the worse it gets into adolescence and adulthood. This is just a personal opinion gathered from books I have no way is this a medical opinion.

You should read up about autism symptoms or ask your doctor to consider it. Obviously ask your doctor about it. Some of these examples are common in children with autism...


Your granddaughter is lucky in having you as a grandma. I think you have done a fab job of explaining what's happening. My son he's 9 now, show's symptoms of autism and a few other ism's after 7 years of going through the system they have decided he is 'normal' I have been desperate for a label to understand how to help him too - I can't offer any guidance or help just to let you know you are not alone and that your understanding and love and persistance will help your granddaughter a lot. I hope you find her the help she needs she sounds like a lovely little girl Louise xxx

ocd/trichotillomania or autism? I'm not sure, as I am not a medical professional and have limited knowledge.. but I would advise that you take her into be tested and looked at every once in a while as she ages if symptoms progress and/or worsen.

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