Presenter

Meg Grabb, Ph.D.
Division of Translational Research

Goal

This effort aims to stimulate research in a major gap area in pediatric psychopharmacology for psychiatric and neurodevelopmental disorders, by encouraging the development of objective pediatric central nervous system (CNS) measures that can be incorporated into pharmacologic trials. The development of these measures/biomarkers can aid in dose selection for future efficacy trials or enable subgroup stratification to identify which subjects respond better or worse to a particular agent. Overall, this research will improve the safety of prescribed medication in youth populations.

Rationale

Over the last decade, limited drugs have been approved for the treatment of psychiatric and neurodevelopmental disorders in youth. There is a need for more objective measures to be built into early-stage pediatric trials (Phase I/II Proof of Concept studies) to ensure that the dosing used in these and in subsequent registration trials is optimal to test the drug mechanism in question.

Pharmacodynamic (PD) measures are objective measures of drug response that exist in many areas of medicine, yet until recently, CNS imaging and electroencephalogram (EEG) technologies could not provide sufficient evidence in trials for psychiatric indications. Currently, there are no validated pediatric PD measures for assessing optimal drug exposure in psychiatric indications. In drug development, PD measures are typically paired with pharmacokinetic (PK) measures (drug levels in blood) to establish PK/PD models for generating CNS dose-response effects. These models are important in establishing safety in dose selection in clinical trials in children and adolescents through a variety of approaches: 1) bridging studies to move from adult to pediatric populations; 2) direct assessment of drug action in pediatric populations using a candidate drug with extensive adult safety data but not yet approved for any pediatric indication.

In addition to PD measures, stratification measures (including multicomponent biomarkers) are needed to objectively identify patient subgroups that may respond better or worse to drug agents. The development of these measures can help determine patterns in variation to treatment response, identify potential safety issues, and aid in designing later stage trials.

Overall, NIMH emphasizes the need for objective measures to be incorporated into pediatric pharmacologic trials to address issues from past trial failures. NIMH also emphasizes the need for multidisciplinary teams of pediatric psychopharmacologists, CNS imaging/EEG researchers, researchers with digital measure expertise, and clinical pharmacologists to collaborate and to establish the measures/models in different pediatric age groups to support this effort.

In February 1975 the New Zealand writer Janet Frame was the subject of a rare interview for television conducted by the journalist Michael Noonan. This relaxed, intimate retrospective of her life and work – Frame and Noonan stroll, laughing together, at the height of summer along a sea-swept beach near her then home on the Whangaparāoa Peninsula, north of Auckland – was made as part of a project to mark the United Nations’ International Women’s Year. Frame would turn 51 that August; on screen she comes across as confident, relaxed, witty and thoughtful, far removed from the introverted and reclusive former psychiatric patient portrayed in Jane Campion’s 1990 film An Angel at My Table. Based on Frame’s bestselling autobiography, it is a legend-enforcing depiction of how Frame transformed her early background of poverty, tragedy and mental illness into literature. The New York Times obituary published the day after her death from leukaemia on 29 January 2004 would categorise Frame in its headline as a “writer who explored madness”.

Frame, whose centenary is celebrated this month with events in the UK and New Zealand, was indubitably a writer “who explored madness”, and yet so much more – internationally renowned, strikingly original and unclassifiable, a dazzling interpreter of and innovator in language, a shrewd investigator of the postcolonial world and New Zealand’s projected image of itself. She was a linguistic explorer into the many meanings of that island nation – for both Māori and settler – and an antidote to the “Man Alone” nationalist realist tradition of Pākehā (white European) male writers that dominated New Zealand literature of the early to mid-20th century.

Her early fiction is imbued with the poetry she learned by rote at school, where she was a gifted scholar – Keats, Shelley, John Greenleaf Whittier – and by the plays on the wireless that she listened to avidly with her siblings. It is suffused with popular culture, and the domestic vernacular and public vocabulary of working-class, small‑town New Zealand during the depression and second world war, as well as that of the postwar England of the late 1950s and early 60s, where she lived for seven years, with its bitter cold and even more bitter dislocations.

In its structure and strangeness her work bears the hallmark of writers as diverse as Stevie Smith, TS Eliot and Virginia Woolf, yet displays a fabular intensity all of its own. Its spiky, mischievous, often macabre and highly personalised humour looks forward to Muriel Spark, Jenny Diski, Siri Hustvedt and Alison Moore. Frame is the only New Zealand writer to have won individual national awards across all four categories: for her poetry, short stories, novels and autobiography. She took the Commonwealth Writers’ prize in 1988 for her novel The Carpathians, was awarded a CBE in 1983, was an Honorary Member of the American Academy of Arts and Letters and in 1990 made Member of the Order of New Zealand, the country’s highest civil honour. Her champions include Hilary Mantel, Anita Brookner, Doris Lessing and Michael Holroyd, who described An Angel at My Table (its three volumes were collectively published under this title in 2008) as “one of the greatest autobiographies written this century”, with the Australian Nobel laureate Patrick White pronouncing it as “among the wonders of the world”. According to New Zealand author Eleanor Catton, winner of the 2013 Booker prize, “any one of her books could be published today and it would be groundbreaking”.

Her achievements are all the more remarkable because she might never have survived to write at all. Janet Paterson Frame was born on 28 August 1924 in Dunedin in New Zealand’s South Island, the third of five children, to George, a railway worker, and Lottie, who was before her marriage a housemaid – including employment in the household of Katherine Mansfield, still possibly New Zealand’s best-known literary export. Frame’s parents were of Scottish descent. “I come from a writing family: my mother sold her poems from door to door,” she comments unselfconsciously in that 1975 TV interview. Due to the peripatetic nature of their father’s job, she and her siblings grew up in various coastal towns, in ramshackle houses without running water or electricity, principally in Oamaru, immortalised as “Waimaru” in her subsequent fiction.

Life was typically tough, and impoverished, made worse by the alarm of the only boy, Geordie, being diagnosed with epilepsy at the age of eight. The four girls shared one bed. Daily chores included milking cows and carrying water; kittens were dispatched in a sack. (Frame’s fiction is full of such matter-of-fact incidents; and of flooded creeks swelled with the bloated bodies of dead sheep and cows.) The children ran wild outdoors in the bush “past orchards and farms, paddocks filled with cattle, sheep, wheat, gorse, and the squatters of the land who were the rabbits eating like modern sculpture into the hills,” she wrote in one of her best-known stories, The Reservoir. They devoured any reading material, entered writing competitions, and were entranced by cinema, longing to go to Hollywood and become film stars. School was both a torment to socially awkward Janet, who stood out with her shock of flaming red hair, and also a release: academically she excelled.

The family was convulsed by the double tragedy of losing two of the girls, Myrtle and Isabel, in separate accidents a decade apart. Both sisters drowned, as a result of the same heart condition. These terrible losses deeply affected Frame. While she was working as a trainee teacher, she attempted to take her own life, and as a result was misdiagnosed with schizophrenia. She would be in and out of psychiatric hospitals for eight years, where she was subjected to countless sessions of ECT and insulin shock therapy.

Frame stated in her autobiography: “It is little wonder that I value writing as a way of life when it actually saved my life.” A volume of short stories, The Lagoon, had been published in 1951. The following year it won the Hubert Church Memorial prize, which was New Zealand’s only literary award. Frame had never heard of it; the previous winner was Frank Sargeson, who, after Frame was eventually discharged from hospital in 1955, lent her his garden shed, where she would live and work for two years on her first novel, the modernist Owls Do Cry (1957). The prize came in the nick of time, as Frame was scheduled for a leucotomy, otherwise known as a prefrontal lobotomy. If this had gone ahead she would quite probably have remained incarcerated in the psychiatric system and never published anything else.

“The leucotomies were silent, docile,” she wrote in An Angel at My Table. “Their eyes were large and dark and their faces pale with damp skin. They were being ‘retrained’ to fit in to the ‘everyday world’ always described as ‘outside’.”

Several years later, when a psychiatrist at the Maudsley in south London told her what she already knew – that she had depression, and had never been schizophrenic – she would, with his encouragement, write about her experiences in her 1961 novel Faces in the Water, “to give me a clearer view of the future”. As Istina Mavet, the protagonist of the novel, explains: “I did not know my own identity. I was burgled of body and hung in the sky like a woman of straw.” Frame’s entire work was concerned with a sense of such violent depersonalisation – what she termed the “homelessness of self”.

But her niece, close friend and literary executor, Pamela Gordon (daughter of Frame’s youngest sister, June) urges readers to focus less on the adversities catalogued in Frame’s biography, and concentrate on the work. “I have spent my life observing the intense attention that her brilliant writing attracted from the very beginning of her long and remarkable career. And I also noted the envy that her achievements elicited from some of her contemporaries,” she says.

“Over all those decades her reputation suffered, especially in New Zealand, from that unfortunate cultural cringe we call here the ‘tall poppy syndrome’. Some of her many successes were hampered by the effects of misogyny, class prejudice, and malicious gossip. These factors are still in play posthumously but I feel they are becoming less powerful. Janet Frame was aware of all this negativity but she believed in the long game.”

Emily Perkins, who this year won New Zealand’s top fiction prize, the Ockham, for her novel Lioness, said: “You can’t help but be penetrated by her intelligence and attunement to the sensory world, just as you can’t help being profoundly moved by her hotline to the beauty, bewilderment and dread of childhood. Her writing can seem like a paradox – she’s an immensely socially astute writer of alienation and a masterful poet of wordlessness. She can make intensely private interior worlds bloom in the reader’s mind.”

Catherine Chidgey, author most recently of The Axeman’s Carnival, said she stored Frame’s “depictions of Aotearoa [the Māori name for New Zealand] in my blood, a beautiful place, a foreboding place, where the natural world is never far from the domestic”.

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Kirsty Gunn, whose latest collection of short fiction is Pretty Ugly, recalls: “My mother introduced me to the work of Frame when I was about 12. I remember how, at that age, Owls Do Cry seemed to be delivered straight into my bloodstream as a kind of racing, trippy experience of pure feeling – like nothing else I’d ever known. I was hooked. Before then, I hadn’t thought of novels being made out of outsider lives.”

In 1957 Frame left for Europe with the aid of a grant from the New Zealand Literary Fund. She had mixed experiences, both personally and professionally, in England, and in Ibiza, where she would live for a year. In her posthumously published novella Towards Another Summer (2008), her character, the writer Grace Cleave, enduring the very cold winter of 1962-63, undergoes a “roots crisis” all too familiar to Frame and other exiles from home.

Frame’s third novel, The Edge of the Alphabet (1962), is this month republished by Fitzcarraldo to commemorate the centenary of Frame’s birth. In it three people meet on board a ship as they leave New Zealand and set off for England and London, a city “covered in antimacassars of fog”: the epileptic Toby Withers (who appears in Frame’s debut, Owls Do Cry), on his first journey overseas; English schoolteacher Zoe Bryce; and jovial but controlling Irishman Pat Keenan – all are uneasy, lonely, marginal. The key question of the novel is “how can one really identify oneself, living so close to the edge of the alphabet?”

It is the most Woolfian of Frame’s work: with intense, often dissociated separate monologues and repeated imagery of light, sounds and shapes evoking the waves, and the long, turbulent journey by sea of Woolf’s first novel, The Voyage Out. Frame even uses Woolf’s trick of killing off a main character to release the others to life. (Margaret Drabble has remarked: “I sometimes think it’s an accident of geography and history and social class that Janet Frame isn’t as well known as Virginia Woolf.”) Publishing the novel has been something of a labour of love for Fitzcarraldo’s publicity director, Clare Bogen, who has a New Zealand background.

“Frame was my first experience of the unhomely in literature,” she says. “The Edge of the Alphabet is explicitly about language and the breakdown of language. Frame isn’t scared of leaving her reader behind in unusual formatting or by introducing layers of metafiction.”

Other centenary celebrations include a special Curzon cinema screening of An Angel at My Table in London in September, a writers’ tribute event at the annual Word Christchurch festival in New Zealand on Frame’s 100th birthday, and a “Reading Janet Frame” symposium in the city of her birth, Dunedin. Virago Modern Classics, which publishes many of her novels and stories, is also reissuing the autobiography in a new edition. “I hope that the spotlight on Frame this year will inspire another generation of readers to discover her visionary voice,” says editorial director Olivia Barber.

For Frame, it was always about the writing. In The Edge of the Alphabet, Toby and Zoe wonder if they, too, could be writers. “Shall I write a book?” ponders Zoe. “Shall I engage in private research of identity?” Toby tells everyone he meets of his plans for a book about a “lost tribe”, and while he cannot even spell his own name, his “pedantic” dreams are masterpieces of eloquence. Living in the Maniototo, Frame’s 1979 novel, continues this theme of selfhood. It is vintage Frame: a work both of social satire and “journeys toward that are believed to be journeys away from, and journeys away that are really journeys within”.

It was the success of her autobiography – written, so she said, “to set the record straight” – that would give her financial security. Its bestseller status and the ensuing Campion film brought publicity to the very private Frame, and has somewhat eclipsed her in the public eye, at least, as a fiction writer. Frame had returned to New Zealand to live permanently in 1963, though she also took up residencies in the US at Yaddo and MacDowell from 1967, which provided enriching friendships and new adventures. After a long period in the North Island, she moved back to the South Island in 1997, where she died in Dunedin. It is there, at the edge of the world, the edge of the alphabet, in “the long shadows of the Southland twilight”, that Frame’s extraordinary vision lives on, “the moments hanging ripe, like red currants”.

75th Anniversary

Overview

As part of the yearlong 75th Anniversary celebration, the National Institute of Mental Health (NIMH) hosted a webinar to explore key advances in genetics and genomics research. Since its establishment, NIMH has recognized the significance of genetics in understanding mental disorders, and has supported research efforts related to gene discovery, functional genomics, and translation to clinical practice.

This webinar brought together four distinguished researchers to shed light on the genetic basis of mental illness, the impact of genetic variation and developmental trajectories in neurodevelopmental and psychiatric disorders, and the future of translating genetic findings to patient care.

Recording

Read the transcript.

Featured presentations

• The Psychiatric Genomics Consortium: Deep Dives into the Fundamentals
  Patrick Sullivan, M.D., University of North Carolina at Chapel Hill ; Karolinska Institute, Stockholm, Sweden  
  Dr. Sullivan described the Psychiatric Genomics Consortium, a highly impactful initiative that has led to fundamental insights about the genetic basis of mental illness.
   
• Precision Health for Neurodevelopmental/Psychiatric Disorders 
  Christa Martin, Ph.D., F.A.C.M.G., Geisinger Health System  
  Dr. Martin talked about both basic and clinical aspects of psychiatric disorders. Dr. Martin is also a principal investigator of the Genes to Mental Health Network, which focuses on understanding the role of genetic variation in rare neurodevelopmental and psychiatric disorders.
   
• Developmental Trajectories in Common Neuropsychiatric Disorders Modeled in Organoids
  Flora Vaccarino, M.D., Yale University  
  Dr. Vaccarino of the PsychENCODE Consortium described molecular studies and developmental trajectories of mental illness.
   
• Putting Genetics to Work in Psychiatric Care 
  Francis McMahon, M.D., National Institute of Mental Health Intramural Research Program 
  Dr. McMahon from the Human Genetics Branch of the NIMH intramural research program described exciting directions of relating genomics findings to patient care.
   

Sponsored by

National Institute of Mental Health, Genomics Team