‘It is a flaw in our cells that becomes a flaw in love’: doctor Siddhartha Mukherjee on the search for a cure for depression

In the spring of 2017, I was overwhelmed by the most profound wave of depression that I have ever experienced. I use the word “wave” deliberately: when it finally burst on me, having crept up slowly for months, I felt as if I were drowning in a tide of sadness I could not swim past or through. Superficially, my life seemed perfectly in control – but inside, I felt drenched in grief. There were days when getting out of bed, or even retrieving the newspaper outside the door, seemed unfathomably difficult. Simple moments of pleasure – my child’s funny drawing of a weeping shark (“Do the tears go up like bubbles, or just mingle into the saltwater?”) – seemed locked away in boxes, with all their keys thrown into the depths of the ocean.

Why? I could not tell. Part of it, perhaps, was coming to terms with my father’s death a year before. In the wake of his passing, I had thrown myself manically back to work, neglecting to give myself time and space to grieve. Some of it was confronting the inevitability of ageing. I was at the edge of the last years of my 40s, staring into what seemed like an abyss. My knees hurt and creaked when I ran. An abdominal hernia appeared out of nowhere. The poems I could recite from memory? I would now have to search my brain for words that had gone missing (“I heard a Fly buzz – when I died – / The Stillness in the Room / Was like” … um … like what?). I was becoming fragmented. It wasn’t my skin that had begun to sag, but my brain. I heard a fly buzz.

Things got worse. I dealt with it by ignoring it, until it had crested fully. I was like the proverbial frog in the pot that doesn’t sense the incremental rise in temperature until the water starts boiling. I started antidepressants (which helped, but only moderately) and began to see a psychiatrist (which helped much more). But the sudden wave of the disorder, and its recalcitrance, mystified me. I was lost. All I could feel was the “dank joylessness” the writer William Styron describes in Darkness Visible.

I was also in the middle of writing what became my new book, The Song of the Cell, and I could not help but draw parallels between the history of cell biology that I was researching and the dank joylessness that was coursing through my life. “All pathology is cellular pathology,” the physician-scientist Rudolf Virchow had concluded in 1858. To understand the core of an illness, we had to understand the function, and dysfunction, of cells – the fundamental living units that make us us.

As an oncologist and cell biologist, that insight from Virchow resonated deeply with me. I focus on cells that have gone rogue, cells that have marauded spaces where they should not exist, cells dividing out of control. The cancer cells I grow in in my lab – and that invade and devastate the bodies of my patients – distort the normal biology of cells (you might think of me as a cell biologist caught in an upside-down world). The story of the cell is stitched into the very fabric of my scientific life – and so it was only natural that I would try to understand the core of my depression in terms of abnormalities in neurons in my brain. To understand my mental anguish, I would need to first understand a cellular anguish.

I called Paul Greengard, a professor at New York’s Rockefeller University. I had met Greengard at a retreat in Maine several years earlier – we had recognised each other as fellow scientists, and walked for a mile on a white-pebbled, windswept beach, talking about cells and biochemistry – and had become close friends. He was substantially older than me – 89 when we met – but his mind seemed perpetually young. Our conversations ranged widely. Neuroscience, cell biology, university gossip, politics, friendships, the latest exhibition at the Museum of Modern Art, the newest findings in cancer research; Greengard was interested in everything.

When I told Greengard of the soupy fog of grief I was experiencing, he invited me to lunch. It was late fall of 2017. We ate at the university cafeteria – he was a slow, fastidious eater, examining each morsel on his fork as if it were a biological specimen before putting it in his mouth – then took a walk around the campus. His bernese mountain dog, Alpha, lumbered by our side.

“Depression is a slow brain problem,” he said. The word “slow” is critical here. In the 1960s and 70s, Greengard’s experiments had led him to an entirely new way of thinking about neuronal communication. Until then, neurobiologists had largely described the communication between neurons as a rapid process. An electrical impulse arrives at the end of the neuron, causing the release of a chemical – a neurotransmitter – into a specialised space between two neuronal cells, termed the synapse. The chemical opens channels in the next neuron and ions surge in, reinitiating the impulse. This is the so-called “electrical” brain – a box of wires and circuits – and this “fast” neurotransmission typically occurs in about a millisecond.

But Greengard discovered that some forms of neurotransmission also involved a more elaborate and deliberative process. The chemical signals sent out by one neuron create a cascade of “slow” signals in the neuron. Neuronal signalling from one cell to the next instigates profound biochemical and metabolic changes in the recipient cell. Unlike “fast” neurotransmission, these changes occur over seconds and minutes – and establishing their physiologic permanence within complex circuits of neurons in the brain might even take days. For decades, this slow cascade was considered peripheral (“Oh, he’ll eventually come around,” another researcher said of Greengard’s work). But the biochemical alterations produced in neuronal cells – the “Greengard cascade” – is now known to permeate the brain. Greengard was awarded the 2000 Nobel prize in medicine for his discoveries.

Over the next two decades, Greengard accumulated evidence that these biochemical changes sat at the very crux of many mental illnesses – including depression. I was reminded of the Carl Sandburg poem: “The fog comes / on little cat feet. / It sits looking / over harbour and city / on silent haunches / and then moves on.” My brain felt perpetually fogged, as if some creature had descended on silent haunches, but would not move on.

Andrew Solomon, the writer, once called depression a “flaw in love”. But in medical terms, Greengard might suggest, it was a flaw in cells. A flaw in neurotransmitters, in the signals they instigate. A flaw that ultimately alters the composition, physiology, metabolism, signalling and behaviour of neurons that regulate mood.

“Which chemicals? What signals?” I asked.

‘When I tried Paxil, and then Prozac, the fog in my brain did not lift.’ Photograph: Chris Buck/The Guardian

I knew serotonin, the neurotransmitter, had something to do with it. Greengard told me the story of the origin of the “brain chemical” theory of depression. In the autumn of 1951, doctors treating tubercular patients at Sea View hospital on Staten Island with a new drug – iproniazid – had observed sudden transformations in their patients’ moods and behaviours. The wards, typically glum and silent, with moribund, lethargic patients, were “bright last week with the happy faces of men and women”, a journalist wrote. Energy flooded back and appetites returned. Many patients, ill and catatonic for months, demanded five eggs for breakfast. When Life magazine sent a photographer to the hospital to investigate, the patients were no longer lying numbly in their beds. They were playing cards, or walking briskly in the corridors.

Researchers later discovered that iproniazid had, as a side-effect, increased serotonin levels in the brain. And the idea that depression was caused by the paucity of the neurotransmitter serotonin, in the neural synapse, gripped psychiatry. There isn’t enough serotonin in the synapse, and so the electrical circuits that respond to the chemical don’t get enough stimulation. The inadequate stimulation of mood-regulating neurons results in depression.

If that was all there was to depression, then increasing serotonin in the brain should solve the crisis. I like to call this theory the “loudspeaker hypothesis” of depression. The mood-regulating neurons in the brain – typically capable of chattering brightly and crisply with each other – have suddenly started to mumble inaudibly. Just amplify the volume of the chatter – unmuffle the loudspeakers – and the pathological mumble that results in joylessness and grief will be restored.

In the 1970s, Arvid Carlsson, a biochemist at the University of Gothenburg in Sweden, collaborated with the Swedish pharmaceutical company Astra AB to develop a drug, zimelidine, that increased the levels of the neurotransmitter in the brain. These early drugs led to more selective chemicals that increased serotonin levels in the brain – the SSRIs, such as Prozac and Paxil. And, indeed, some depressed patients, treated with these SSRIs, experienced profound remissions in their disease. In her bestselling 1994 memoir Prozac Nation, author Elizabeth Wurtzel wrote of a transformational experience. Before she began treatment with antidepressants, she floated from one “suicidal reverie” to the next. Yet, just a few weeks after starting Prozac, her life was changed. “One morning I woke up and really did want to live … It was as if the miasma of depression had lifted off me, in the same way that the fog in San Francisco rises as the day wears on.”

But the response to SSRIs was far from universally positive. In some trials with the most severely depressed patients, there was a measurable improvement in symptoms for those who received the drug versus those who had a placebo, while in other studies the effect was marginal, often vanishingly so. And the time to obtain the effect – often weeks, or months – did not suggest that simply raising the level of serotonin could reset the level of some electrical circuit and thereby cure depression. When I tried Paxil, and then Prozac, the fog in my brain did not lift. One thing was obvious: merely adjusting the level of serotonin in the synapses of neurons couldn’t be the answer.

Greengard nodded in agreement. His lab at Rockefeller University had just discovered a “slow” pathway, instigated by serotonin, that might be responsible for depression. Serotonin, Greengard and other researchers had found, doesn’t only act as a “fast” neurotransmitter, and depression isn’t just a malfunctioning neuronal circuit that can be reset by increasing serotonin in the synapse. Rather, serotonin sets off a “slow” signal in neurons – biochemical signals that come on cat’s feet – including altering the physiology, activity and function of several intracellular proteins that Greengard’s lab had identified. Greengard believed that these proteins are crucial to the slow signalling in neurons that regulate mood and emotional homeostasis.

“It’s not just the level of serotonin,” Greengard said emphatically, jabbing his fingers in the air. The New York air was clear and bitingly cold, and his breath left a drifting trail of mist behind him. “That’s way too simple. It’s what serotonin does to the neuron. The way it changes the neuron’s chemistry, and its metabolism,” he said. “And that might vary from one individual to the next.” He turned to face me. “In your case, there might be inputs, or genetic reasons, that make the response more difficult to sustain or restore.

“We are looking for new drugs that will affect this slow pathway,” Greengard continued. He was searching for an entirely new paradigm for depression, and thereby a new way of treating this disorder.

Our walk had come to an end. He had not touched me, but I felt as if he had healed some implacable wound inside me. I waved goodbye and watched him return to his lab. Alpha was exhausted, but Greengard was energised.

Depression is a flaw in love. But more fundamentally, perhaps, it is also a flaw in how neurons respond – slowly – to neurotransmitters. It is not just a wiring problem, Greengard believed, but rather a cellular disorder – of a signal, instigated by neurotransmitters, that somehow malfunctions and creates a dysfunctional state in a neuron. It is a flaw in our cells that becomes a flaw in love.

Paul Greengard died of a heart attack in April 2019 at 93. I miss him dearly.

I met Helen Mayberg at Mount Sinai hospital in New York on a November afternoon in 2021. The wind stung my face as I walked to her office. Autumnal leaves were falling around me like snowflakes, presaging the winter. Mayberg is a neurologist who specialises in neuropsychiatric diseases and runs a centre called Advanced Circuit Therapeutics. She is one of the pioneers of a technique called deep brain stimulation (DBS), in which minuscule electrodes are surgically inserted deep into very specific parts of the brain. Tiny bolts of electricity are sent through those electrodes to cells of the brain whose malfunction may be responsible for neuropsychiatric diseases. By modulating these areas of the brain with electrical stimulation, Mayberg hopes to treat the most recalcitrant forms of depression that are resistant to normal therapies. It is cellular therapy of sorts – or, rather, a therapy aimed at cell circuits.

In the early 2000s, taking a radical turn from the then-current prominence of drugs such as Prozac and Paxil, Mayberg began to use a variety of techniques to map cellular circuits in the brain that may be responsible for depression. Deep brain stimulation had already been used to treat Parkinson’s disease, and researchers had noted that it could improve the coordination of movement in affected patients. But DBS was yet to be tried in recalcitrant depression. Using powerful imaging techniques, the circuit mapping of neuronal cells, and neuropsychiatric tests, Mayberg found one area of the brain, called Brodmann area 25 (BA25), the presumptive residence of cells that seem to regulate emotional tone, anxiety, motivation, drive, self-reflection and even sleep. BA25 was hyperactive in patients with recalcitrant depression, Mayberg found. Chronic electrical stimulation, she knew, can diminish the activity of a brain area. Mayberg reasoned that electrical stimulation delivered to cells in BA25 might relieve the symptoms of chronic, severe depression.

Brodmann area 25 is not an easy place to access. If you imagine the human brain as a folded boxing glove in its punching position, BA25 sits in the deep centre of the clutch, just where the middle finger might be (there’s one area on either side of the brain). As one journalist described it: “In a pair of pale-pink curves of neural flesh called the subcallosal cingulate, each about the size and shape of a newborn’s crooked finger, [Brodmann] area 25 occupies the fingertips.” In 2003, collaborating with neurosurgeons in Toronto, Mayberg launched a trial to insert electrodes on both sides of the brain and stimulate BA25 in patients who were suffering from treatment-resistant depression. It seemed like an impossibly delicate task: tickling a newborn’s fingertips to make her laugh.

There were six patients in the study: three men and three women, ranging between 37 and 48 years old. “I remember each one of those patients,” Mayberg told me. “The first was a nurse with a physical disability. She described herself as totally numb,” as if permanently anesthetised. “Like many patients that I’ve seen before and after her, her metaphors for her illness were vertical. She was trapped inside a hole, a void. She had fallen into it. Others would talk about caves; about force fields that pushed them down into something. I hadn’t realised it then, but listening to the metaphors was absolutely vital. It was the metaphors that allowed me to track whether a patient was responding or not.”

Oncologist Siddhartha Mukherjee, in black jacket and scarf, against green background, photographed in New York, October 2022
‘The electrical stimulation of cellular circuits is trying to become a new kind of medicine.’ Photograph: Chris Buck/The Guardian. Grooming: Dana Arcidy

To position the electrode accurately into BA25, the neurosurgeon collaborating with Mayberg, Andres Lozano, had to put a frame around the patient’s head (the frame acts like a three-dimensional GPS system to track the electrode’s position as the surgeon introduces it into the brain). As Mayberg tightened the clasps of the stereotactic frame, the patient looked at her blankly, registering neither fear nor apprehension. “Here she was, a woman about to have holes bored into her head and a totally untested procedure performed in her brain, and all she could register was numbness. Nothing. That’s when I knew how bad it was for her.”

Mayberg brought her to the operating room. “Gosh, we were so apprehensive. We had no idea what the stimulation might do.” Would it make the blood pressure drop? Turn on a cellular circuit that neuroscientists knew nothing about? Unleash some unexpected psychosis? The surgeon bored through the patient’s skull and inserted the electrodes. The position seemed right and Mayberg turned the current on, slowly increasing the frequency.

“And then it happened,” Mayberg said. “As we hit the right spot, she [the patient] suddenly said: ‘What did you do?’”

“What do you mean?” Mayberg asked.

“I mean you did something, and the void lifted.”

The void lifted. Mayberg turned the stimulator off.

“Oh, maybe I just felt something weird. Never mind.”

Mayberg turned it on again. The void lifted again. “Describe it,” Mayberg urged her.

“I’m not sure I can. It’s like the difference between a smile and laughter.”

“That’s why you have to listen to the metaphors,” Mayberg told me. The difference between a smile and laughter. There was a picture in her office of a stream with a deep sinkhole in the middle, where water gushed in from all sides. “A patient sent me that picture to describe her depression.” Another void, a hole. Vertical, inescapable traps. When Mayberg turned the stimulator on, the woman said she saw herself lifted out of the sinkhole and sitting on a rock above the water. She could see her former self in the hole – but she was on a rock, sitting above the hole. “These pictures, these descriptions, tell you so much more than checking boxes on a depression scale.”

Mayberg has treated nearly a hundred patients with DBS. “Everyone doesn’t respond, and we don’t know why,” she told me. But in some patients, the effect is almost immediate. One woman, also a nurse, described her illness as a complete incapacity to feel emotional, or even sensory, connections. “She told me that when she held her own children she felt nothing. No sensation, no comfort, no pleasure.” When Mayberg turned the DBS on, the patient turned to her and said: “You know what’s strange? I feel connected to you.” Another patient remembered the precise moment of the onset of her disease. “She was walking her dog along a lake, and felt that all the colours had gone. They had become black and white. Or just grey.” When Mayberg turned the DBS on, the patient looked startled. “The colours just popped.” Yet another woman described her response as if a season was about to turn. It wasn’t spring yet, but she felt the portent of spring. “The crocuses. They just came out.”

“There are still all sorts of mysteries that I don’t understand,” Mayberg continued. “You know that depression has a psychomotor component to it – patients often cannot move. They lie in bed, they become catatonic. When we turn the DBS on, patients want to move again, but the activities that they want to do involve cleaning out rooms. Taking the trash out of the kitchen. Washing dishes. One patient, before he fell into his depression, used to be a thrill-seeker. He would jump out of planes. When we turned the DBS on, he said he wanted to move again.”

“What do you want to do?” Mayberg asked him.

“I want to clean my garage.”

More stringent studies – randomised, controlled, multi-institutional trials – focusing on DBS for the alleviation of treatment-resistant depression are ongoing. Significantly, a pivotal study, initiated in 2008, was halted because early data did not show anywhere near the kind of efficacy that Mayberg had seen in her first studies. In 2013, when data was available on about 90 patients who had had DBS for at least six months, their depression scores were no better than those of the control group – patients who had undergone the surgery, but without the stimulator turned “on”. (And worse: some patients with the implant suffered multiple complications of the surgery. Some had infections, some had intolerable headaches, some reported increases in depression and anxiety.)

Mayberg thinks there are a variety of reasons as to why the Broaden study (named for Brodmann area 25 Deep Brain Neuromodulation) went wrong. “We have to find the right patient, the right area and the right way to monitor the response. There’s a lot here that we still have to learn.” Some of her harshest critics remain unconvinced. (“Electroceuticals are in, and pharmaceuticals are out,” a blogger wrote, with biting sarcasm.)

But intriguingly, over many months, the patients in the halted study who chose to keep their DBS devices “on” began to experience potent and objective responses. I was reminded again of Greengard’s cascade; perhaps it takes weeks before the physiology of neuronal circuits that regulate cellular mood can “reset” itself. The biochemical changes that Greengard had described are not simply levels of neurotransmitters being increased or decreased; they change the fundamental behaviour and nature of the cell. And at a macroscopic level, when an entire mood-regulating circuit needs to be altered permanently, perhaps the process might stretch into months.

In a paper published in the Lancet Psychiatry in 2017, when patients were tracked for two years rather than the six months used in the initial analysis, 31% had experienced a remission – nearing the remission rates that Mayberg had documented in her initial studies. And so there’s renewed enthusiasm for DBS for the treatment of chronic, severe depression. “We just have to do the study the right way,” Mayberg said. The field has gone through its own cyclical mood disorder: hopelessness, followed by ecstatic (and perhaps premature) optimism, then a relapse into despair. Finally, there is renewed but cautious hope again. Mayberg, it seemed to me that November afternoon, had begun to feel the portent of a season turning. There were no crocuses in the gardens outside Mount Sinai West – this was November, after all – but I knew that they would bloom in February.

Meanwhile, deep brain stimulation – “cell circuit” therapy, as I like to think about it – is being attempted for a variety of neuropsychiatric and neurological disorders, including obsessive compulsive disorder and addiction, among others.

The point is this: the electrical stimulation of cellular circuits is trying to become a new kind of medicine. Some of these attempts might succeed; some might fail. But if these attempts garner even a measure of success, they will generate a new kind of person (and personhood) – humans implanted with “brain pacemakers” to modulate their cellular circuitry. They will presumably wander about the world with rechargeable batteries on their belts and move through airport security saying: “I have a battery in my body with an electrode through my skull that sends impulses into the cells of my brain to regulate my mood.”

Maybe I will be among them.

This is an edited extract from The Song of the Cell: An Exploration of Medicine and the New Human by Siddhartha Mukherjee, published by Bodley Head on 3 November at £25. To support the Guardian and Observer, order your copy at guardianbookshop.com. Delivery charges may apply

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