Into the Abyss

A neuropsychiatrist's notes on troubled minds

Anthony David

• Publisher: Oneworld Publications
• Year: 2020
• ISBN:
  9781786077066
• Topic: Medicine
• Subtopic: Psychiatry & Mental Health

'Highly eloquent, fascinating and deeply compassionate' Henry Marsh, author of Do No Harm We cannot know how to fix a problem until we understand its causes. But even for some of the most common mental health problems, specialists argue over whether the answers lie in the person's biology, their psychology or their circumstances.As a cognitive neuropsychiatrist, Anthony David brings together many fields of enquiry, from social and cognitive psychology to neurology. The key for each patient might be anything from a traumatic memory to a chemical imbalance, an unhealthy way of thinking or a hidden tumour.Patrick believes he is dead. Jennifer's schizophrenia medication helped with her voices but did it cause Parkinson's? Emma is in a coma – or is she just refusing to respond? Drawing from Professor David's career as a clinician and academic, these fascinating case studies reveal the unique complexity of the human mind, stretching the limits of our understanding.

1

Dopamine

I first met Jennifer on an acute medical ward, lying in bed motionless. Literally motionless. She was lying on her back, slightly hunched forward, her head touching the pillow but not resting on it. She had a complicated, even contradictory, set of problems and had stopped taking her medication. She was losing weight and getting dehydrated. She had been admitted to hospital as an emergency.

Jennifer was in her mid-thirties. She was from a fairly ordinary middle-class family. Her parents separated during her childhood and she lived with her mother until her early teens, at which point her mother developed mental health problems and became increasingly paranoid and religiose, although she never saw a psychiatrist. From then, Jennifer started spending more time with her father. She was a good student and had won a place at art school. She took to photography and experimented with prolonged exposures of objects in motion (for example, trains passing, kids running and gliding birds), all of which produced unsettling blurry images. Midway through, when she was about twenty-one years old, Jennifer began to become paranoid, just as her mother was, convinced that people were stealing her ideas and possessions. She started to hear the voice of a famous film star who lived in her area. The voice said nasty, spiteful things and demanded that she cease painting or else… She felt compelled to obey such orders. He said he knew what she was thinking. There was also a female voice that she didn’t recognise, and the two voices would speak to each other, commenting on what Jennifer was doing: “Look at her now, she’s getting out of bed. Who does she think she is?” Bizarrely, the voices seemed to transform into the physical realm and invade her body, pulling at her sexual organs. These strange experiences are diagnostic symptoms of that most iconic mental disorder, schizophrenia.

She was seen by a psychiatrist at that time and, despite attempts to help her with medication and general support, she couldn’t complete her art course. Without that major focus in her life, she became increasingly isolated, living alone in a bedsit on state benefits. She engaged only reluctantly with the local mental health team, tending not to trust them, but she did accept antipsychotic medication. It ‘dampened down’ the voices but didn’t eradicate them.

In fact, she didn’t really trust anyone. She believed that people entered her flat and went through her things, changed the furniture around and stole what few valuables she had. She took to going everywhere with a rucksack on her back stuffed with everything she owned, including letters, papers, CDs and sketches, so that they would be safe. Slung around her chest was a hefty, expensive but now battered camera. She behaved like a photojournalist without a subject, snapping frantically whenever she met someone or went somewhere new. The explanation was that she wanted to keep a record of her life so that she could, if need be, check up on what happened, who was there, where the objects were and so on, in order to use it as evidence. Evidence for what? Her defence? The prosecution? It wasn’t clear.

In time, things settled down. Jennifer was looking after herself, venturing out to the shops to buy essential supplies, taking pictures from time to time and doing pastel self-portraits. She studiously avoided other people, but after many visits, a community psychiatric nurse began to establish a tenuous relationship with her. Over the next few years, they tried different medications to control her symptoms, but the clinical team were struck by the appearance of some very marked side effects. She complained that her movements were stiff and that she was dribbling excessively. She developed a tremor, especially in her right hand, which interfered with her drawing. It was as if, by blocking the crucial dopamine receptors in her brain, the antipsychotic medication had given her the symptoms of Parkinson’s disease.

***

Antipsychotics were discovered in the early 1950s and hailed as the first drugs that could calm an individual without making them sleepy. One of the key areas of research was on the neurotransmitter dopamine, which attracted the attention of Arvid Carlsson, a Swedish pharmacologist working in the US National Institutes of Health. He showed that chemically induced depletion of dopamine led to loss of movement in experimental animals and he speculated that Parkinson’s disease, the hallmark of which is a similar slowing of movement, may be caused by a lack of dopamine.¹

It was well known that patients with Parkinson’s disease showed degeneration of a small cluster of cells in the midbrain, called the substantia nigra because of its dark colour, which has a high concentration of the chemical neuromelanin, a precursor of dopamine. Those cells feed into the basal ganglia, which is crucially involved in movement control and contains high concentrations of dopamine. The basal ganglia are a small collection of neurones (ganglia) on either side, deep in the base (basal area) of the brain. Experimental and clinical studies in the early 1960s gave doctors the ability to replace the lost dopamine in Parkinson’s patients, and the treatment showed dramatic benefits. It became the established treatment for what was previously an untreatable condition, and for his work Carlsson went on to share the Nobel Prize in Physiology or Medicine in 2000.

Over the same time period, a drug called chlorpromazine started to be used as a ‘tranquilliser’ for people with schizophrenia. For the first time, here was a treatment that was really effective at reducing psychotic symptoms, but doctors noticed that it produced side effects that were reminiscent of Parkinson’s disease. And so we began to see the two diseases as mirror images of each other: schizophrenia was due to too much dopamine in key areas of the brain, whereas Parkinson’s disease was due to too little. That theory, the original version of the dopamine hypothesis of schizophrenia, still accounts for many of the facts around schizophrenia. For example, most drugs which produce schizophrenia-like effects have been shown to act via an increase in dopamine transmission and, conversely, most drugs with antipsychotic effects do the opposite: they block or deplete the amount of dopamine in the brain.

We can think of neurotransmitters as being like the baton in a relay race. Nerves convey information in the form of electrical impulses. This is like the runner taking off down the track. Once they reach the end of their leg, they need to pass the baton to the hand of the next runner. The gap between the two runners is analogous to the synapse, a tiny cleft between two nerves. Once the new nerve is safely in receipt of the baton, the message is able to continue further. As in a relay race, this is a point where flow can be enhanced or disrupted. In Parkinson’s disease there just aren’t enough runners carrying the dopamine baton and not enough batons reach the destination. Dopamine-replacement therapy is like putting out extra batons at the changeover point, increasing the chances that some will get picked up. Other dopamine-enhancing therapies prevent the breakdown of dopamine at the receptors – a bit like allowing stray batons to ‘stay live’ even if dropped, and permitting runners to pick them up.

With schizophrenia, each runner is carrying too many batons, making the changeover chaotic. Many ‘messages’ are being passed on even without being officially part of the race; the person has perceptions of things that are not really there. Antipsychotic agents are thought to work by blocking the receptors, either by giving fake batons (which don’t count) to the receiving runner or, according to another version of the theory, loosening the binding of dopamine onto the receptor – coating the hands of the receiving runner in grease so that they drop the baton.

If it is all about an excess or a lack of dopamine, we would expect that medications to treat Parkinson’s disease run the risk of causing schizophrenia-like symptoms and that antipsychotic medications are liable to produce parkinsonism, the symptoms of Parkinson’s disease. But over the years, the theory has started to creak under the weight of evidence that doesn’t quite fit. In fact, it has proved quite hard to show that all patients with schizophrenia have an excess of dopamine, and not all patients respond to dopamine-blocking drugs.²

One early challenge to the theory was the rare case of a patient who had Parkinson’s disease and schizophrenia. Surely, you can’t have both too much dopamine and too little? Tim Crow, a prominent psychiatry researcher, published a series of four cases in 1976 in which the patients had all developed Parkinson’s disease many years before developing psychosis.³ None was being treated with dopamine replacement or enhancement at the time the psychosis emerged, so according to the theory, what was happening should have been impossible. Perhaps schizophrenia and Parkinson’s disease were not two extremes on a single, neat spectrum, but something altogether more complex.

***

Jennifer had responded moderately well to antipsychotic medication but seemed to be developing unusually severe parkinsonism, her hands shaking constantly beyond her conscious control. Her clinical team were concerned and started, slowly and cautiously, to reduce her medication. Jennifer could not have been more pleased given that she never really liked taking her tablets and now felt horrible. The team thought that they were simply dealing with side effects and that they could reach a happy medium with the minimum effective dose of medication – just enough to control the symptoms of hallucinations and paranoia without slowing her down noticeably. What followed was a rather difficult couple of years. Predictably perhaps, reducing her medication meant a return to her conviction that she was being followed and persecuted, and as a result she shut herself away and even hid from her community psychiatric nurse (CPN) when she came round to visit. Not only that, the reduction in medication led to only minimal improvement to her movements. It became increasingly difficult for the team to maintain any kind of contact with Jennifer. Coming off all medication, her mental state was deteriorating and her physical state was worsening as well. Her movements were sloth-like, and she walked with a stooped posture like a woman twice her age.

Having been ‘stuck’ in this unfortunate condition for several months, her consultant psychiatrist sought my opinion and we agreed that her case was unusual and that it might be useful for her to get an expert neurological assessment. After much persuasion, she agreed. The neurologist examined Jennifer and admitted her to the general hospital for some tests. Eventually, after much prevarication, the consultant was forced to at least entertain the idea that she might actually be suffering from Parkinson’s disease as well as schizophrenia; after all, she had been off all medication for over a year by that point. If it was merely drug induced, it surely would have improved a lot more by that point.

The tests included a dopamine transporter scan. This involves injecting a tiny amount of a radioactive tracer into the patient’s vein, which allows us to see the special transporter proteins that tidy up stray dopamine molecules when we do the scan. In a healthy brain, there is supposed to be a ‘hot spot’ showing a concentration of dopamine transporter in the basal ganglia. It should appear as normal for people who have only drug-induced symptoms of Parkinson’s, whereas people with real Parkinson’s disease have a weaker and cooler hot spot. Early in the disease, production of the transporter falls; after all, you don’t need so many transporters if the amount of dopamine has dropped dramatically. Jennifer’s scan showed a significant cooling of the hot spot. Furthermore, the scan was asymmetrical, with more loss on the left side of the brain (which controls the right side of the body), which tallied with her worst symptoms. An asymmetrical scan is typical of Parkinson’s disease, especially early on, due to degeneration of the substantia nigra starting on one side first, and counts against any drug-induced or toxic effects since these would be expected to affect all regions equally.

The neurologist concluded that Jennifer must have a form of Parkinson’s disease that was not simply drug induced, although it might have been drug triggered; that is, she may have been vulnerable to developing Parkinson’s disease at some point in the future, but exposure to antipsychotic, dopamine-blocking drugs probably brought this point much closer. (This is just a hypothesis and there isn’t as yet good evidence to show that this can actually happen.) Most people develop Parkinson’s disease in their sixties and seventies, but in rare cases it can affect young adults. In these early-onset cases, there may be a family history of the condition and predisposing genes are often found. Neither of these circumstances applied to Jennifer.

Not surprisingly, Jennifer became increasingly despondent, then depressed, then suicidal. She was now hearing voices almost continuously – haranguing her, telling her what to do, including urging her to kill herself. Working with the neurologist, we offered Jennifer some medications which improve some of the symptoms of Parkinson’s disease without acting through the dopamine system. Such drugs, known as anticholinergics, are mostly effective early in the disease. They helped with the dribbling and tremor; however, the psychotic symptoms could not be ignored. Jennifer was so distressed by the hallucinations that she accepted the offer of new antipsychotic medication. This time we used a drug called clozapine which often works for ‘treatment-resistant schizophrenia’ and is one of the few drugs not to cause parkinsonism or to worsen Parkinson’s disease.⁴ Thanks to clozapine, anticholinergics and regular support from the community psychiatric team, who encouraged Jennifer to attend a day centre from time to time, she enjoyed a period of relative stability.

A few years went by and Jennifer’s physical symptoms, particularly the slowing of movement, worsened, as would be expected in someone suffering from Parkinson’s disease. Her neurology consultant added some very-low-dose levodopa (also known as L-DOPA): standard treatment for Parkinson’s disease, it is the chemical which is converted to dopamine in the brain. The neurologist was worried that this would exacerbate the hallucinations and other symptoms. She was right.

Jennifer believed, with some justification, that she was a human guinea pig. We were nudging up the clozapine here, reducing L-DOPA there, tweaking the other meds, doing our best – but not really sure we were going to improve the situation. Jennifer started avoiding us. She would occasionally turn up at the day centre with her rucksack and camera, looking dishevelled and gaunt, and would disappear before we could make any plans to address her needs. The CPN would visit her flat, but often she did not answer the door; when she did, she would only get out of bed with huge encouragement....