by David Adam
The basal ganglia works closely with the brain’s orbitofrontal cortex (OFC), which sits just behind the eyebrows. The OFC processes sensory information from the eyes and elsewhere and passes signals to a region of the basal ganglia called the striatum. From there, the message goes to a separate brain structure called the thalamus, which controls motor systems. In response, the thalamus passes signals back to the OFC.
This happens in a non-stop loop, and it might help us respond to external threats. Told about events in the world by the OFC, the striatum and thalamus select the appropriate motor response, the right programme, and tell the OFC to make it happen. I see a lion. Yikes. Run away. When the circumstances change, the danger passes, the OFC signals the all-clear and the thalamus stands down.
What’s important for the model of OCD is that the OFC can pass these signals to the thalamus in two different ways. The signal to switch on passes through the striatum, and is called direct. The stand-down is indirect; it is sent to the thalamus through the striatum and then via other parts of the basal ganglia.
In this model of obsessive behaviour, OCD occurs when the thalamus runs out of control and sends inappropriate instructions back to the OFC. The instructions and the behaviour no longer suit the circumstance, and this puts the OFC in a bind. Information from the senses, updates from the outside world, indicates everything is fine. Yet signals from the thalamus suggest not. The consequent motor behaviour, the ritual, continues even while the senses tell the OFC that there is no danger, and no need for the behaviour. That’s the paradox of OCD right there. The water shrew jumps the removed stone. The clean hands are washed. I check the fresh paper towel for blood.
That’s a stripped-down version of the, itself simplified, model of the OCD brain. But here’s an even more simplified one: The direct route that excites the thalamus is an accelerator pedal. The indirect route is a brake. In normal function, the accelerator and brake work together to control speed. In OCD, the brake fails.
From this model of the way an obsessive brain works it’s clear why a common response from others − that someone with OCD just should not be so ridiculous − does not and will never work. Don’t you think we might have tried that? You merely tell us what we can see with our own eyes, that our hands are clean, that the towel is free of blood. We see and yet we can’t stop. A driver who points out that a speeding car is going too fast does not slow it down. We need to fix the brake.
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One way to try to fix the brake is to use drugs. The Leeds psychiatrist who gave me the rubber band had also convinced me to take Prozac. It was still a wonder drug back then, and Elizabeth Wurtzel’s bestselling account of her depression, Prozac Nation, had made those little green and cream pills almost a fashion accessory. Prozac didn’t help me much. I wasn’t depressed, just unhappy. I told the psychiatrist that I didn’t feel any better. He offered me an alternative drug. I don’t remember what it was called, just that he said it would turn me into a happy zombie. I wasn’t sure whether that was an endorsement or a warning. I still don’t know. I turned it down.
Some fifteen years later, the first thing that the psychiatrists I went to see at the specialist OCD unit did was to put me back on drugs. Not Prozac, but something similar. This time, the chance they would turn me into a happy zombie wasn’t discussed.
ELEVEN
Daddy’s little helper
Sertraline hydrochloride is what chemists call a psychotropic medication. I call it a lifeline, a route back to the light from the darkest regions inside my head. I take 200 mg every morning. The two white tablets taste bitter, so it’s best to swallow them with plenty of water. Here goes. Gulp.
Seconds after I swallow the pills, acidic juice in my stomach starts to eat away at the thin layer of polymer film that covers them; within minutes the film is weak enough to release the crystal powder inside. Some of this powder dissolves quickly in the water and drops into the small intestine, the inch-wide and several-feet-long hosepipe coiled somewhere under my belly button, where it will work gently for hours along my intestinal tract.
As these freed drug molecules rub up against the wall of the gut, they leak through its porous lining and into the blood held by the tributaries of thin vessels on the other side, which trickle and pool into my giant hepatic portal vein. Inside the vein and buffeted by blood cells, most of the dissolved drug binds to giant serum proteins. It must hold tight, because its next stop is the liver.
The armies of PhD chemists who design drugs like sertraline hate the liver, because the liver hates chemicals like sertraline. It’s the liver’s job to strip foreign bodies from the blood, and sure enough it tears into the sertraline with its most powerful weapons – enzymes to break it down and convert the drug to something else.
Enzymes to the right of them, enzymes to the left of them, enzymes in front of them,* boldly the sertraline charges my liver’s metabolic guns. Much of the drug is hit, and changed by the biological defences into clumps of derivative molecules called N-desmethylsertraline – still useful, but weaker. Together with traces of the original drug that manage to slip through, these start to pour with the blood that carries them into the central circulatory system.
It takes about six hours after I swallow the sertraline for the drug to peak in my circulatory blood. After the liver it visits the heart, from where it is flung to all corners of the body – some sertraline uselessly bounces around my toes and floods through my eyes. Some, by chance, takes the route that passes the mouth, where its journey began, and reaches the top of my head. There, the drug molecules face a formidable challenge, to breach perhaps the best-defended wall in all of nature, the blood-brain barrier.
Some four times longer than the former Berlin Wall, the blood-brain barrier is a thin layer of tightly knit cells painted onto the outside of the blood vessels that deliver nourishment to the brain. Unlike the cells that line the small intestine, which make it as easy as possible for stuff to move from the gut into the blood, the brain barrier does the opposite. The job of this coating layer is to resist and to make it difficult for the same stuff to shift through it, out of the blood vessels and into the surrounding cells and tissue of the brain. (Picture the barrier as the lagging that surrounds and insulates hot water pipes. The pipe is the blood vessel, the space around it the brain.) There’s a good reason for that resistance. Brain cells are fragile and sensitive. They must live a sheltered life, protected from possible poisons or the volatile spikes and dips in blood chemicals that follow food or exercise.
The chemistry of the barrier dictates what goes from the blood into the brain and what does not. Heroin, for instance, is much more addictive than morphine because a quirk of its structure makes heroin a hundred times more soluble in fat, and so more able to cross the fatty blood-brain barrier. Even expert drug designers who can safely guide their best medicines through the liver come up short when they try to access the brain. They discover to their great frustration that the blood-brain barrier blocks even useful molecules like antibiotics and anti-cancer drugs.
Drugs that do penetrate the barrier must either dissolve in its fatty centre, like the heroin, or Trojan horse–style must smuggle themselves in. Sertraline seems able to do the latter and sticks to gateway proteins on the barrier’s surface, which confuse the drug with something they were expecting, and so let it pass.
The battle of the liver is tough for the sertraline, but the blood-brain barrier is tougher – most of the sertraline molecules are rebuffed by its defences. But, as each beat of my heart delivers fresh blood and renewed reinforcements, and the sertraline keeps up its assault, it edges into the barrier and eventually through to the other side. It enters my brain.
Just a tiny fraction of the original 200 mg, the two bitter tablets, will ever get near a brain neuron. But it is enough. When I swallow the pills, the sertraline hydrochloride renews its daily battle against my OCD. My brain starts to change and my mind changes with it.
* * *
Sertraline, sold
also as Zoloft and Lustral, is one of a class of widely prescribed antidepressant medicines known as the SSRIs – selective serotonin reuptake inhibitors. Prozac is another. The SSRI drugs are controversial, partly because of the huge quantity of them routinely dished out, and also because of a claimed association with increased suicide risk in teenagers. There are doubts about if and how they really do work for depression. But they are a popular front-line treatment for OCD.
Psychiatrists have thrown dozens of different drugs at OCD over the years, from LSD, lithium and amphetamines to nicotine patches and the horse tranquilizer ketamine. The only chemicals that seem to consistently help are those that work – like the SSRIs do − on serotonin, a hormone found mostly in the gut but usually recognized for its role in the brain.
Dozens of trials of OCD treatment with SSRIs – sertraline, Prozac and a handful of others – have now been carried out with hundreds of people, and a consistent picture has emerged. Patients with obsessions and compulsions who take the drugs are more likely to improve – measured as a significant decrease in their Yale-Brown scores of obsessive and compulsive symptoms over time – than those who do not. The drugs don’t help everybody, but then nothing does.
Before SSRI drugs became available in the 1980s and 1990s, OCD was treated with clomipramine, a brute of an antidepressant drug with nasty side effects that carried the risk of a fatal overdose. The risks were considered worth it because clomipramine gave hope to people with OCD. Hope that was discovered only thanks to random chance and a little cross-border narcotics smuggling.
* * *
Clomipramine is a little different from the SSRI drugs, but it’s similar to an antidepressant called imipramine, which was launched by the Swiss drug company Ciba in the 1950s. Both are tricyclic compounds – they have three joined carbon rings at their heart. On a trip to Switzerland in the 1960s, where imipramine was widely available, a French psychoanalyst called Jean Guyotat stuffed some into his pockets and took the pills back to his private practice in Lyon, where he started to give them to his obsessional patients. ‘This was somewhat illegal maybe now but it was possible at the time,’ he later recalled.
Guyotat wanted to try the new drug because he believed that some obsessions were masked forms of depression. He treated fifteen obsessional or phobic patients, either with the Swiss imipramine or stocks of clomipramine that his clinic already gave as liquid infusions for severe depression. One patient was a male teacher who turned anger at a colleague who played Wagner records a little too loud into rituals to cope with obsessional thoughts of noise. Another was a woman who for the previous seven years had felt compelled to speak her thoughts out loud. The excitement of extramarital affairs eased the compulsion but, as Guyotat explained, this method of self-treatment had to stop when her husband found out. The drugs transformed some of his patients, Guyotat said, sometimes within a few days. In 1967 he published his results and announced to the world imipramine and clomipramine as the first chemical treatments for OCD.
Some six hundred miles to the southwest, psychiatrists at a hospital in Madrid learned of the work in France. They had plenty of intravenous clomipramine so they decided to try it on their own severely obsessional patients. Just like the French, the Spanish team reported rapid improvements. Juan Lopez-Ibor, a psychiatrist who worked at the hospital with his father, saw this change in the way one OCD patient on the ward played table tennis. The first sign of recovery came when the man, whose fear of germs had previously left him unable to touch things, was able to hold a communal bat, as long as he went to wash his hands immediately after he finished. When Lopez-Ibor saw the man complete his own game and then, without washing, choose to stay and watch other patients play, he knew they had stumbled onto something special.
In northwest England, George Beaumont noted keenly the success with OCD the Spanish doctors reported for clomipramine. Beaumont had worked as a GP in Stockport, near Manchester, but then took a job as medical adviser on psychiatrics with Geigy, a pharmaceutical company. Geigy owned clomipramine and Beaumont saw OCD as a potential new market for it − a big one.
Beaumont suggested to UK psychiatrists that they treat OCD with clomipramine. He arranged for them to visit Lopez-Ibor in Madrid and set up some basic clinical trials of the drug. Beaumont worked closely with staff at the Warrington mental hospital that had treated the claustrophobic American woman we met earlier, who compulsively checked to avoid being buried alive. Just like in France and Spain, some British patients seemed to show rapid improvement.
Encouraged by colleagues in Geigy’s marketing department, Beaumont applied for an official licence that would allow doctors to prescribe the drug for obsessions and compulsions. He wrote the 2,000-page application himself – it took three months – and in 1975 clomipramine was approved to treat OCD in the UK, and later other places too. ‘Everyone at that time thought that OCD was an unusual, bizarre and rare condition,’ Beaumont said later. ‘But as soon as you have a treatment for a condition you discover that it is more common than everybody supposed it to be.’*
For years, OCD sufferers in the United States were denied the drug. The licensing body there, the Food and Drug Administration, was wary of what it saw as a copycat antidepressant that offered no benefit beyond those drugs already available. In response, a frustrated Judith Rapoport described in The Boy Who Couldn’t Stop Washing how − just like Guyotat twenty years earlier – she had helped to bring the unlicensed drug into the country. The FDA relented and approved clomipramine – known in the US as Anafranil – for OCD in 1990.
* * *
Sertraline is a powerful drug, especially at the high daily doses given for OCD, but I only notice its impact when I don’t take it. Just a day or so without it and, in apparent withdrawal symptoms, my dreams lift from monochrome Kansas to Technicolor Oz. They become so vivid and intense that the emotions they carry linger for most of the day; I can wake myself shouting, once with my eyes wet with tears. And the smells – forget to take my pills and I have smelly dreams. I can wake to the aroma of pungent wood smoke or sweet caramel.
On the drugs, it’s harder to describe the effect. It’s not like the mood lift reported by people given them for depression. It doesn’t feel like anything is fixed or restored, though the medication does take the edge off the anxiety that weird thoughts cause. The thoughts still come – no surprise there, as we’ve seen, they are common and normal – but they seem less sticky. How long will I take the sertraline for? I’m afraid to stop; rapid relapse among those who do is common apparently. I don’t see a downside. What gets you well keeps you well, my psychiatrist says.
* * *
The impact on OCD of the SSRI and some tricyclic drugs has led scientists who work on the causes and nature of obsession to focus on the chemical that the medicines work on: serotonin.
The brain needs serotonin because, as complex and marvellous as it is, most of its neurons can’t communicate directly with each other. At the business end of these neurons there lies a tiny gap that separates them from their neighbours. For neuron A to pass a signal to neuron B it needs serotonin. Specifically, the electrical signal, when activated, releases serotonin molecules into the gap between A and B, some of which bump into B. When that happens, B electrically activates and releases its own chemical messages to pass the signal to C, and so on right through the alphabet. Spare serotonin sloshing around in the gaps is reclaimed (taken up) by the neurons for when they will need it again.
That is about all we know for sure about how serotonin works in the OCD brain. Much of the rest of the so-called serotonin hypothesis for OCD is based on some reverse engineering. The logic goes like this: The SSRI drugs keep levels of serotonin in the free space between the cells higher than they would be otherwise. The drugs inhibit the uptake. This seems to relieve OCD symptoms, at least in some people. Therefore, the reverse engineering says, OCD must be caused by abnormally low serotonin levels.
It’s notoriously difficult to track and measure neurotransmitt
er activity, so there’s no direct evidence to support this hypothesis. It’s certainly possible that the extra serotonin might help to ease OCD because it frees the jammed brake in the basal ganglia, and so allows the thalamus to recognize the stand-down signals sent by the orbitofrontal cortex. But it’s equally possible that the change is due to something else.
It could be down to dopamine, another neurotransmitter, which tends to cancel out the effects of serotonin. Drugs that boost dopamine levels in the basal ganglia seem to trigger the sudden onsets of compulsive gambling and theft sometimes seen in Parkinson’s patients. A failure to produce enough serotonin might allow dopamine levels to rise to the point where they have a stronger influence on the striatum, which plays a key role in the model of the OCD brain. PET brain scans of people with OCD show reduced serotonin transmission and increased dopamine release in the right areas.
Very recently, neuroscientists have fingered a third neurotransmitter, glutamate, for possible conspiracy to cause OCD. Or there could be a role for oxytocin, labelled as the hug hormone by some because of its role in pair-bonding and maternal behaviour. Oxytocin action is linked to serotonin and can bring on repetitive grooming behaviour in rats. In the mid-1990s scientists at Yale University tried to test its effect on humans. Sadly, regular squirts of oxytocin up the noses of seven OCD patients failed to lift their obsessions with contamination and cleaning.
Although the majority of people with OCD are helped by the SSRIs, a significant number – perhaps up to 40 per cent − see no benefit, even after they have tried four or five different drugs. This has led some scientists to look for obsession elsewhere in the brain, beyond the neurotransmitter systems of the basal ganglia. In 2008, neuroscientists in Turkey reported how they used MRI scans to measure the size of the amygdala and hippocampus in the brains of fourteen OCD patients who had not responded to drug treatment, and compared them to the brains of fourteen normal people. They found both structures were smaller in the OCD group, and the smallest were found in those who had suffered from the condition the longest.