Computational chemistry

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Computational_chemistry 

Computational chemistry is a branch of chemistry that uses computer simulation to assist in solving chemical problems. It uses methods of theoretical chemistry, incorporated into computer programs, to calculate the structures and properties of molecules, groups of molecules, and solids. It is necessary because, apart from relatively recent results concerning the hydrogen molecular ion (dihydrogen cation, see references therein for more details), the quantum many-body problem cannot be solved analytically, much less in closed form. While computational results normally complement the information obtained by chemical experiments, it can in some cases predict hitherto unobserved chemical phenomena. It is widely used in the design of new drugs and materials.

Examples of such properties are structure (i.e., the expected positions of the constituent atoms), absolute and relative (interaction) energies, electronic charge density distributions, dipoles and higher multipole moments, vibrational frequencies, reactivity, or other spectroscopic quantities, and cross sections for collision with other particles.

The methods used cover both static and dynamic situations. In all cases, the computer time and other resources (such as memory and disk space) increase rapidly with the size of the system being studied. That system can be one molecule, a group of molecules, or a solid. Computational chemistry methods range from very approximate to highly accurate; the latter are usually feasible for small systems only. Ab initio methods are based entirely on quantum mechanics and basic physical constants. Other methods are called empirical or semi-empirical because they use additional empirical parameters.

Both ab initio and semi-empirical approaches involve approximations. These range from simplified forms of the first-principles equations that are easier or faster to solve, to approximations limiting the size of the system (for example, periodic boundary conditions), to fundamental approximations to the underlying equations that are required to achieve any solution to them at all. For example, most ab initio calculations make the Born–Oppenheimer approximation, which greatly simplifies the underlying Schrödinger equation by assuming that the nuclei remain in place during the calculation. In principle, ab initio methods eventually converge to the exact solution of the underlying equations as the number of approximations is reduced. In practice, however, it is impossible to eliminate all approximations, and residual error inevitably remains. The goal of computational chemistry is to minimize this residual error while keeping the calculations tractable.

In some cases, the details of electronic structure are less important than the long-time phase space behavior of molecules. This is the case in conformational studies of proteins and protein-ligand binding thermodynamics. Classical approximations to the potential energy surface are used, typically with molecular mechanics force fields, as they are computationally less intensive than electronic calculations, to enable longer simulations of molecular dynamics. Furthermore, cheminformatics uses even more empirical (and computationally cheaper) methods like machine learning based on physicochemical properties. One typical problem in cheminformatics is to predict the binding affinity of drug molecules to a given target. Other problems include predicting binding specificity, off-target effects, toxicity, and pharmacokinetic properties.

History

Building on the founding discoveries and theories in the history of quantum mechanics, the first theoretical calculations in chemistry were those of Walter Heitler and Fritz London in 1927, using valence bond theory. The books that were influential in the early development of computational quantum chemistry include Linus Pauling and E. Bright Wilson's 1935 Introduction to Quantum Mechanics – with Applications to Chemistry, Eyring, Walter and Kimball's 1944 Quantum Chemistry, Heitler's 1945 Elementary Wave Mechanics – with Applications to Quantum Chemistry, and later Coulson's 1952 textbook Valence, each of which served as primary references for chemists in the decades to follow.

With the development of efficient computer technology in the 1940s, the solutions of elaborate wave equations for complex atomic systems began to be a realizable objective. In the early 1950s, the first semi-empirical atomic orbital calculations were performed. Theoretical chemists became extensive users of the early digital computers. One major advance came with the 1951 paper in Reviews of Modern Physics by Clemens C. J. Roothaan in 1951, largely on the "LCAO MO" approach (Linear Combination of Atomic Orbitals Molecular Orbitals), for many years the second-most cited paper in that journal. A very detailed account of such use in the United Kingdom is given by Smith and Sutcliffe. The first ab initio Hartree–Fock method calculations on diatomic molecules were performed in 1956 at MIT, using a basis set of Slater orbitals. For diatomic molecules, a systematic study using a minimum basis set and the first calculation with a larger basis set were published by Ransil and Nesbet respectively in 1960. The first polyatomic calculations using Gaussian orbitals were performed in the late 1950s. The first configuration interaction calculations were performed in Cambridge on the EDSAC computer in the 1950s using Gaussian orbitals by Boys and coworkers. By 1971, when a bibliography of ab initio calculations was published, the largest molecules included were naphthalene and azulene. Abstracts of many earlier developments in ab initio theory have been published by Schaefer.

In 1964, Hückel method calculations (using a simple linear combination of atomic orbitals (LCAO) method to determine electron energies of molecular orbitals of π electrons in conjugated hydrocarbon systems) of molecules, ranging in complexity from butadiene and benzene to ovalene, were generated on computers at Berkeley and Oxford. These empirical methods were replaced in the 1960s by semi-empirical methods such as CNDO.

In the early 1970s, efficient ab initio computer programs such as ATMOL, Gaussian, IBMOL, and POLYAYTOM, began to be used to speed ab initio calculations of molecular orbitals. Of these four programs, only Gaussian, now vastly expanded, is still in use, but many other programs are now in use. At the same time, the methods of molecular mechanics, such as MM2 force field, were developed, primarily by Norman Allinger.

One of the first mentions of the term computational chemistry can be found in the 1970 book Computers and Their Role in the Physical Sciences by Sidney Fernbach and Abraham Haskell Taub, where they state "It seems, therefore, that 'computational chemistry' can finally be more and more of a reality." During the 1970s, widely different methods began to be seen as part of a new emerging discipline of computational chemistry. The Journal of Computational Chemistry was first published in 1980.

Computational chemistry has featured in several Nobel Prize awards, most notably in 1998 and 2013. Walter Kohn, "for his development of the density-functional theory", and John Pople, "for his development of computational methods in quantum chemistry", received the 1998 Nobel Prize in Chemistry. Martin Karplus, Michael Levitt and Arieh Warshel received the 2013 Nobel Prize in Chemistry for "the development of multiscale models for complex chemical systems".

Fields of application

The term theoretical chemistry may be defined as a mathematical description of chemistry, whereas computational chemistry is usually used when a mathematical method is sufficiently well developed that it can be automated for implementation on a computer. In theoretical chemistry, chemists, physicists, and mathematicians develop algorithms and computer programs to predict atomic and molecular properties and reaction paths for chemical reactions. Computational chemists, in contrast, may simply apply existing computer programs and methodologies to specific chemical questions.

Computational chemistry has two different aspects:

• Computational studies, used to find a starting point for a laboratory synthesis, or to assist in understanding experimental data, such as the position and source of spectroscopic peaks.
• Computational studies, used to predict the possibility of so far entirely unknown molecules or to explore reaction mechanisms not readily studied via experiments.

Thus, computational chemistry can assist the experimental chemist or it can challenge the experimental chemist to find entirely new chemical objects.

Several major areas may be distinguished within computational chemistry:

• The prediction of the molecular structure of molecules by the use of the simulation of forces, or more accurate quantum chemical methods, to find stationary points on the energy surface as the position of the nuclei is varied.
• Storing and searching for data on chemical entities (see chemical databases).
• Identifying correlations between chemical structures and properties (see quantitative structure–property relationship (QSPR) and quantitative structure–activity relationship (QSAR)).
• Computational approaches to help in the efficient synthesis of compounds.
• Computational approaches to design molecules that interact in specific ways with other molecules (e.g. drug design and catalysis).

Accuracy

Computational chemistry is not an exact description of real-life chemistry, as our mathematical models of the physical laws of nature can only provide us with an approximation. However, the majority of chemical phenomena can be described to a certain degree in a qualitative or approximate quantitative computational scheme.

Molecules consist of nuclei and electrons, so the methods of quantum mechanics apply. Computational chemists often attempt to solve the non-relativistic Schrödinger equation, with relativistic corrections added, although some progress has been made in solving the fully relativistic Dirac equation. In principle, it is possible to solve the Schrödinger equation in either its time-dependent or time-independent form, as appropriate for the problem in hand; in practice, this is not possible except for very small systems. Therefore, a great number of approximate methods strive to achieve the best trade-off between accuracy and computational cost.

Accuracy can always be improved with greater computational cost. Significant errors can present themselves in ab initio models comprising many electrons, due to the computational cost of full relativistic-inclusive methods. This complicates the study of molecules interacting with high atomic mass unit atoms, such as transitional metals and their catalytic properties. Present algorithms in computational chemistry can routinely calculate the properties of small molecules that contain up to about 40 electrons with errors for energies less than a few kJ/mol. For geometries, bond lengths can be predicted within a few picometers and bond angles within 0.5 degrees. The treatment of larger molecules that contain a few dozen atoms is computationally tractable by more approximate methods such as density functional theory (DFT).

There is some dispute within the field whether or not the latter methods are sufficient to describe complex chemical reactions, such as those in biochemistry. Large molecules can be studied by semi-empirical approximate methods. Even larger molecules are treated by classical mechanics methods that use what are called molecular mechanics (MM). In QM-MM methods, small parts of large complexes are treated quantum mechanically (QM), and the remainder is treated approximately (MM).

Methods

One molecular formula can represent more than one molecular isomer: a set of isomers. Each isomer is a local minimum on the energy surface (called the potential energy surface) created from the total energy (i.e., the electronic energy, plus the repulsion energy between the nuclei) as a function of the coordinates of all the nuclei. A stationary point is a geometry such that the derivative of the energy with respect to all displacements of the nuclei is zero. A local (energy) minimum is a stationary point where all such displacements lead to an increase in energy. The local minimum that is lowest is called the global minimum and corresponds to the most stable isomer. If there is one particular coordinate change that leads to a decrease in the total energy in both directions, the stationary point is a transition structure and the coordinate is the reaction coordinate. This process of determining stationary points is called geometry optimization.

The determination of molecular structure by geometry optimization became routine only after efficient methods for calculating the first derivatives of the energy with respect to all atomic coordinates became available. Evaluation of the related second derivatives allows the prediction of vibrational frequencies if harmonic motion is estimated. More importantly, it allows for the characterization of stationary points. The frequencies are related to the eigenvalues of the Hessian matrix, which contains second derivatives. If the eigenvalues are all positive, then the frequencies are all real and the stationary point is a local minimum. If one eigenvalue is negative (i.e., an imaginary frequency), then the stationary point is a transition structure. If more than one eigenvalue is negative, then the stationary point is a more complex one, and is usually of little interest. When one of these is found, it is necessary to move the search away from it if the experimenter is looking solely for local minima and transition structures.

The total energy is determined by approximate solutions of the time-dependent Schrödinger equation, usually with no relativistic terms included, and by making use of the Born–Oppenheimer approximation, which allows for the separation of electronic and nuclear motions, thereby simplifying the Schrödinger equation. This leads to the evaluation of the total energy as a sum of the electronic energy at fixed nuclei positions and the repulsion energy of the nuclei. A notable exception are certain approaches called direct quantum chemistry, which treat electrons and nuclei on a common footing. Density functional methods and semi-empirical methods are variants on the major theme. For very large systems, the relative total energies can be compared using molecular mechanics. The ways of determining the total energy to predict molecular structures are:

Ab initio methods

Main article: Ab initio quantum chemistry methods

The programs used in computational chemistry are based on many different quantum-chemical methods that solve the molecular Schrödinger equation associated with the molecular Hamiltonian. Methods that do not include any empirical or semi-empirical parameters in their equations – being derived directly from theoretical principles, with no inclusion of experimental data – are called ab initio methods. This does not imply that the solution is an exact one; they are all approximate quantum mechanical calculations. It means that a particular approximation is rigorously defined on first principles (quantum theory) and then solved within an error margin that is qualitatively known beforehand. If numerical iterative methods must be used, the aim is to iterate until full machine accuracy is obtained (the best that is possible with a finite word length on the computer, and within the mathematical and/or physical approximations made).

Diagram illustrating various ab initio electronic structure methods in terms of energy. Spacings are not to scale.

The simplest type of ab initio electronic structure calculation is the Hartree–Fock method (HF), an extension of molecular orbital theory, in which the correlated electron-electron repulsion is not specifically taken into account; only its average effect is included in the calculation. As the basis set size is increased, the energy and wave function tend towards a limit called the Hartree–Fock limit. Many types of calculations (termed post-Hartree–Fock methods) begin with a Hartree–Fock calculation and subsequently correct for electron-electron repulsion, referred to also as electronic correlation. As these methods are pushed to the limit, they approach the exact solution of the non-relativistic Schrödinger equation. To obtain exact agreement with experiment, it is necessary to include relativistic and spin orbit terms, both of which are far more important for heavy atoms. In all of these approaches, along with choice of method, it is necessary to choose a basis set. This is a set of functions, usually centered on the different atoms in the molecule, which are used to expand the molecular orbitals with the linear combination of atomic orbitals (LCAO) molecular orbital method ansatz. Ab initio methods need to define a level of theory (the method) and a basis set.

The Hartree–Fock wave function is a single configuration or determinant. In some cases, particularly for bond breaking processes, this is inadequate, and several configurations must be used. Here, the coefficients of the configurations, and of the basis functions, are optimized together.

The total molecular energy can be evaluated as a function of the molecular geometry; in other words, the potential energy surface. Such a surface can be used for reaction dynamics. The stationary points of the surface lead to predictions of different isomers and the transition structures for conversion between isomers, but these can be determined without a full knowledge of the complete surface.

A particularly important objective, called computational thermochemistry, is to calculate thermochemical quantities such as the enthalpy of formation to chemical accuracy. Chemical accuracy is the accuracy required to make realistic chemical predictions and is generally considered to be 1 kcal/mol or 4 kJ/mol. To reach that accuracy in an economic way it is necessary to use a series of post-Hartree–Fock methods and combine the results. These methods are called quantum chemistry composite methods.

Density functional methods

Main article: Density functional theory

Density functional theory (DFT) methods are often considered to be ab initio methods for determining the molecular electronic structure, even though many of the most common functionals use parameters derived from empirical data, or from more complex calculations. In DFT, the total energy is expressed in terms of the total one-electron density rather than the wave function. In this type of calculation, there is an approximate Hamiltonian and an approximate expression for the total electron density. DFT methods can be very accurate for little computational cost. Some methods combine the density functional exchange functional with the Hartree–Fock exchange term and are termed hybrid functional methods.

Semi-empirical methods

Main article: Semi-empirical quantum chemistry methods

Semi-empirical quantum chemistry methods are based on the Hartree–Fock method formalism, but make many approximations and obtain some parameters from empirical data. They were very important in computational chemistry from the 60s to the 90s, especially for treating large molecules where the full Hartree–Fock method without the approximations were too costly. The use of empirical parameters appears to allow some inclusion of correlation effects into the methods.

Primitive semi-empirical methods were designed even before, where the two-electron part of the Hamiltonian is not explicitly included. For π-electron systems, this was the Hückel method proposed by Erich Hückel, and for all valence electron systems, the extended Hückel method proposed by Roald Hoffmann. Sometimes, Hückel methods are referred to as "completely emprirical" because they do not derive from a Hamiltonian.Yet, the term "empirical methods", or "empirical force fields" is usually used to describe Molecular Mechanics.

Molecular mechanics

Main article: Molecular mechanics

In many cases, large molecular systems can be modeled successfully while avoiding quantum mechanical calculations entirely. Molecular mechanics simulations, for example, use one classical expression for the energy of a compound, for instance the harmonic oscillator. All constants appearing in the equations must be obtained beforehand from experimental data or ab initio calculations.

The database of compounds used for parameterization, i.e., the resulting set of parameters and functions is called the force field, is crucial to the success of molecular mechanics calculations. A force field parameterized against a specific class of molecules, for instance proteins, would be expected to only have any relevance when describing other molecules of the same class.

These methods can be applied to proteins and other large biological molecules, and allow studies of the approach and interaction (docking) of potential drug molecules.

Methods for solids

Main article: Computational chemical methods in solid state physics

Computational chemical methods can be applied to solid state physics problems. The electronic structure of a crystal is in general described by a band structure, which defines the energies of electron orbitals for each point in the Brillouin zone. Ab initio and semi-empirical calculations yield orbital energies; therefore, they can be applied to band structure calculations. Since it is time-consuming to calculate the energy for a molecule, it is even more time-consuming to calculate them for the entire list of points in the Brillouin zone.

Chemical dynamics

Once the electronic and nuclear variables are separated (within the Born–Oppenheimer representation), in the time-dependent approach, the wave packet corresponding to the nuclear degrees of freedom is propagated via the time evolution operator (physics) associated to the time-dependent Schrödinger equation (for the full molecular Hamiltonian). In the complementary energy-dependent approach, the time-independent Schrödinger equation is solved using the scattering theory formalism. The potential representing the interatomic interaction is given by the potential energy surfaces. In general, the potential energy surfaces are coupled via the vibronic coupling terms.

The most popular methods for propagating the wave packet associated to the molecular geometry are:

• the split operator technique,
• the Chebyshev (real) polynomial,
• the multi-configuration time-dependent Hartree method (MCTDH),
• the semiclassical method.

Molecular dynamics

Main article: Molecular dynamics

Molecular dynamics (MD) use either quantum mechanics, molecular mechanics or a mixture of both to calculate forces which are then used to solve Newton's laws of motion to examine the time-dependent behaviour of systems. The result of a molecular dynamics simulation is a trajectory that describes how the position and velocity of particles varies with time. The phase point of a system described by the positions and momenta of all its particles on a previous time point, will determine the next phase point in time by integrating over Newton's laws of motion.

Monte Carlo

Monte Carlo (MC) generates configurations of a system by making random changes to the positions of its particles, together with their orientations and conformations where appropriate. It is a random sampling method, which makes use of the so-called importance sampling. Importance sampling methods are able to generate low energy states, as this enables properties to be calculated accurately. The potential energy of each configuration of the system can be calculated, together with the values of other properties, from the positions of the atoms.

Quantum mechanics/Molecular mechanics (QM/MM)

Main article: QM/MM

QM/MM is a hybrid method that attempts to combine the accuracy of quantum mechanics with the speed of molecular mechanics. It is useful for simulating very large molecules such as enzymes.

Interpreting molecular wave functions

The atoms in molecules (QTAIM) model of Richard Bader was developed to effectively link the quantum mechanical model of a molecule, as an electronic wavefunction, to chemically useful concepts such as atoms in molecules, functional groups, bonding, the theory of Lewis pairs, and the valence bond model. Bader has demonstrated that these empirically useful chemistry concepts can be related to the topology of the observable charge density distribution, whether measured or calculated from a quantum mechanical wavefunction. QTAIM analysis of molecular wavefunctions is implemented, for example, in the AIMAll software package.

Software packages

Many self-sufficient computational chemistry software packages exist. Some include many methods covering a wide range, while others concentrate on a very specific range or even on one method. Details of most of them can be found in:

• Biomolecular modelling programs: proteins, nucleic acid.
• Molecular mechanics programs.
• Quantum chemistry and solid state physics software supporting several methods.
• Molecular design software
• Semi-empirical programs.
• Valence bond programs.

Bulimia nervosa

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Bulimia_nervosa 

 

Bulimia nervosa
Other names	Bulimia
Loss of enamel (acid erosion) from the inside of the upper front teeth as a result of bulimia
Specialty	Psychiatry, clinical psychology
Symptoms	Eating a large amount of food in a short amount of time followed by vomiting or the use of laxatives, often normal weight
Complications	Breakdown of the teeth, depression, anxiety, substance use disorders, suicide
Causes	Genetic and environmental factors
Diagnostic method	Based on person's medical history
Differential diagnosis	Anorexia, binge eating disorder, Kleine-Levin syndrome, borderline personality disorder
Treatment	Cognitive behavioral therapy
Medication	Selective serotonin reuptake inhibitors, tricyclic antidepressant
Prognosis	Half recover over 10 years with treatment
Frequency	3.6 million (2015)

Bulimia nervosa, also known as simply bulimia, is an eating disorder characterized by binge eating followed by purging; and excessive concern with body shape and weight. The aim of this activity is to expel the body of calories eaten from the binging phase of the process. Binge eating refers to eating a large amount of food in a short amount of time. Purging refers to the attempts to get rid of the food consumed. This may be done by vomiting or taking laxatives. Other efforts to lose weight may include the use of diuretics, stimulants, water fasting, or excessive exercise. Most people with bulimia are at a normal weight. The forcing of vomiting may result in thickened skin on the knuckles, breakdown of the teeth and effects on metabolic rate and caloric intake which cause thyroid dysfunction. Bulimia is frequently associated with other mental disorders such as depression, anxiety, bipolar disorder and problems with drugs or alcohol. There is also a higher risk of suicide and self-harm. Clinical studies show a relationship between bulimia and vulnerable narcissism as caused by childhood 'parental invalidation' leading to a later need for social validation.

Bulimia is more common among those who have a close relative with the condition. The percentage risk that is estimated to be due to genetics is between 30% and 80%. Other risk factors for the disease include psychological stress, cultural pressure to attain a certain body type, poor self-esteem, and obesity. Living in a culture that promotes dieting and having parents that worry about weight are also risks. Diagnosis is based on a person's medical history; however, this is difficult, as people are usually secretive about their binge eating and purging habits. Further, the diagnosis of anorexia nervosa takes precedence over that of bulimia. Other similar disorders include binge eating disorder, Kleine-Levin syndrome, and borderline personality disorder.

Cognitive behavioral therapy is the primary treatment for bulimia. Antidepressants of the selective serotonin reuptake inhibitor (SSRI) or tricyclic antidepressant classes may have a modest benefit. While outcomes with bulimia are typically better than in those with anorexia, the risk of death among those affected is higher than that of the general population. At 10 years after receiving treatment about 50% of people are fully recovered.

Globally, bulimia was estimated to affect 3.6 million people in 2015. About 1% of young women have bulimia at a given point in time and about 2% to 3% of women have the condition at some point in their lives. The condition is less common in the developing world. Bulimia is about nine times more likely to occur in women than men. Among women, rates are highest in young adults. Bulimia was named and first described by the British psychiatrist Gerald Russell in 1979.

Signs and symptoms

How bulimia affects the body

 

The erosion on the lower teeth was caused by bulimia. For comparison, the upper teeth were restored with porcelain veneers.

Bulimia typically involves rapid and out-of-control eating, which may stop when the person is interrupted by another person or the stomach hurts from over-extension, followed by self-induced vomiting or other forms of purging. This cycle may be repeated several times a week or, in more serious cases, several times a day and may directly cause:

• Chronic gastric reflux after eating, secondary to vomiting
• Dehydration and hypokalemia due to renal potassium loss in the presence of alkalosis and frequent vomiting
• Electrolyte imbalance, which can lead to abnormal heart rhythms, cardiac arrest, and even death
• Esophagitis, or inflammation of the esophagus
• Mallory-Weiss tears
• Boerhaave syndrome, a rupture in the esophageal wall due to vomiting
• Oral trauma, in which repetitive insertion of fingers or other objects causes lacerations to the lining of the mouth or throat
• Russell's sign: calluses on knuckles and back of hands due to repeated trauma from incisors
• Perimolysis, or severe dental erosion of tooth enamel
• Swollen salivary glands (for example, in the neck, under the jaw line)
• Gastroparesis, or delayed gastric emptying
• Constipation or diarrhea
• Tachycardia or palpitations
• Hypotension
• Peptic ulcers
• Infertility
• Constant weight fluctuations are common
• Elevated blood sugar, cholesterol, and amylase levels may occur
• Hypoglycemia may occur after vomiting

These are some of the many signs that may indicate whether someone has bulimia nervosa:

• A fixation on the number of calories consumed
• A fixation on and extreme consciousness of one's weight
• Low self-esteem and/or self-harming
• Suicidal tendencies
• An irregular menstrual cycle in women
• Regular trips to the bathroom, especially soon after eating
• Depression, anxiety disorders and sleep disorders
• Frequent occurrences involving consumption of abnormally large portions of food
• The use of laxatives, diuretics, and diet pills
• Compulsive or excessive exercise
• Unhealthy/dry skin, hair, nails, and lips
• Fatigue, or exhaustion

As with many psychiatric illnesses, delusions can occur, in conjunction with other signs and symptoms, leaving the person with a false belief that is not ordinarily accepted by others.

People with bulimia nervosa may also exercise to a point that excludes other activities.

Interoceptive

People with bulimia exhibit several interoceptive deficits, in which one experiences impairment in recognizing and discriminating between internal sensations, feelings, and emotions. People with bulimia may also react negatively to somatic and affective states. In relation to interoceptive sensitivity, hyposensitive individuals may not detect feelings of fullness in a normal and timely fashion, and therefore are prone to eating more calories.

Examining from a neural basis also connects elements of interoception and emotion; notable overlaps occur in the medial prefrontal cortex, anterior and posterior cingulate, and anterior insula cortices, which are linked to both interoception and emotional eating.

Related disorders

People with bulimia are more likely than people without bulimia to have an affective disorder, such as depression or general anxiety disorder. One study found 70% had depression at some time in their lives (as opposed to 26% for adult females in the general population), rising to 88% for all affective disorders combined. Another study by the Royal Children's Hospital in Melbourne on a cohort of 2,000 adolescents similarly found that those meeting at least two of the DSM-IV criteria for bulimia nervosa or anorexia nervosa had a sixfold increase in risk of anxiety and a doubled risk for substance dependency. Some with anorexia nervosa exhibit episodes of bulimic tendencies through purging (either through self-induced vomiting or laxatives) as a way to quickly remove food in their system. There may be an increased risk for diabetes mellitus type 2. Bulimia also has negative effects on a person's teeth due to the acid passed through the mouth from frequent vomiting causing acid erosion, mainly on the posterior dental surface.

Research has shown that there is a relationship between bulimia and narcissism. According to a study by the Australian National University, eating disorders are more susceptible among vulnerable narcissists. This can be caused by a childhood in which inner feelings and thoughts were minimized by parents, leading to "a high focus on receiving validation from others to maintain a positive sense of self".

A study by the Psychopharmacology Research Program of the University of Cincinnati College of Medicine "leaves little doubt that bipolar and eating disorders--particularly bulimia nervosa and bipolar II disorder--are related." The research shows that most clinical studies indicate that patients with bipolar disorder have higher rates of eating disorders, and vice versa. There is overlap in phenomenology, course, comorbidity, family history, and pharmacologic treatment response of these disorders. This is especially true of "eating dysregulation, mood dysregulation, impulsivity and compulsivity, craving for activity and/or exercise".

Studies have shown a relationship between bulimia's effect on metabolic rate and caloric intake with thyroid dysfunction.

Causes

Biological

As with anorexia nervosa, there is evidence of genetic predispositions contributing to the onset of this eating disorder. Abnormal levels of many hormones, notably serotonin, have been shown to be responsible for some disordered eating behaviors. Brain-derived neurotrophic factor (BDNF) is under investigation as a possible mechanism.

There is evidence that sex hormones may influence appetite and eating in women and the onset of bulimia nervosa. Studies have shown that women with hyperandrogenism and polycystic ovary syndrome have a dysregulation of appetite, along with carbohydrates and fats. This dysregulation of appetite is also seen in women with bulimia nervosa. In addition, gene knockout studies in mice have shown that mice that have the gene encoding estrogen receptors have decreased fertility due to ovarian dysfunction and dysregulation of androgen receptors. In humans, there is evidence that there is an association between polymorphisms in the ERβ (estrogen receptor β) and bulimia, suggesting there is a correlation between sex hormones and bulimia nervosa.

Bulimia has been compared to drug addiction, though the empirical support for this characterization is limited. However, people with bulimia nervosa may share dopamine D2 receptor-related vulnerabilities with those with substance use disorders.

Dieting, a common behaviour in bulimics, is associated with lower plasma tryptophan levels. Decreased tryptophan levels in the brain, and thus the synthesis of serotonin, such as via acute tryptophan depletion, increases bulimic urges in currently and formerly bulimic individuals within hours.

Abnormal blood levels of peptides important for the regulation of appetite and energy balance are observed in individuals with bulimia nervosa, but it remains unknown if this is a state or trait.

In recent years, evolutionary psychiatry as an emerging scientific discipline has been studying mental disorders from an evolutionary perspective. If eating disorders, Bulimia nervosa in particular, have evolutionary functions or if they are new modern "lifestyle" problems is still debated.

Social

Media portrayals of an 'ideal' body shape are widely considered to be a contributing factor to bulimia. In a 1991 study by Weltzin, Hsu, Pollicle, and Kaye, it was stated that 19% of bulimics undereat, 37% of bulimics eat an average or normal amount of food, and 44% of bulimics overeat. A survey of 15- to 18-year-old high school girls in Nadroga, Fiji, found the self-reported incidence of purging rose from 0% in 1995 (a few weeks after the introduction of television in the province) to 11.3% in 1998. In addition, the suicide rate among people with bulimia nervosa is 7.5 times higher than in the general population.

When attempting to decipher the origin of bulimia nervosa in a cognitive context, Christopher Fairburn et al.'s cognitive-behavioral model is often considered the golden standard. Fairburn et al.'s model discusses the process in which an individual falls into the binge-purge cycle and thus develops bulimia. Fairburn et al. argue that extreme concern with weight and shape coupled with low self-esteem will result in strict, rigid, and inflexible dietary rules. Accordingly, this would lead to unrealistically restricted eating, which may consequently induce an eventual "slip" where the individual commits a minor infraction of the strict and inflexible dietary rules. Moreover, the cognitive distortion due to dichotomous thinking leads the individual to binge. The binge subsequently should trigger a perceived loss of control, promoting the individual to purge in hope of counteracting the binge. However, Fairburn et al. assert the cycle repeats itself, and thus consider the binge-purge cycle to be self-perpetuating.

In contrast, Byrne and Mclean's findings differed slightly from Fairburn et al.'s cognitive-behavioral model of bulimia nervosa in that the drive for thinness was the major cause of purging as a way of controlling weight. In turn, Byrne and Mclean argued that this makes the individual vulnerable to binging, indicating that it is not a binge-purge cycle but rather a purge-binge cycle in that purging comes before bingeing. Similarly, Fairburn et al.'s cognitive-behavioral model of bulimia nervosa is not necessarily applicable to every individual and is certainly reductionist. Every one differs from another, and taking such a complex behavior like bulimia and applying the same one theory to everyone would certainly be invalid. In addition, the cognitive-behavioral model of bulimia nervosa is very culturally bound in that it may not be necessarily applicable to cultures outside of Western society. To evaluate, Fairburn et al..'s model and more generally the cognitive explanation of bulimia nervosa is more descriptive than explanatory, as it does not necessarily explain how bulimia arises. Furthermore, it is difficult to ascertain cause and effect, because it may be that distorted eating leads to distorted cognition rather than vice versa.

A considerable amount of literature has identified a correlation between sexual abuse and the development of bulimia nervosa. The reported incident rate of unwanted sexual contact is higher among those with bulimia nervosa than anorexia nervosa.

When exploring the etiology of bulimia through a socio-cultural perspective, the "thin ideal internalization" is significantly responsible. The thin-ideal internalization is the extent to which individuals adapt to the societal ideals of attractiveness. Studies have shown that young females that read fashion magazines tend to have more bulimic symptoms than those females who do not. This further demonstrates the impact of media on the likelihood of developing the disorder. Individuals first accept and "buy into" the ideals, and then attempt to transform themselves in order to reflect the societal ideals of attractiveness. J. Kevin Thompson and Eric Stice claim that family, peers, and most evidently media reinforce the thin ideal, which may lead to an individual accepting and "buying into" the thin ideal. In turn, Thompson and Stice assert that if the thin ideal is accepted, one could begin to feel uncomfortable with their body shape or size since it may not necessarily reflect the thin ideal set out by society. Thus, people feeling uncomfortable with their bodies may cause suffering from body dissatisfaction and may develop a certain drive for thinness. Consequently, body dissatisfaction coupled with a drive for thinness is thought to promote dieting and negative effects, which could eventually lead to bulimic symptoms such as purging or bingeing. Binges lead to self-disgust which causes purging to prevent weight gain.

A study dedicated to investigating the thin ideal internalization as a factor of bulimia nervosa is Thompson's and Stice's research. Their study aimed to investigate how and to what degree media affects the thin ideal internalization. Thompson and Stice used randomized experiments (more specifically programs) dedicated to teaching young women how to be more critical when it comes to media, to reduce thin-ideal internalization. The results showed that by creating more awareness of the media's control of the societal ideal of attractiveness, the thin ideal internalization significantly dropped. In other words, less thin ideal images portrayed by the media resulted in less thin-ideal internalization. Therefore, Thompson and Stice concluded that media greatly affected the thin ideal internalization. Papies showed that it is not the thin ideal itself, but rather the self-association with other persons of a certain weight that decide how someone with bulimia nervosa feels. People that associate themselves with thin models get in a positive attitude when they see thin models and people that associate with overweight get in a negative attitude when they see thin models. Moreover, it can be taught to associate with thinner people.

Diagnosis

The onset of bulimia nervosa is often during adolescence, between 13 and 20 years of age, and many cases have previously suffered from obesity, with many sufferers relapsing in adulthood into episodic bingeing and purging even after initially successful treatment and remission. A lifetime prevalence of 0.5 percent and 0.9 percent for adult and adolescent sufferers, respectively, is estimated among the United States population. Bulimia nervosa may affect up to 1% of young women and, after 10 years of diagnosis, half will recover fully, a third will recover partially, and 10–20% will still have symptoms.

Adolescents with bulimia nervosa are more likely to have self-imposed perfectionism and compulsivity issues in eating compared to their peers. This means that the high expectations and unrealistic goals that these individuals set for themselves are internally motivated rather than by social views or expectations.

Criteria

Bulimia nervosa can be difficult to detect, compared to anorexia nervosa, because bulimics tend to be of average or slightly above average weight. Many bulimics may also engage in significantly disordered eating and exercise patterns without meeting the full diagnostic criteria for bulimia nervosa. Recently, the Diagnostic and Statistical Manual of Mental Disorders was revised, which resulted in the loosening of criteria regarding the diagnoses of bulimia nervosa and anorexia nervosa. The diagnostic criteria utilized by the DSM-5 includes repetitive episodes of binge eating (a discrete episode of overeating during which the individual feels out of control of consumption) compensated for by excessive or inappropriate measures taken to avoid gaining weight. The diagnosis also requires the episodes of compensatory behaviors and binge eating to happen a minimum of once a week for a consistent time period of 3 months. The diagnosis is made only when the behavior is not a part of the symptom complex of anorexia nervosa and when the behavior reflects an overemphasis on physical mass or appearance. Purging often is a common characteristic of a more severe case of bulimia nervosa.

Treatment

There are two main types of treatment given to those suffering with bulimia nervosa; psychopharmacological and psychosocial treatments.

Psychotherapy

There are several supported psychosocial treatments for bulimia. Cognitive behavioral therapy (CBT), which involves teaching a person to challenge automatic thoughts and engage in behavioral experiments (for example, in session eating of "forbidden foods") has a small amount of evidence supporting its use.

By using CBT people record how much food they eat and periods of vomiting with the purpose of identifying and avoiding emotional fluctuations that bring on episodes of bulimia on a regular basis. Barker (2003) states that research has found 40–60% of people using cognitive behaviour therapy to become symptom free. He states in order for the therapy to work, all parties must work together to discuss, record and develop coping strategies. Barker (2003) claims by making people aware of their actions they will think of alternatives. People undergoing CBT who exhibit early behavioral changes are most likely to achieve the best treatment outcomes in the long run. Researchers have also reported some positive outcomes for interpersonal psychotherapy and dialectical behavior therapy.

Maudsley family therapy, developed at the Maudsley Hospital in London for the treatment of anorexia has been shown promising results in bulimia.

The use of Cognitive Behavioral Therapy (CBT) has been shown to be quite effective for treating bulimia nervosa (BN) in adults, but little research has been done on effective treatments of BN for adolescents. Although CBT is seen as more cost-efficient and helps individuals with BN in self-guided care, Family Based Treatment (FBT) might be more helpful to younger adolescents who need more support and guidance from their families. Adolescents are at the stage where their brains are still quite malleable and developing gradually. Therefore, young adolescents with BN are less likely to realize the detrimental consequences of becoming bulimic and have less motivation to change, which is why FBT would be useful to have families intervene and support the teens. Working with BN patients and their families in FBT can empower the families by having them involved in their adolescent's food choices and behaviors, taking more control of the situation in the beginning and gradually letting the adolescent become more autonomous when they have learned healthier eating habits.

Medication

Antidepressants of the selective serotonin reuptake inhibitors (SSRI) class may have a modest benefit. This includes fluoxetine, which is FDA approved, for the treatment of bulimia, other antidepressants such as sertraline may also be effective against bulimia. Topiramate may also be useful but has greater side effects. Compared to placebo, the use of a single antidepressant has been shown to be effective.

Combining medication with counseling can improve outcomes in some circumstances. Some positive outcomes of treatments can include: abstinence from binge eating, a decrease in obsessive behaviors to lose weight and in shape preoccupation, less severe psychiatric symptoms, a desire to counter the effects of binge eating, as well as an improvement in social functioning and reduced relapse rates.

Alternative medicine

Some researchers have also claimed positive outcomes in hypnotherapy.

Epidemiology

Deaths due to eating disorders per million persons in 2012

  0-0

  1-1

  2-2

  3-3

  4–25

There is little data on the percentage of people with bulimia in general populations. Most studies conducted thus far have been on convenience samples from hospital patients, high school or university students. These have yielded a wide range of results: between 0.1% and 1.4% of males, and between 0.3% and 9.4% of females. Studies on time trends in the prevalence of bulimia nervosa have also yielded inconsistent results. According to Gelder, Mayou and Geddes (2005) bulimia nervosa is prevalent between 1 and 2 percent of women aged 15–40 years. Bulimia nervosa occurs more frequently in developed countries and in cities, with one study finding that bulimia is five times more prevalent in cities than in rural areas. There is a perception that bulimia is most prevalent amongst girls from middle-class families; however, in a 2009 study girls from families in the lowest income bracket studied were 153 percent more likely to be bulimic than girls from the highest income bracket.

There are higher rates of eating disorders in groups involved in activities which idealize a slim physique, such as dance, gymnastics, modeling, cheerleading, running, acting, swimming, diving, rowing and figure skating. Bulimia is thought to be more prevalent among Caucasians; however, a more recent study showed that African-American teenage girls were 50 percent more likely than Caucasian girls to exhibit bulimic behavior, including both binging and purging.

Country	Year	Sample size and type	% affected
Australia	2008	1,943 adolescents (ages 15–17)	1.0% male	6.4% female
Portugal	2006	2,028 high school students		0.3% female
Brazil	2004	1,807 students (ages 7–19)	0.8% male	1.3% female
Spain	2004	2,509 female adolescents (ages 13–22)		1.4% female
Hungary	2003	580 Budapest residents	0.4% male	3.6% female
Australia	1998	4,200 high school students	0.3% combined
United States	1996	1,152 college students	0.2% male	1.3% female
Norway	1995	19,067 psychiatric patients	0.7% male	7.3% female
Canada	1995	8,116 (random sample)	0.1% male	1.1% female
Japan	1995	2,597 high school students	0.7% male	1.9% female
United States	1992	799 college students	0.4% male	5.1% female

History

Etymology

The term bulimia comes from Greek βουλιμία boulīmia, "ravenous hunger", a compound of βοῦς bous, "ox" and λιμός, līmos, "hunger". Literally, the scientific name of the disorder, bulimia nervosa, translates to "nervous ravenous hunger".

Before the 20th century

Although diagnostic criteria for bulimia nervosa did not appear until 1979, evidence suggests that binging and purging were popular in certain ancient cultures. The first documented account of behavior resembling bulimia nervosa was recorded in Xenophon's Anabasis around 370 B.C, in which Greek soldiers purged themselves in the mountains of Asia Minor. It is unclear whether this purging was preceded by binging. In ancient Egypt, physicians recommended purging once a month for three days to preserve health. This practice stemmed from the belief that human diseases were caused by the food itself. In ancient Rome, elite society members would vomit to "make room" in their stomachs for more food at all-day banquets. Emperors Claudius and Vitellius both were gluttonous and obese, and they often resorted to habitual purging.

Historical records also suggest that some saints who developed anorexia (as a result of a life of asceticism) may also have displayed bulimic behaviors. Saint Mary Magdalen de Pazzi (1566–1607) and Saint Veronica Giuliani (1660–1727) were both observed binge eating—giving in, as they believed, to the temptations of the devil. Saint Catherine of Siena (1347–1380) is known to have supplemented her strict abstinence from food by purging as reparation for her sins. Catherine died from starvation at age thirty-three.

While the psychological disorder "bulimia nervosa" is relatively new, the word "bulimia," signifying overeating, has been present for centuries. The Babylon Talmud referenced practices of "bulimia," yet scholars believe that this simply referred to overeating without the purging or the psychological implications bulimia nervosa. In fact, a search for evidence of bulimia nervosa from the 17th to late 19th century revealed that only a quarter of the overeating cases they examined actually vomited after the binges. There was no evidence of deliberate vomiting or an attempt to control weight.

20th century

At the turn of the century, bulimia (overeating) was described as a clinical symptom, but rarely in the context of weight control. Purging, however, was seen in anorexic patients and attributed to gastric pain rather than another method of weight control.

In 1930, admissions of anorexia nervosa patients to the Mayo Clinic from 1917 to 1929 were compiled. Fifty-five to sixty-five percent of these patients were reported to be voluntarily vomiting to relieve weight anxiety. Records show that purging for weight control continued throughout the mid-1900s. Several case studies from this era reveal patients suffering from the modern description of bulimia nervosa. In 1939, Rahman and Richardson reported that out of their six anorexic patients, one had periods of overeating, and another practiced self-induced vomiting. Wulff, in 1932, treated "Patient D," who would have periods of intense cravings for food and overeat for weeks, which often resulted in frequent vomiting. Patient D, who grew up with a tyrannical father, was repulsed by her weight and would fast for a few days, rapidly losing weight. Ellen West, a patient described by Ludwig Binswanger in 1958, was teased by friends for being fat and excessively took thyroid pills to lose weight, later using laxatives and vomiting. She reportedly consumed dozens of oranges and several pounds of tomatoes each day, yet would skip meals. After being admitted to a psychiatric facility for depression, Ellen ate ravenously yet lost weight, presumably due to self-induced vomiting. However, while these patients may have met modern criteria for bulimia nervosa, they cannot technically be diagnosed with the disorder, as it had not yet appeared in the Diagnostic and Statistical Manual of Mental Disorders at the time of their treatment.

An explanation for the increased instances of bulimic symptoms may be due to the 20th century's new ideals of thinness. The shame of being fat emerged in the 1940s when teasing remarks about weight became more common. The 1950s, however, truly introduced the trend of aspiration for thinness.

In 1979, Gerald Russell first published a description of bulimia nervosa, in which he studied patients with a "morbid fear of becoming fat" who overate and purged afterward. He specified treatment options and indicated the seriousness of the disease, which can be accompanied by depression and suicide. In 1980, bulimia nervosa first appeared in the DSM-III.

After its appearance in the DSM-III, there was a sudden rise in the documented incidences of bulimia nervosa. In the early 1980s, incidences of the disorder rose to about 40 in every 100,000 people. This decreased to about 27 in every 100,000 people at the end of the 1980s/early 1990s. However, bulimia nervosa's prevalence was still much higher than anorexia nervosa's, which at the time occurred in about 14 people per 100,000.

In 1991, Kendler et al. documented the cumulative risk for bulimia nervosa for those born before 1950, from 1950 to 1959, and after 1959. The risk for those born after 1959 is much higher than those in either of the other cohorts.