Spooling The Tangles

Manny: “I guess I was hoping for a miracle.”
Attendant: “It happens but it takes time.”
Manny (to his wife): “Rose…?”
Attendant: “She’s not listening now.”

—The Wrong Man, Alfred Hitchcock

Yes, it’s taking time. Over half a century has passed since this 1956 film, where a gloomy protagonist leaves his wife Rose behind in the asylum, staring vacantly out of the window—her bare room an allegory for the white funk of her mind. In all these years, countless scenes like this one would have unfolded on screen and in real life—only superficialities separating them, and a mind-numbing sameness marking their essence. Why so? Most branches of medicine are miles away from where they stood in the 1950s, in depth of understanding, diagnostic perfection and targeted intervention. But with mental illness, it’s as if science is still staring vacantly, like Rose, at a formless white fog outside the window.

The contrast is striking. AI is upon us, machines are beginning to self-learn, information systems modelled on the human brain’s neural pathways have changed the world. But the mysteries of the human mind are as impenetrable as ever. We don’t fully know how it gets things right. So to zero in on what has gone wrong—and then to fix it—is like shooting in the dark. That’s why Dr David J. Anderson, a neurobiologist working at the California Institute of Technology, summed up the situation, during a recent interview in India, with these stark words: “There hasn’t been a fundamentally new neuropsychiatric drug in the last 50 years”.

Anderson is right, of course. Recent years have seen a spurt of new drugs, particularly for cancer. In most years since 2011, FDA’s Center for Drug Evaluation and Research (CDER) approved 40 or more drugs—and 2017 saw a glut of applications. Yet, none of these bear any glad tidings for people with neuropsychiatric problems. Now look at the timeline for significant developments in psychiatric treatment:

• Electro-convulsive therapy, still among the most effective treatments available, was developed about 80 years ago, in the 1930s, and then improved upon.

• The use of lithium dates back to 1949.

• The anti-psychotic drug Chlorpromazine, which paved the way for many more in that vein, came in 1950.

• Imipramine, an anti-depressant, was developed in 1958.

• L-dopa, first administered back in the 1960s, remains pretty much the main drug for Parkinson’s, a neurological disorder. Pharma majors have either abandoned or are in the process of abandoning search for new ones.

“Basically, between 1938 and 1960, there were major developments, subsequent to which there haven’t been any breakthroughs,” says Dr Chittaranjan Andrade, who heads the department of psychopharmacology at NIMHANS, Bangalore. “There have been some extraordinary improvements in what already exists...but not breakthroughs.” In a world bristling with advances almost too fast to be comprehended, this is an astonishing gap. All the more so if you consider a quarter of humanity experiences mental disorder issues once in a lifetime. The world counts about 450 million patients now—tens of millions of them are in India.

Celia George (name changed), a Delhi-based corporate communications expert, is one of these millions and her predicament is reflective of the overall crisis. She suffers from depressive spectrum disorder—a complex web of depression, mood disorder and anxiety. In her late 30s now, she knew she had an issue at age 29 when she started getting manic depressive episodes that turned to spells of hopelessness sometimes, and sometimes anti-social tendencies. No doctor could classify her precise ailment. It’s been a long decade of trial and error with sundry drugs, of stoically bearing the side-effects, all the time trying to calm her trepidation about no one understanding the disease she has.

The Brain Riddle

Why is the medical world still struggling to comprehend the issues and evolve sharp, effective, targeted treatment options? The reasons are many. Mental disorders are a complex amalgam of genetic, biological and social factors—it’s logically impossible to isolate cause and effect cleanly because it’s always an ensemble of causes, leading to similar surface effects or symptoms. Says Dr Andrade: “Today, in 2018, we still don’t know the causes of any of the mental illnesses. We know there are genetic factors involved, we know there are environmental factors, and we know there’s a gene-environment interaction.” The only partial solace, he says, are “the available treatments for psychiatry work...they help patients. They may not be perfect, they may have side-effects, but they are helping patients.”

In a spectrum that goes from stress, Attention Deficit Hyperactivity Disorder (ADHD) or obsessive compulsive disorder, up the scale to depression, drug addiction or alcoholism, epilepsy, schizophrenia, bipolarity, to neurodevelopmental issues like autism or Asperger’s, to degenerative diseases like Alzheimer’s, it’s sometimes difficult to say where one ends and the other begins.

Indeed, we don’t even know whether the illnesses we describe as bipolar or schizophrenia are just one disease, says Prof B.N. Gangadhar, director, NIMHANS. “We have no idea at all,” he says. “And until a true biological process of an illness is known, to identify a medicine for that condition can be a challenge. So there’s no last word yet about even definitive lines of treatment, like lithium.” Dr Vikram Patel, a psychiatrist and researcher based in Harvard, concurs: “Psychoneuropathic drugs available to us only treat symptoms, not the disease. Several mental health diseases present similar symptoms and the drugs are non-specific in effect.”

Neuro and cognitive sciences, for all their advances, sometimes seem trapped in a lingering infancy—and mutually incompatible models. The knowledge rut then paralyses pharma companies, who naturally like to get good returns on their research funding. The negative momentum built by the science-industry interface in this case is made worse by other factors—the stigma attached to mental disorders, and less-than-conducive conditions for testing.

None of this means there was stasis: in the frenetic search for direction, some efforts succeed, both in pure science and in drug discovery. A new study published in the February edition of the journal Science reports that certain patterns of genetic activity appear to be common among five distinct psychiatric disorders—autism, schizophrenia, bipolarity, depression and alcoholism—with similar levels of particular molecules in the brains of different sets of patients. Getting a fix on the molecular basis of disorders, naturally, would help.

Nor does the stagnancy owe to want of trying. “A lot of medicines in the 1990s and in the new millenium have explored different mechanisms of action in controlling behavioural disorders,” says Arun B. Nair, assistant professor in psychiatry at Trivandum Medical College, pointing to the category of serotonin-dopamine antagonists, or atypical anti-psychotics, found useful in conditions like schizophrenia and mood disorders. “The only areas in which something still has to emerge is in degenerative disorders of the brain like dementia, Alzhiemer’s and so on. Here, there is no clear-cut solution yet,” says Nair.

In the last 10-15 years, around $15 billion has been invested in developing drugs for Alzheimer’s alone, but every drug has failed. So the outlook here is pretty dim currently with most pharma companies having almost ceased their efforts. Yet, a leading Indian neuroscience researcher says progress hasn’t been absent. “New molecules did come, some successful. Like Prozac, which came out in the 1980s. Further research revealed they act on multiple systems…they’re not target-specific, but promiscuous in the way they act. We also learnt to use existing drugs for other illnesses. For instance, a lot of anti-epileptic drugs are being used for management of bipolarity,” he says.

How come drug discovery can be so serendipitous in nature? The flux it seeks to address is part of the reason. To begin with, mental health conditions are not similar to physical ones like TB or diabetes. “Mental health disorders are not purely biological and have social and mental ecologies...there is no particular pathology for the diseases that we can address and solve,” says Soumitra Pathare, a psychiatrist and one of the chief designers of the Mental Health Act in India.

Fallow Pharmlands

There are also big impediments outside of science: a combination of prohibitive laws and guidelines and social factors. The stigma still associated with mental diseases means volunteers are hard to come by for testing, a field anyway fraught with a host of difficulties. “In order to test a drug, we need to run it on a target group of people. Unlike most other drug trials, involving diseases that manifest in physical indicators, mental illness patients are not willing to come forward and even less willing to allow new drugs to be tested on them,” says Pathare. Dr Jyoti Kapoor, senior consultant (psychiatry) at Paras Hospital, Delhi, cites the severe lack of animal equivalents for testing. “No one has been able to recreate such mental diseases on animals. Thus, even if there was a drug one could try, there’s no way of getting FDA or even a local government approval,” she says.

One of Dr Anderson’s basic contentions, in fact, is that of a disconnect between the animal model and the human model. Sumantra Chattarji, professor of neurobiology, National Centre for Biological Sciences, Bangalore, explains: “Much of the preclinical research was done using animal models like mice and rats. The results looked very attractive. But when it came to human drug trials, they failed at very high rates. So clearly the mice are not able to capture many of the human symptoms.” Also, adds Chattarji, “patient cohort data is difficult to get and very expensive in the West, so the drug companies face a huge challenge.”

Even when you get a drug that looks half decent through phase-two human trials and beyond, its actual efficacy is unpredictable. And the bar for brain disorder drugs is much higher than it is for, say, cancer. Fair results over three to six months in a cancer patient is seen as progress—and patients are willing to live with side-effects. Not so with the brain!

In fact, some of the more contentious debates belong here. “Any chemical drug you give for a mental illness will only damage the brain and not do anything for the patient unless he or she is violent,” says Dr B.M. Hegde, noted cardiologist and a fervent advocate of ‘coordinated medicine’, an approach that favours taking elements from various systems of medicine like Ayurveda and allopathy.

Besides, there’s the laborious drug trial design itself. Neuropsychiatric drugs see one placebo and one active drug being tried for a few years, then another. At the end of 6-15 years, you may or not get results. Cancer allows multi-adaptive drug trials—one placebo plus several drugs being run and assessed simultaneously. This delivers much faster and better results. And with the bar much lower, even a few side-effects don’t preclude USFDA approval.

A bit of a knowledge gap too has crept in, says Chattarji. “Drug companies, in their search for the magic drug, have for the longest time been focusing on a single receptor or molecule that will help them make their big bucks—the best compound that would act on specific targets in the brain, for say the treatment of Alzheimer’s or schizophrenia. But it now turns out that a specific receptor or molecule can act differently in different regions of the brain depending on the neural context, triggering very different effects. So it’s not like one size fits all,” says Chattarji, who works in the area of stress-induced disorders and autism.

There’s now greater understanding of how brain phenom­ena are related to entire neural circuits, where different parts of the brain are involved, not just one receptor. Unfortunat­ely, drug companies have not kept up with the progress in neuroscience and are still stuck with the linear approach typical of the 20th century—rendering them, among other things, incapable of predicting side-effects. The complexity of circuits, and how circuits in different parts of the brain interact with each other, also means models of depression and anxiety have to be revisited.

Dr Naren P. Rao, psychiatrist at NIMHANS, says the new molecules are not fundamentally different—they decrease symptoms, but do not cure. “If a patient doesn’t respond to one medicine, it’s very likely s/he won’t respond to other medications either. Resistance has been a major challenge,” he says. “While the newer molecules are much safer, with lesser side-effects, they focus on the same neurotransmitters because of the easy reward. But now we know other neurotransmitters, neuropeptides and immunomodulatory molecules play a key role.” A good example is oxytocin. This molecule is conserved evolutionarily and is vital for social cognitive functions across species—not independently, but in interaction with other molecules. “We now know a region of the brain does not work in isolation. Similarly, a single neurotransmitter does not determine behaviour,” explains Rao.

Dr Sridharan Devarajan of the Centre for Neuroscience, Indian Institute of Science, Bangalore, also rubbishes the belief that most human activities are controlled by a fraction of the neuro­transmitters in the brain. Imaging technology has shown that diverse areas of the brain become active during the performance of even routine tasks. “We don’t know the precise function of many neurotransmitters in the central nervous system. Some (e.g. acetylcholine, dopamine, GABA, glutamate) have been historically more heavily studied. But even these can have a different effect depending on the place of action, and the ‘receptor’ on which they act! Each neurotransmitter wears many hats,” says Devarajan.

Future research will have to unravel the precise role of the lesser known neurotransmitters. And no drug-based treatment can afford to not think about group-genetic and individual variations. As of now, the skew in drug trial design, cost and time, and outdated models, all combine to make for a huge deterrent. “Over the last decade, many drug companies pulled out lock, stock and barrel…they get much better results in drugs for heart, cancer etc,” concedes Chattarji. Those who shut down work in this field include AstraZeneca, Pfizer, even Novartis. Some of them are reconsidering on a smaller scale, some just not going back. So the pipeline has dried up almost completely.

This is why neuropsychiatric conditions are essentially being treated the same way for decades. Doctors have only about 60 drugs to treat a spectrum of ailments—from depression to alcoholism, even schizophrenia. Else, you have the non-pharmacotherapy methods—deep brain stimulation, electroconvulsive therapy, transcranial magnetic stimulation et al—which are used sparingly in India. While the absence of options creates “therapeutic nihilism” among some clinicians, it also engenders a sloppy, broad-spectrum approach.

Take Celia. She was put on Valprol, an anti-psychotic drug, to rein in her manic episodes. Incidentally, the same drug is used to treat epilepsy, bipolar disorder and even migraine. Or take Delhiite Zulfi Ahmed (name changed), who suffers from severe bipolar disorder with a mix of schizophrenia. Now in his mid-30s, he was diagnosed at 25 and was put on DIVA OD and Arip MT, both for mood stabilisation. The latter proved useful, but DIVA resulted in severe side-­effects and weight gain. It also made him more susceptible to anxiety. It took over half a decade of trial and error for him and his doctors to figure out a correct combination.

Many individuals recovering from drug or alcohol addiction too are usually given anti-epilepsy drugs—the drugs simply treat attacks of epilepsy that might be brought on by alcohol or drug withdrawal. “Such drugs are not targeting the part of the brain that compels us to take a drink or do drugs,” says Dr Rajesh Dhume, who is part of the Indian Psychiatrist Society’s pharmacological management team. Dr Patel describes the effect of such drugs as “hitting the nail with a sledgehammer”.

To top it off, the pharma sector in the Indian context has its own peculiar bottlenecks, beyond the universal factor of lack of funding. “This field is not a lucrative one...pharma companies are unable to market these drugs openly as compared to drugs for diabetes or cancer,” says Prof T.C. James, a fellow at the policy research institute RIS. The few Indian pharma companies that do anyway rely on reverse-engineering generic drugs to make their stash, and those who do R&D would rather have nothing to do with drugs for mental disorders.

Devesh Malladi, of the Indian Drug Manufacturers Association, blames government guidelines. The problem is indeed complex. Drugs for mental health disorders—66 in all, ­according to the Indian Medical Society—legally fall under the category of psychotropic drugs in India, and so distribution is severely controlled by the Narcotic Drugs and Psychotropic Substances Act, 1985! The licence and sale of such drugs also need to comply with the Drug Control Authority and are regulated by the Central Bureau of Narcotics. “We have three different nodal agencies looking into drugs of this type. And yet, no communication among them. The atmosphere not only dissuades inventors, but also impedes distribution,” says Malladi. No single body is responsible for licensing doctors or distributors. The consequences can be dire. Any lapse in filing reports on the number of drugs produced or marketed means manufacturers, distributors and doctors are looking at a minimum of 10 years in jail (and a maximum of 20). Hardly an encouraging set of policies!

The environment of fear is such, says Malladi, that manufacturers keep a safe distance from such drugs. He substantiates this with an example—in 2015, a circular by the Drug Control General of India said Buprenorphine, used to treat heroin addiction, could only be sold through government hospitals. The Drug Control Authority wasn’t in the loop. “This changed the way the drug was manu­factured, distributed and prescribed. Many private doctors in Punjab and Haryana who prescribed the medicine were jailed for violating the order,” he says. Yet, the Drug Control Order clearly states that Buprenorphine was a schedule “H” drug, which meant private doctors are allowed to possess and prescribe the drug.

The fear of harassment has seen several companies withdrawing “psychotropic” drugs from the Indian market. Take Lupin—half a decade ago, Lupin produced mental disorder drugs of all segments, but over the years they have systematically exited the Indian market. This, while their marketshare in these drugs in the US has only increased. Ditto with pharma giant Dr Reddy. Stakeholders have made several repre­sentations to the government, says Malladi, but to no effect.

So it’s not just the scientists or pharma firms that need to revisit their models, even the government needs a neural rewiring. The Mental Health Act is a positive step, but it barely touches on drug development. The science, of course, can’t be willed to progress. Dr M.S. Valiathan, noted academic and former president of the Indian National Science Academy, points out that even in the old classical texts like Charaka Samhita, which “described various types of procedures and medicinal formulations”, mental illness was thought of as “a very difficult problem”. The approach to treatment must innovate based on present knowledge. NIMHANS’s Gangadhar, for instance, hopes to see research on alternative treatments bearing fruit: for example, biological markers that give pointers about the remedial effects of yoga in people with depression. But to end the famine in drugs, it’s time for the State to incentivise R&D. That may help lift the depression.

By Lola Nayar and Arushi Bedi in Delhi and Ajay Sukumaran in Bangalore