document_title: Reserve Bank of India

question_text: how many branches of reserve bank of india in india

text: Reserve Bank of India

text: Preamble[edit]

text: The preamble of the Reserve Bank of India describes the basic functions of the reserve bank as:

text: "to regulate the issue of Bank notes and keeping of reserves with a view to securing monetary stability in India and generally to operate the currency and credit system of the country to its advantage; to have a modern monetary policy framework to meet the challenge of an increasingly complex economy, to maintain price stability while keeping in mind the objective of growth."

text: History[edit]

text: The Reserve Bank of India was founded on 1 April 1935 to respond to economic troubles after the First World War.[11] The Reserve Bank of India was conceptualized based on the guidelines presented by the Central Legislative Assembly which passed these guidelines as the RBI Act 1934.[12] RBI was conceptualized as per the guidelines, working style and outlook presented by B. R. Ambedkar in his book titled “The Problem of the Rupee – Its origin and its solution” and presented to the Hilton Young Commission. The bank was set up based on the recommendations of the 1926 Royal Commission on Indian Currency and Finance, also known as the Hilton–Young Commission.[13] The original choice for the seal of RBI was The East India Company Double Mohur, with the sketch of the Lion and Palm Tree. However, it was decided to replace the lion with the tiger, the national animal of India. The Preamble of the RBI describes its basic functions to regulate the issue of bank notes, keep reserves to secure monetary stability in India, and generally to operate the currency and credit system in the best interests of the country.[14] The Central Office of the RBI was established in Calcutta (now Kolkata) but was moved to Bombay (now Mumbai) in 1937. The RBI also acted as Burma's (now Myanmar) central bank until April 1947 (except during the years of Japanese occupation (1942–45)), even though Burma seceded from the Indian Union in 1937. After the Partition of India in 1947, the bank served as the central bank for Pakistan until June 1948 when the State Bank of Pakistan commenced operations. Though set up as a shareholders’ bank, the RBI has been fully owned by the Government of India since its nationalization in 1949.[15] RBI has monopoly of note issue.

text: In the 1950s, the Indian government, under its first Prime Minister Jawaharlal Nehru, developed a centrally planned economic policy that focused on the agricultural sector. The administration nationalized commercial banks[16] and established, based on the Banking Companies Act, 1949 (later called the Banking Regulation Act), a central bank regulation as part of the RBI. Furthermore, the central bank was ordered to support economic plan with loans.[17]

text: As a result of bank crashes, the RBI was requested to establish and monitor a deposit insurance system. Meant to restore the trust in the national bank system, it was initialized on 7 December 1961. The Indian government founded funds to promote the economy, and used the slogan "Developing Banking". The government of India restructured the national bank market and nationalized a lot of institutes. As a result, the RBI had to play the central part in controlling and supporting this public banking sector.

text: In 1969, Indira Gandhi-headed government nationalized 14 major commercial banks. Upon Gandhi's return to India in 1980 a further 6 banks were nationalized.[13] The regulation of the economy and especially the financial sector was reinforced by the Government of India in the 1970s and 1980s.[18] The central bank became the central player and increased its policies a lot for a lot of tasks like interests, reserve ratio and visible deposits.[19] These measures aimed at better economic development and had a huge effect on the company policy of the institutes. The banks lent money in selected sectors, like agri-business and small trade companies.[20]

text: The branch was forced to establish two new offices in the country for every newly established office in a town.[21] The oil crises in 1973 resulted in increasing inflation, and the RBI restricted monetary policy to reduce the effects.[22]

text: A lot of committees analysed the Indian economy between 1985 and 1991. Their results had an effect on the RBI. The Board for Industrial and Financial Reconstruction, the Indira Gandhi Institute of Development Research and the Security & Exchange Board of India investigated the national economy as a whole, and the security and exchange board proposed better methods for more effective markets and the protection of investor interests. The Indian financial market was a leading example for so-called "financial repression" (Mckinnon and Shaw).[23] The Discount and Finance House of India began its operations in the monetary market in April 1988; the National Housing Bank, founded in July 1988, was forced to invest in the property market and a new financial law improved the versatility of direct deposit by more security measures and liberalisation.[24]

text: 1991–2000 the new century[edit]

text: The national economy contracted in July 1991 as the Indian rupee was devalued.[25] The currency lost 18% relative to the US dollar, and the Narsimham Committee advised restructuring the financial sector by a temporal reduced reserve ratio as well as the statutory liquidity ratio. New guidelines were published in 1993 to establish a private banking sector. This turning point was meant to reinforce the market and was often called neo-liberal.[26] The central bank deregulated bank interests and some sectors of the financial market like the trust and property markets.[27] This first phase was a success and the central government forced a diversity liberalisation to diversify owner structures in 1998.[28]

text: The National Stock Exchange of India took the trade on in June 1994 and the RBI allowed nationalized banks in July to interact with the capital market to reinforce their capital base. The central bank founded a subsidiary company—the Bharatiya Reserve Bank Note Mudran Private Limited—on 3 February 1995 to produce banknotes.[29]

text: Since 2000[edit]

text: The Foreign Exchange Management Act, 1999 came into force in June 2000. It should improve the item in 2004–2005 (National Electronic Fund Transfer).[30] The Security Printing & Minting Corporation of India Ltd., a merger of nine institutions, was founded in 2006 and produces banknotes and coins.[31]

text: The national economy's growth rate came down to 5.8% in the last quarter of 2008–2009[32] and the central bank promotes the economic development.[33]

text: Structure[edit]

text: The central board of directors is the main committee of the central bank. The Government of India appoints the directors for a 4-year term. The Board consists of a governor, and not more than 4 deputy governors; 4 directors to represent the regional boards;[34] 2 — usually the Economic Affairs Secretary and the Financial Services Secretary — from the Ministry of Finance and 10 other directors from various fields. RBI wants to create a post of Chief Operating Officer (COO) and re-allocate work between the five of them (4 deputy governor and COO).[35][36]

text: The bank is headed by the governor and the post is currently held by economist Urjit Patel. There are 4 deputy governors BP Kanungo,[37] S S Mundra, N S Vishwanathan and Viral Acharya.[38] Two of the four deputy governors are traditionally from RBI ranks and are selected from the Bank's Executive Directors. One is nominated from among the Chairpersons of public sector banks and the other is an economist. An Indian Administrative Service officer can also be appointed as deputy governor of RBI and later as the governor of RBI as with the case of Y. Venugopal Reddy and Duvvuri Subbarao. Other persons forming part of the central board of directors of the RBI are Dr. Nachiket Mor, Y C Deveshwar, Prof Damodar Acharya, Ajay Tyagi and Anjuly Duggal.

text: Uma Shankar, chief general manager (CGM) in charge of the Reserve Bank of India's financial inclusion and development department has taken over as executive director (ED) in the central bank.[citation needed]

text: Branches and support bodies[edit]

text: The RBI has four zonal offices at Chennai, Delhi, Kolkata and Mumbai.[39] It has 20 regional offices and 11 sub-offices. Regional offices are located in Ahmedabad, Bangalore, Bhopal, Bhubaneswar, Chandigarh, Chennai, Delhi, Guwahati, Hyderabad, Jaipur, Jammu, Kanpur, Kochi, Kolkata, Dewas, Lucknow, Mumbai, Nagpur, Patna, Dehradun and Thiruvananthapuram and sub-offices are located in Agartala, Aizawal, Dehradun, Gangtok, Imphal, Panaji, Raipur, Ranchi, Shillong, Shimla and Srinagar.[40]

text: The RBI has four regional representations: North in New Delhi, South in Chennai, East in Kolkata and West in Mumbai. The representations are formed by five members, appointed for four years by the central government and with the advice of the central board of directors serve as a forum for regional banks and to deal with delegated tasks from the Central Board.[41]

text: It has two training colleges for its officers, viz. Reserve Bank Staff College, Chennai and College of Agricultural Banking, Pune. There are three autonomous institutions run by RBI namely National Institute of Bank Management (NIBM), Indira Gandhi Institute of Development Research (IGIDR), Institute for Development and Research in Banking Technology (IDRBT).[42] There are also four Zonal Training Centres at Mumbai, Chennai, Kolkata and New Delhi.

text: The Board of Financial Supervision (BFS), formed in November 1994, serves as a CCBD committee to control the financial institutions. It has four members, appointed for two years, and takes measures to strength the role of statutory auditors in the financial sector, external monitoring and internal controlling systems. The Tarapore committee was set up by the Reserve Bank of India under the chairmanship of former RBI deputy governor S.S.Tarapore to "lay the road map" to capital account convertibility. The five-member committee recommended a three-year time frame for complete convertibility by 1999–2000.

text: On 8 December 2017, Surekha Marandi, Executive Director (ED) of Reserve Bank of India, said RBI will open an office in the north-eastern state of Arunachal Pradesh[43]

text: Main functions[edit]

text: Financial Supervision[edit]

text: The primary objective of BFS is to undertake consolidated supervision of the financial sector comprising commercial banks, financial institutions and non-banking finance companies.

text: The Board is constituted by co-opting four Directors from the Central Board as members for a term of two years and is chaired by the governor. The deputy governors of the reserve bank are ex-officio members. One deputy governor, usually, the deputy governor in charge of banking regulation and supervision, is nominated as the vice-chairman of the board. The Board is required to meet normally once every month. It considers inspection reports and other supervisory issues placed before it by the supervisory departments.

text: BFS through the Audit Sub-Committee also aims at upgrading the quality of the statutory audit and internal audit functions in banks and financial institutions. The audit sub-committee includes deputy governor as the chairman and two Directors of the Central Board as members. The BFS oversees the functioning of Department of Banking Supervision (DBS), Department of Non-Banking Supervision (DNBS) and Financial Institutions Division (FID) and gives directions on the regulatory and supervisory issues.

text: Regulator and supervisor of the financial system[edit]

text: The institution is also the regulator and supervisor of the financial system and prescribes broad parameters of banking operations within which the country's banking and financial system functions. Its objectives are to maintain public confidence in the system, protect depositors' interest and provide cost-effective banking services to the public. The Banking Ombudsman Scheme has been formulated by the Reserve Bank of India (RBI) for effective addressing of complaints by bank customers. The RBI controls the monetary supply, monitors economic indicators like the gross domestic product and has to decide the design of the rupee banknotes as well as coins.[45]

text: Managing foreign exchange[edit]

text: The central bank manages to reach different goals of the Foreign Exchange Management Act, 1999. Their objective is to facilitate external trade and payment and promote orderly development and maintenance of foreign exchange market in India.

text: Issue of currency and other Functions[edit]

text: The bank issues and exchanges currency notes and coins and destroys the same when they are not fit for circulation. All the money issued by the central bank is its monetary liability, i.e., the central bank is obliged to back the currency with assets of equal value, to enhance public confidence in paper currency. The objectives are to issue bank notes and give public adequate supply of the same, to maintain the currency and credit system of the country to utilize it in its best advantage, and to maintain the reserves. RBI maintains the economic structure of the country so that it can achieve the objective of price stability as well as economic development because both objectives are diverse in themselves. For printing of notes, the Security Printing and Minting Corporation of India Limited (SPMCIL), a wholly owned company of the Government of India, has set up printing presses at Nashik, Maharashtra and Dewas, Madhya Pradesh. The Bharatiya Reserve Bank Note Mudran Private Limited (BRBNMPL), also has set up printing presses in Mysore in Karnataka and Salboni in West Bengal. In all, there are four printing presses.[46] And for the minting of coins, SPMCIL has four mints at Mumbai, Noida (UP), Kolkata and Hyderabad for coin production.[47] Commercial banks create credit. It is the duty of the RBI to control the credit through the CRR, bank rate and open market operations. As banker's bank, the RBI facilitates the clearing of cheques between the commercial banks and helps the inter-bank transfer of funds. It can grant financial accommodation to schedule banks. It acts as the lender of the last resort by providing emergency advances to the banks. It supervises the functioning of the commercial banks and takes action against it if the need arises. The RBI also advices the banks on various matters for example Corporate Social Responsibility.

text: Detection of fake currency[edit]

text: In order to curb the fake currency menace, RBI has launched a website to raise awareness among masses about fake notes in the market. www.paisaboltahai.rbi.org.in provides information about identifying fake currency.[48]

text: On 22 January 2014; RBI gave a press release stating that after 31 March 2014, it will completely withdraw from circulation all banknotes issued prior to 2005. From 1 April 2014, the public will be required to approach banks for exchanging these notes. Banks will provide exchange facility for these notes until further communication. The reserve bank has also clarified that the notes issued before 2005 will continue to be legal tender. This would mean that banks are required to exchange the notes for their customers as well as for non-customers. From 1 July 2014, however, to exchange more than 15 pieces of `500 and `1000 notes, non-customers will have to furnish proof of identity and residence as well as show aadhar to the bank branch in which she/he wants to exchange the notes.

text: This move from the reserve bank is expected to unearth black money held in cash. As the new currency notes have added security features, they would help in curbing the menace of fake currency.[49]

text: Developmental role[edit]

text: The central bank has to perform a wide range of promotional functions to support national objectives and industries.[17] The RBI faces a lot of inter-sectoral and local inflation-related problems. Some of these problems are results of the dominant part of the public sector.[50]

text: Related functions[edit]

text: The RBI is also a banker to the government and performs merchant banking function for the central and the state governments. It also acts as their banker. The National Housing Bank (NHB) was established in 1988 to promote private real estate acquisition.[51] The institution maintains banking accounts of all scheduled banks, too. RBI on 7 August 2012 said that Indian banking system is resilient enough to face the stress caused by the drought-like situation because of poor monsoon this year.[52]

text: Demonetisation[edit]

text: On 8 November 2016, the Government of India announced the demonetisation of all ₹500 (US$7.70) and ₹1,000 (US$15) banknotes of the Mahatma Gandhi Series on the recommendation of the Reserve Bank of India (RBI).[53] The government claimed that the action would curtail the shadow economy and crack down on the use of illicit and counterfeit cash to fund illegal activity and terrorism.[54][55]

text: Policy Rates and Reserve Ratios[edit]

text:
Policy rates, reserve ratios, lending and deposit rates as of March 2018

Policy rates

Bank Rate
6.25%

Repo Rate
6.0%

Reverse Repo Rate
5.75%

Marginal Standing Facility Rate
6.25%

Reserve ratios

Cash Reserve Ratio (CRR)
4%

Statutory Liquidity Ratio (SLR)
19.5%

Lending and deposit rates

Base Rate
8.65%–9.45%

MCLR (overnight)
7.70%–7.95%

Savings Deposit Rate
3.50%–4.00%

Term Deposit Rate for > 1year
6.25%–6.75%

tag: table

text: Repo Rate[edit]

text: Repo (Repurchase) rate also known as the benchmark interest rate is the rate at which the RBI lends money to the banks for a short-term (max. 90 days). When the repo rate increases, borrowing from RBI becomes more expensive. If RBI wants to make it more expensive for the banks to borrow money, it increases the repo rate similarly, if it wants to make it cheaper for banks to borrow money it reduces the repo rate. If the repo rate is increased, banks can't carry out their business at a profit whereas the very opposite happens when the repo rate is cut down. Generally, repo rates are cut down whenever the country needs to progress in banking and economy. Currently, the new RBI governor Sri Urjit Patel has cut the previous Repo rate to 6.00% for facilitation of India's economy.

text: in its fifth bi-monthly Monetary policy review on 6 December 2017, RBI unchanged Repo Rate and kept at 6%.

text: Reverse Repo Rate (RRR)[edit]

text: Reverse Repo rate is the short term borrowing rate at which RBI borrows money from banks. The reserve bank uses this tool when it feels there is too much money floating in the banking system. An increase in the reverse repo rate means that the banks will get a higher rate of interest from RBI. As a result, banks prefer to lend their money to RBI which is always safe instead of lending it to others (people, companies etc.) which is always risky.

text: Repo Rate signifies the rate at which liquidity is injected into the banking system by RBI, whereas Reverse Repo rate signifies the rate at which the central bank absorbs liquidity from the banks. Currently, Reverse Repo Rate is pegged to be 0.25% below Repo Rate.

text: Statutory liquidity ratio (SLR)[edit]

text: Apart from the CRR, banks are required to maintain liquid assets in the form of gold, cash and approved securities. Higher liquidity ratio forces commercial banks to maintain a larger proportion of their resources in liquid form and thus reduces their capacity to grant loans and advances, thus it is an anti-inflationary impact. A higher liquidity ratio diverts the bank funds from loans and advances to investment in government and approved securities. In well-developed economies, central banks use open market operations—buying and selling of eligible securities by the central bank in the money market—to influence the volume of cash reserves with commercial banks and thus influence the volume of loans and advances they can make to the commercial and industrial sectors. In the open money market, government securities are traded at market-related rates of interest. The RBI is resorting more to open market operations in the more recent years. Generally, RBI uses

text:
Minimum margins for lending against specific securities.
Ceiling on the amounts of credit for certain purposes.
The discriminatory rate of interest charged on certain types of advances.

text: Direct credit controls in India are of three types:

text:
Part of the interest rate structure, i.e., on small savings and provident funds, are administratively set.
Banks are mandatory required to keep 19.50% of their NDTL (Net Demand and Time Liabilities) in the form of liquid assets.
Banks are required to lend to the priority sectors to the extent of 40% of their advances.

text: Publications[edit]

text: A report titled "Trend and Progress of Banking In India" is published annually, as required by the Banking Regulation Act, 1949. The report sums up trends and developments throughout the financial sector.[56] Starting in April 2014, the Reserve Bank of India publishes bi-monthly policy updates.[57]

text: Further reading[edit]

text:
S. L. N. Simha. History of the Reserve Bank of India, Volume 1: 1935–1951. RBI. 1970. ISBN 81-7596-247-X. (2005 reprint PDF)
Reserve Bank of India: Functions and Working. RBI. 2005.(2005 reprint PDF )
G. Balachandran. The Reserve Bank of India, 1951–1967. Oxford University Press. 1998. ISBN 0-19-564468-9. (PDF)
A. Vasudevan et al. The Reserve Bank of India, Volume 3: 1967–1981. RBI. 2005. ISBN 81-7596-299-2. (PDF)
Cecil Kisch: Review "The Monetary Policy of the Reserve Bank of India" by K. N. Raj. In: The Economic Journal. Vol. 59, No. 235 (Sep., 1949), pp. 436–438.
Findlay G. Shirras: The Reserve Bank of India. In The Economic Journal. Vol. 44, No. 174 (Jun., 1934), pp. 258–274.
Narenda Jadhav, Partha Ray, Dhritidyuti Bose, Indranil Sen Gupta: The Reserve Bank of India’s Balance Sheet: Analytics and Dynamics of Evolution, November 2004.


document_title: History of scientific method

question_text: who was an early advocate for using scientific methods based on inductive reasoning

question_tokens: who was an early advocate for using scientific methods based on inductive reasoning

root

text: History of scientific method

text: Early methodology[edit]

text: There are few explicit discussions of scientific methodologies in surviving records from early cultures. The most that can be inferred about the approaches to undertaking science in this period stems from descriptions of early investigations into nature, in the surviving records. An Egyptian medical textbook, the Edwin Smith papyrus, (c. 1600 BCE), applies the following components: examination, diagnosis, treatment and prognosis, to the treatment of disease,[2] which display strong parallels to the basic empirical method of science and according to G. E. R. Lloyd[3] played a significant role in the development of this methodology. The Ebers papyrus (c. 1550 BCE) also contains evidence of traditional empiricism.

tag: p

text: By the middle of the 1st millennium BCE in Mesopotamia, Babylonian astronomy had evolved into the earliest example of a scientific astronomy, as it was "the first and highly successful attempt at giving a refined mathematical description of astronomical phenomena." According to the historian Asger Aaboe, "all subsequent varieties of scientific astronomy, in the Hellenistic world, in India, in the Islamic world, and in the West – if not indeed all subsequent endeavour in the exact sciences – depend upon Babylonian astronomy in decisive and fundamental ways."[4]

text: The early Babylonians and Egyptians developed much technical knowledge, crafts, and mathematics[5] used in practical tasks of divination, as well as a knowledge of medicine,[6] and made lists of various kinds. While the Babylonians in particular had engaged in the earliest forms of an empirical mathematical science, with their early attempts at mathematically describing natural phenomena, they generally lacked underlying rational theories of nature.[4][7][8] It was the ancient Greeks who engaged in the earliest forms of what is today recognized as a rational theoretical science,[7][9] with the move towards a more rational understanding of nature which began at least since the Archaic Period (650 – 480 BCE) with the Presocratic school. Thales was the first to use natural explanations, proclaiming that every event had a natural cause, even though he is known for saying "all things are full of gods" and sacrificed an ox when he discovered his theorem.[10] Leucippus, went on to develop the theory of atomism – the idea that everything is composed entirely of various imperishable, indivisible elements called atoms. This was elaborated in great detail by Democritus.

text: Similar atomist ideas emerged independently among ancient Indian philosophers of the Nyaya, Vaisesika and Buddhist schools.[11] In particular, like the Nyaya, Vaisesika, and Buddhist schools, the Cārvāka epistemology was materialist, and skeptical enough to admit perception as the basis for unconditionally true knowledge, while cautioning that if one could only infer a truth, then one must also harbor a doubt about that truth; an inferred truth could not be unconditional.[12]

text: Towards the middle of the 5th century BCE, some of the components of a scientific tradition were already heavily established, even before Plato, who was an important contributor to this emerging tradition, thanks to the development of deductive reasoning, as propounded by his student, Aristotle. In Protagoras (318d-f), Plato mentioned the teaching of arithmetic, astronomy and geometry in schools. The philosophical ideas of this time were mostly freed from the constraints of everyday phenomena and common sense. This denial of reality as we experience it reached an extreme in Parmenides who argued that the world is one and that change and subdivision do not exist.

text: In the 3rd and 4th centuries BCE, the Greek physicians Herophilos (335–280 BCE) and Erasistratus of Chios employed experiments to further their medical research; Erasistratus at one time repeatedly weighing a caged bird, and noting its weight loss between feeding times.[13]

text: Aristotle[edit]

text: Aristotle's inductive-deductive method used inductions from observations to infer general principles, deductions from those principles to check against further observations, and more cycles of induction and deduction to continue the advance of knowledge.[14]

text: The Organon (Greek: Ὄργανον, meaning "instrument, tool, organ") is the standard collection of Aristotle's six works on logic. The name Organon was given by Aristotle's followers, the Peripatetics. The order of the works is not chronological (the chronology is now difficult to determine) but was deliberately chosen by Theophrastus to constitute a well-structured system.[citation needed] Indeed, parts of them seem to be a scheme of a lecture on logic. The arrangement of the works was made by Andronicus of Rhodes around 40 BCE.[15]

text: The Organon comprises the following six works:

text:
The Categories (Latin: Categoriae) introduces Aristotle's 10-fold classification of that which exists: substance, quantity, quality, relation, place, time, situation, condition, action, and passion.
On Interpretation (Latin:De Interpretatione, Greek Perihermenias) introduces Aristotle's conception of proposition and judgment, and the various relations between affirmative, negative, universal, and particular propositions. Aristotle discusses the square of opposition or square of Apuleius in Chapter 7 and its appendix Chapter 8. Chapter 9 deals with the problem of future contingents.
The Prior Analytics (Latin: Analytica Priora) introduces Aristotle's syllogistic method (see term logic), argues for its correctness, and discusses inductive inference.
The Posterior Analytics (Latin: Analytica Posteriora) deals with demonstration, definition, and scientific knowledge.
The Topics (Latin: Topica) treats of issues in constructing valid arguments, and of inference that is probable, rather than certain. It is in this treatise that Aristotle mentions the predicables, later discussed by Porphyry and by the scholastic logicians.
The Sophistical Refutations (Latin: De Sophisticis Elenchis) gives a treatment of logical fallacies, and provides a key link to Aristotle's work on rhetoric.

tag: ol

text: Aristotle's Metaphysics has some points of overlap with the works making up the Organon but is not traditionally considered part of it; additionally there are works on logic attributed, with varying degrees of plausibility, to Aristotle that were not known to the Peripatetics.

text: Aristotle introduced what may be called a scientific method.[16] His demonstration method is found in Posterior Analytics. He provided another of the ingredients of scientific tradition: empiricism. For Aristotle, universal truths can be known from particular things via induction. To some extent then, Aristotle reconciles abstract thought with observation, although it would be a mistake to imply that Aristotelian science is empirical in form. Indeed, Aristotle did not accept that knowledge acquired by induction could rightly be counted as scientific knowledge. Nevertheless, induction was for him a necessary preliminary to the main business of scientific enquiry, providing the primary premises required for scientific demonstrations.

text: Aristotle largely ignored inductive reasoning in his treatment of scientific enquiry. To make it clear why this is so, consider this statement in the Posterior Analytics:

text: We suppose ourselves to possess unqualified scientific knowledge of a thing, as opposed to knowing it in the accidental way in which the sophist knows, when we think that we know the cause on which the fact depends, as the cause of that fact and of no other, and, further, that the fact could not be other than it is.

text: It was therefore the work of the philosopher to demonstrate universal truths and to discover their causes.[17] While induction was sufficient for discovering universals by generalization, it did not succeed in identifying causes. For this task Aristotle used the tool of deductive reasoning in the form of syllogisms. Using the syllogism, scientists could infer new universal truths from those already established.

text: Aristotle developed a complete normative approach to scientific inquiry involving the syllogism, which he discusses at length in his Posterior Analytics. A difficulty with this scheme lay in showing that derived truths have solid primary premises. Aristotle would not allow that demonstrations could be circular (supporting the conclusion by the premises, and the premises by the conclusion). Nor would he allow an infinite number of middle terms between the primary premises and the conclusion. This leads to the question of how the primary premises are found or developed, and as mentioned above, Aristotle allowed that induction would be required for this task.

text: Towards the end of the Posterior Analytics, Aristotle discusses knowledge imparted by induction.

text: Thus it is clear that we must get to know the primary premises by induction; for the method by which even sense-perception implants the universal is inductive. [...] it follows that there will be no scientific knowledge of the primary premises, and since except intuition nothing can be truer than scientific knowledge, it will be intuition that apprehends the primary premises. [...] If, therefore, it is the only other kind of true thinking except scientific knowing, intuition will be the originative source of scientific knowledge.

text: The account leaves room for doubt regarding the nature and extent of Aristotle's empiricism. In particular, it seems that Aristotle considers sense-perception only as a vehicle for knowledge through intuition. He restricted his investigations in natural history to their natural settings,[18] such as at the Pyrrha lagoon,[19] now called Kalloni, at Lesbos. Aristotle and Theophrastus together formulated the new science of biology,[20] inductively, case by case, for two years before Aristotle was called to tutor Alexander. Aristotle performed no modern-style experiments in the form in which they appear in today's physics and chemistry laboratories.[21] Induction is not afforded the status of scientific reasoning, and so it is left to intuition to provide a solid foundation for Aristotle's science. With that said, Aristotle brings us somewhat closer an empirical science than his predecessors.

text: Epicurus[edit]

text: In his work Kαvώv ('canon', a straight edge or ruler, thus any type of measure or standard, referred to as 'canonic'), Epicurus laid out his first rule for inquiry in physics: 'that the first concepts be seen,[22]:p.20 and that they not require demonstration '.[22]:pp.35–47

text: His second rule for inquiry was that prior to an investigation, we are to have self-evident concepts,[22]:pp.61–80 so that we might infer [έχωμεν οις σημειωσόμεύα] both what is expected [τò ποσμένον], and also what is non-apparent [τò άδηλον].[22]:pp.83–103

text: Epicurus applies his method of inference (the use of observations as signs, Asmis' summary, p. 333: the method of using the phenomena as signs (σημεīα) of what is unobserved)[22]:pp.175–196 immediately to the atomic theory of Democritus. In Aristotle's Prior Analytics, Aristotle himself employs the use of signs.[22]: pp.212–224[23] But Epicurus presented his 'canonic' as rival to Aristotle's logic.[22]:pp.19–34 See: Lucretius (c. 99 BCE – c. 55 BCE) De rerum natura (On the nature of things) a didactic poem explaining Epicurus' philosophy and physics.

text: Emergence of inductive experimental method[edit]

text: During the Middle Ages issues of what is now termed science began to be addressed. There was greater emphasis on combining theory with practice in the Islamic world than there had been in Classical times, and it was common for those studying the sciences to be artisans as well, something that had been "considered an aberration in the ancient world." Islamic experts in the sciences were often expert instrument makers who enhanced their powers of observation and calculation with them.[24] Muslim scientists used experiment and quantification to distinguish between competing scientific theories, set within a generically empirical orientation, as can be seen in the works of Jābir ibn Hayyān (721–815)[25] and Alkindus (801–873)[26] as early examples. Several scientific methods thus emerged from the medieval Muslim world by the early 11th century, all of which emphasized experimentation as well as quantification to varying degrees.

text: Ibn al-Haytham[edit]

text: The Arab physicist Ibn al-Haytham (Alhazen) used experimentation to obtain the results in his Book of Optics (1021). He combined observations, experiments and rational arguments to support his intromission theory of vision, in which rays of light are emitted from objects rather than from the eyes. He used similar arguments to show that the ancient emission theory of vision supported by Ptolemy and Euclid (in which the eyes emit the rays of light used for seeing), and the ancient intromission theory supported by Aristotle (where objects emit physical particles to the eyes), were both wrong.[28]

text: Experimental evidence supported most of the propositions in his Book of Optics and grounded his theories of vision, light and colour, as well as his research in catoptrics and dioptrics. His legacy was elaborated through the 'reforming' of his Optics by Kamal al-Din al-Farisi (d. c. 1320) in the latter's Kitab Tanqih al-Manazir (The Revision of [Ibn al-Haytham's] Optics).[29][30]

text: Alhazen viewed his scientific studies as a search for truth: "Truth is sought for its own sake. And those who are engaged upon the quest for anything for its own sake are not interested in other things. Finding the truth is difficult, and the road to it is rough. ...[31]

text: Alhazen's work included the conjecture that "Light travels through transparent bodies in straight lines only", which he was able to corroborate only after years of effort. He stated, "[This] is clearly observed in the lights which enter into dark rooms through holes. ... the entering light will be clearly observable in the dust which fills the air."[27] He also demonstrated the conjecture by placing a straight stick or a taut thread next to the light beam.[32]

text: Ibn al-Haytham also employed scientific skepticism and emphasized the role of empiricism. He also explained the role of induction in syllogism, and criticized Aristotle for his lack of contribution to the method of induction, which Ibn al-Haytham regarded as superior to syllogism, and he considered induction to be the basic requirement for true scientific research.[33]

text: Something like Occam's razor is also present in the Book of Optics. For example, after demonstrating that light is generated by luminous objects and emitted or reflected into the eyes, he states that therefore "the extramission of [visual] rays is superfluous and useless."[34] He may also have been the first scientist to adopt a form of positivism in his approach. He wrote that "we do not go beyond experience, and we cannot be content to use pure concepts in investigating natural phenomena", and that the understanding of these cannot be acquired without mathematics. After assuming that light is a material substance, he does not further discuss its nature but confines his investigations to the diffusion and propagation of light. The only properties of light he takes into account are those treatable by geometry and verifiable by experiment.[35]

text: Al-Biruni[edit]

text: The Persian scientist Abū Rayhān al-Bīrūnī introduced early scientific methods for several different fields of inquiry during the 1020s and 1030s. For example, in his treatise on mineralogy, Kitab al-Jawahir (Book of Precious Stones), al-Biruni is "the most exact of experimental scientists", while in the introduction to his study of India, he declares that "to execute our project, it has not been possible to follow the geometric method" and thus became one of the pioneers of comparative sociology in insisting on field experience and information.[36] He also developed an early experimental method for mechanics.[37]

text: Al-Biruni's methods resembled the modern scientific method, particularly in his emphasis on repeated experimentation. Biruni was concerned with how to conceptualize and prevent both systematic errors and observational biases, such as "errors caused by the use of small instruments and errors made by human observers." He argued that if instruments produce errors because of their imperfections or idiosyncratic qualities, then multiple observations must be taken, analyzed qualitatively, and on this basis, arrive at a "common-sense single value for the constant sought", whether an arithmetic mean or a "reliable estimate."[38] In his scientific method, "universals came out of practical, experimental work" and "theories are formulated after discoveries", as with inductivism.[36]

text: Ibn Sina (Avicenna)[edit]

text: In the On Demonstration section of The Book of Healing (1027), the Persian philosopher and scientist Avicenna (Ibn Sina) discussed philosophy of science and described an early scientific method of inquiry. He discussed Aristotle's Posterior Analytics and significantly diverged from it on several points. Avicenna discussed the issue of a proper procedure for scientific inquiry and the question of "How does one acquire the first principles of a science?" He asked how a scientist might find "the initial axioms or hypotheses of a deductive science without inferring them from some more basic premises?" He explained that the ideal situation is when one grasps that a "relation holds between the terms, which would allow for absolute, universal certainty." Avicenna added two further methods for finding a first principle: the ancient Aristotelian method of induction (istiqra), and the more recent method of examination and experimentation (tajriba). Avicenna criticized Aristotelian induction, arguing that "it does not lead to the absolute, universal, and certain premises that it purports to provide." In its place, he advocated "a method of experimentation as a means for scientific inquiry."[39]

text: Earlier, in The Canon of Medicine (1025), Avicenna was also the first to describe what is essentially methods of agreement, difference and concomitant variation which are critical to inductive logic and the scientific method.[40][41][42] However, unlike his contemporary al-Biruni's scientific method, in which "universals came out of practical, experimental work" and "theories are formulated after discoveries", Avicenna developed a scientific procedure in which "general and universal questions came first and led to experimental work."[36] Due to the differences between their methods, al-Biruni referred to himself as a mathematical scientist and to Avicenna as a philosopher, during a debate between the two scholars.[43]

text: Robert Grosseteste[edit]

text: During the European Renaissance of the 12th century, ideas on scientific methodology, including Aristotle's empiricism and the experimental approaches of Alhazen and Avicenna, were introduced to medieval Europe via Latin translations of Arabic and Greek texts and commentaries. Robert Grosseteste's commentary on the Posterior Analytics places Grosseteste among the first scholastic thinkers in Europe to understand Aristotle's vision of the dual nature of scientific reasoning. Concluding from particular observations into a universal law, and then back again, from universal laws to prediction of particulars. Grosseteste called this "resolution and composition". Further, Grosseteste said that both paths should be verified through experimentation to verify the principles.[44]

text: Roger Bacon[edit]

text: Roger Bacon was inspired by the writings of Grosseteste. In his account of a method, Bacon described a repeating cycle of observation, hypothesis, experimentation, and the need for independent verification. He recorded the way he had conducted his experiments in precise detail, perhaps with the idea that others could reproduce and independently test his results.

text: About 1256 he joined the Franciscan Order and became subject to the Franciscan statute forbidding Friars from publishing books or pamphlets without specific approval. After the accession of Pope Clement IV in 1265, the Pope granted Bacon a special commission to write to him on scientific matters. In eighteen months he completed three large treatises, the Opus Majus, Opus Minus, and Opus Tertium which he sent to the Pope.[45] William Whewell has called Opus Majus at once the Encyclopaedia and Organon of the 13th century.[46]

text:
Part I (pp. 1–22) treats of the four causes of error: authority, custom, the opinion of the unskilled many, and the concealment of real ignorance by a pretense of knowledge.
Part VI (pp. 445–477) treats of experimental science, domina omnium scientiarum. There are two methods of knowledge: the one by argument, the other by experience. Mere argument is never sufficient; it may decide a question, but gives no satisfaction or certainty to the mind, which can only be convinced by immediate inspection or intuition, which is what experience gives.
Experimental science, which in the Opus Tertium (p. 46) is distinguished from the speculative sciences and the operative arts, is said to have three great prerogatives over all sciences:

It verifies their conclusions by direct experiment;
It discovers truths which they could never reach;
It investigates the secrets of nature, and opens to us a knowledge of past and future.

Roger Bacon illustrated his method by an investigation into the nature and cause of the rainbow, as a specimen of inductive research.[47]

tag: ul

text: Renaissance humanism and medicine[edit]

text: Aristotle’s ideas became a framework for critical debate beginning with absorption of the Aristotelian texts into the university curriculum in the first half of the 13th century.[48] Contributing to this was the success of medieval theologians in reconciling Aristotelian philosophy with Christian theology. Within the sciences, medieval philosophers were not afraid of disagreeing with Aristotle on many specific issues, although their disagreements were stated within the language of Aristotelian philosophy. All medieval natural philosophers were Aristotelians, but "Aristotelianism" had become a somewhat broad and flexible concept. With the end of Middle Ages, the Renaissance rejection of medieval traditions coupled with an extreme reverence for classical sources led to a recovery of other ancient philosophical traditions, especially the teachings of Plato.[49] By the 17th century, those who clung dogmatically to Aristotle's teachings were faced with several competing approaches to nature.[50]

text: The discovery of the Americas at the close of the 15th century showed the scholars of Europe that new discoveries could be found outside of the authoritative works of Aristotle, Pliny, Galen, and other ancient writers.

text: Galen of Pergamon (129 – c. 200 AD) had studied with four schools in antiquity — Platonists, Aristotelians, Stoics, and Epicureans, and at Alexandria, the center of medicine at the time. In his Methodus Medendi, Galen had synthesized the empirical and dogmatic schools of medicine into his own method, which was preserved by Arab scholars. After the translations from Arabic were critically scrutinized, a backlash occurred and demand arose in Europe for translations of Galen's medical text from the original Greek. Galen's method became very popular in Europe. Thomas Linacre, the teacher of Erasmus, thereupon translated Methodus Medendi from Greek into Latin for a larger audience in 1519.[51] Limbrick 1988 notes that 630 editions, translations, and commentaries on Galen were produced in Europe in the 16th century, eventually eclipsing Arabic medicine there, and peaking in 1560, at the time of the scientific revolution.[52]

text: By the late 15th century, the physician-scholar Niccolò Leoniceno was finding errors in Pliny's Natural History. As a physician, Leoniceno was concerned about these botanical errors propagating to the materia medica on which medicines were based.[53] To counter this, a botanical garden was established at Orto botanico di Padova, University of Padua (in use for teaching by 1546), in order that medical students might have empirical access to the plants of a pharmacopia. Other Renaissance teaching gardens were established, notably by the physician Leonhart Fuchs, one of the founders of botany.[54]

text: The first published work devoted to the concept of method is Jodocus Willichius, De methodo omnium artium et disciplinarum informanda opusculum (1550).[citation needed]

text: Skepticism as a basis for understanding[edit]

text: In 1562 "Outlines of Pyrrhonism" by Sextus Empiricus (c. 160-210 AD) appeared in print and in Latin, quickly placing the arguments of classical skepticism in the European mainstream. Skepticism either denies or strongly doubts (depending on the school) the possibility of certain knowledge. Descartes' famous "Cogito" argument is an attempt to overcome skepticism and reestablish a foundation for certainty but other thinkers responded by revising what the search for knowledge, particularly physical knowledge, might be.

text: The first of these, philosopher and physician Francisco Sanches, was led by his medical training at Rome, 1571–73, to search for a true method of knowing (modus sciendi), as nothing clear can be known by the methods of Aristotle and his followers[55] — for example, 1) syllogism fails upon circular reasoning; 2) Aristotle's modal logic was not stated clearly enough for use in medieval times, and remains a research problem to this day.[56] Following the physician Galen's method of medicine, Sanches lists the methods of judgement and experience, which are faulty in the wrong hands,[57] and we are left with the bleak statement That Nothing is Known (1581, in Latin Quod Nihil Scitur). This challenge was taken up by René Descartes in the next generation (1637), but at the least, Sanches warns us that we ought to refrain from the methods, summaries, and commentaries on Aristotle, if we seek scientific knowledge. In this, he is echoed by Francis Bacon who was influenced by another prominent exponent of skepticism, Montaigne; Sanches cites the humanist Juan Luis Vives who sought a better educational system, as well as a statement of human rights as a pathway for improvement of the lot of the poor.

text: "Sanches develops his scepticism by means of an intellectual critique of Aristotelianism, rather than by an appeal to the history of human stupidity and the variety and contrariety of previous theories." —Popkin 1979, p. 37, as cited by Sanches, Limbrick & Thomson 1988, pp. 24–5

text: "To work, then; and if you know something, then teach me; I shall be extremely grateful to you. In the meantime, as I prepare to examine Things, I shall raise the question anything is known, and if so, how, in the introductory passages of another book,[58] a book in which I will expound, as far as human frailty allows,[59] the method of knowing. Farewell.

text: WHAT IS TAUGHT HAS NO MORE STRENGTH THAN IT DERIVES FROM HIM WHO IS TAUGHT.

text: WHAT?" —Francisco Sanches (1581) Quod Nihil Scitur p. 100[60]

text: Francis Bacon's eliminative induction[edit]

text: "If a man will begin with certainties, he shall end in doubts; but if he will be content to begin with doubts, he shall end in certainties." —Francis Bacon (1605) The Advancement of Learning, Book 1, v, 8

text: Francis Bacon (1561–1626) entered Trinity College, Cambridge in April 1573, where he applied himself diligently to the several sciences as then taught, and came to the conclusion that the methods employed and the results attained were alike erroneous; he learned to despise the current Aristotelian philosophy. He believed philosophy must be taught its true purpose, and for this purpose a new method must be devised. With this conception in his mind, Bacon left the university.[47]

text: Bacon attempted to describe a rational procedure for establishing causation between phenomena based on induction. Bacon's induction was, however, radically different than that employed by the Aristotelians. As Bacon put it,

text: [A]nother form of induction must be devised than has hitherto been employed, and it must be used for proving and discovering not first principles (as they are called) only, but also the lesser axioms, and the middle, and indeed all. For the induction which proceeds by simple enumeration is childish. —Novum Organum section CV

text: Bacon's method relied on experimental histories to eliminate alternative theories.[61] Bacon explains how his method is applied in his Novum Organum (published 1620). In an example he gives on the examination of the nature of heat, Bacon creates two tables, the first of which he names "Table of Essence and Presence", enumerating the many various circumstances under which we find heat. In the other table, labelled "Table of Deviation, or of Absence in Proximity", he lists circumstances which bear resemblance to those of the first table except for the absence of heat. From an analysis of what he calls the natures (light emitting, heavy, colored, etc.) of the items in these lists we are brought to conclusions about the form nature, or cause, of heat. Those natures which are always present in the first table, but never in the second are deemed to be the cause of heat.

text: The role experimentation played in this process was twofold. The most laborious job of the scientist would be to gather the facts, or 'histories', required to create the tables of presence and absence. Such histories would document a mixture of common knowledge and experimental results. Secondly, experiments of light, or, as we might say, crucial experiments would be needed to resolve any remaining ambiguities over causes.

text: Bacon showed an uncompromising commitment to experimentation. Despite this, he did not make any great scientific discoveries during his lifetime. This may be because he was not the most able experimenter.[62] It may also be because hypothesising plays only a small role in Bacon's method compared to modern science.[63] Hypotheses, in Bacon's method, are supposed to emerge during the process of investigation, with the help of mathematics and logic. Bacon gave a substantial but secondary role to mathematics "which ought only to give definiteness to natural philosophy, not to generate or give it birth" (Novum Organum XCVI). An over-emphasis on axiomatic reasoning had rendered previous non-empirical philosophy impotent, in Bacon's view, which was expressed in his Novum Organum:

text: XIX. There are and can be only two ways of searching into and discovering truth. The one flies from the senses and particulars to the most general axioms, and from these principles, the truth of which it takes for settled and immoveable, proceeds to judgment and to the discovery of middle axioms. And this way is now in fashion. The other derives axioms from the senses and particulars, rising by a gradual and unbroken ascent, so that it arrives at the most general axioms last of all. This is the true way, but as yet untried.

text: In Bacon's utopian novel, The New Atlantis, the ultimate role is given for inductive reasoning:

text: Lastly, we have three that raise the former discoveries by experiments into greater observations, axioms, and aphorisms. These we call interpreters of nature.

text: Descartes[edit]

text: In 1619, René Descartes began writing his first major treatise on proper scientific and philosophical thinking, the unfinished Rules for the Direction of the Mind. His aim was to create a complete science that he hoped would overthrow the Aristotelian system and establish himself as the sole architect[64] of a new system of guiding principles for scientific research.

text: This work was continued and clarified in his 1637 treatise, Discourse on Method, and in his 1641 Meditations. Descartes describes the intriguing and disciplined thought experiments he used to arrive at the idea we instantly associate with him: I think therefore I am.

text: From this foundational thought, Descartes finds proof of the existence of a God who, possessing all possible perfections, will not deceive him provided he resolves "[...] never to accept anything for true which I did not clearly know to be such; that is to say, carefully to avoid precipitancy and prejudice, and to comprise nothing more in my judgment than what was presented to my mind so clearly and distinctly as to exclude all ground of methodic doubt."[65]

text: This rule allowed Descartes to progress beyond his own thoughts and judge that there exist extended bodies outside of his own thoughts. Descartes published seven sets of objections to the Meditations from various sources[66] along with his replies to them. Despite his apparent departure from the Aristotelian system, a number of his critics felt that Descartes had done little more than replace the primary premises of Aristotle with those of his own. Descartes says as much himself in a letter written in 1647 to the translator of Principles of Philosophy,

text: a perfect knowledge [...] must necessarily be deduced from first causes [...] we must try to deduce from these principles knowledge of the things which depend on them, that there be nothing in the whole chain of deductions deriving from them that is not perfectly manifest.[67]

text: And again, some years earlier, speaking of Galileo's physics in a letter to his friend and critic Mersenne from 1638,

text: without having considered the first causes of nature, [Galileo] has merely looked for the explanations of a few particular effects, and he has thereby built without foundations.[68]

text: Whereas Aristotle purported to arrive at his first principles by induction, Descartes believed he could obtain them using reason only. In this sense, he was a Platonist, as he believed in the innate ideas, as opposed to Aristotle's blank slate (tabula rasa), and stated that the seeds of science are inside us.[69]

text: Unlike Bacon, Descartes successfully applied his own ideas in practice. He made significant contributions to science, in particular in aberration-corrected optics. His work in analytic geometry was a necessary precedent to differential calculus and instrumental in bringing mathematical analysis to bear on scientific matters.

text: Galileo Galilei[edit]

text: During the period of religious conservatism brought about by the Reformation and Counter-Reformation, Galileo Galilei unveiled his new science of motion. Neither the contents of Galileo’s science, nor the methods of study he selected were in keeping with Aristotelian teachings. Whereas Aristotle thought that a science should be demonstrated from first principles, Galileo had used experiments as a research tool. Galileo nevertheless presented his treatise in the form of mathematical demonstrations without reference to experimental results. It is important to understand that this in itself was a bold and innovative step in terms of scientific method. The usefulness of mathematics in obtaining scientific results was far from obvious.[70] This is because mathematics did not lend itself to the primary pursuit of Aristotelian science: the discovery of causes.

text: Whether it is because Galileo was realistic about the acceptability of presenting experimental results as evidence or because he himself had doubts about the epistemological status of experimental findings is not known. Nevertheless, it is not in his Latin treatise on motion that we find reference to experiments, but in his supplementary dialogues written in the Italian vernacular. In these dialogues experimental results are given, although Galileo may have found them inadequate for persuading his audience. Thought experiments showing logical contradictions in Aristotelian thinking, presented in the skilled rhetoric of Galileo's dialogue were further enticements for the reader.

text: As an example, in the dramatic dialogue titled Third Day from his Two New Sciences, Galileo has the characters of the dialogue discuss an experiment involving two free falling objects of differing weight. An outline of the Aristotelian view is offered by the character Simplicio. For this experiment he expects that "a body which is ten times as heavy as another will move ten times as rapidly as the other". The character Salviati, representing Galileo's persona in the dialogue, replies by voicing his doubt that Aristotle ever attempted the experiment. Salviati then asks the two other characters of the dialogue to consider a thought experiment whereby two stones of differing weights are tied together before being released. Following Aristotle, Salviati reasons that "the more rapid one will be partly retarded by the slower, and the slower will be somewhat hastened by the swifter". But this leads to a contradiction, since the two stones together make a heavier object than either stone apart, the heavier object should in fact fall with a speed greater than that of either stone. From this contradiction, Salviati concludes that Aristotle must, in fact, be wrong and the objects will fall at the same speed regardless of their weight, a conclusion that is borne out by experiment.

text: In his 1991 survey of developments in the modern accumulation of knowledge such as this Charles Van Doren[71] considers that the Copernican Revolution really is the Galilean Cartesian (René Descartes) or simply the Galilean revolution on account of the courage and depth of change brought about by the work of Galileo.

text: Isaac Newton[edit]

text: Both Bacon and Descartes wanted to provide a firm foundation for scientific thought that avoided the deceptions of the mind and senses. Bacon envisaged that foundation as essentially empirical, whereas Descartes provides a metaphysical foundation for knowledge. If there were any doubts about the direction in which scientific method would develop, they were set to rest by the success of Isaac Newton. Implicitly rejecting Descartes' emphasis on rationalism in favor of Bacon's empirical approach, he outlines his four "rules of reasoning" in the Principia,

text:
We are to admit no more causes of natural things than such as are both true and sufficient to explain their appearances.
Therefore to the same natural effects we must, as far as possible, assign the same causes.
The qualities of bodies, which admit neither intension nor remission of degrees, and which are found to belong to all bodies within the reach of our experiments, are to be esteemed the universal qualities of all bodies whatsoever.
In experimental philosophy we are to look upon propositions collected by general induction from phænomena as accurately or very nearly true, notwithstanding any contrary hypotheses that may be imagined, until such time as other phænomena occur, by which they may either be made more accurate, or liable to exceptions.[72]

text: But Newton also left an admonition about a theory of everything:

text: To explain all nature is too difficult a task for any one man or even for any one age. 'Tis much better to do a little with certainty, and leave the rest for others that come after you, than to explain all things.[73]

text: Newton's work became a model that other sciences sought to emulate, and his inductive approach formed the basis for much of natural philosophy through the 18th and early 19th centuries. Some methods of reasoning were later systematized by Mill's Methods (or Mill's canon), which are five explicit statements of what can be discarded and what can be kept while building a hypothesis. George Boole and William Stanley Jevons also wrote on the principles of reasoning.

text: Integrating deductive and inductive method[edit]

text: Attempts to systematize a scientific method were confronted in the mid-18th century by the problem of induction, a positivist logic formulation which, in short, asserts that nothing can be known with certainty except what is actually observed. David Hume took empiricism to the skeptical extreme; among his positions was that there is no logical necessity that the future should resemble the past, thus we are unable to justify inductive reasoning itself by appealing to its past success. Hume's arguments, of course, came on the heels of many, many centuries of excessive speculation upon excessive speculation not grounded in empirical observation and testing. Many of Hume's radically skeptical arguments were argued against, but not resolutely refuted, by Immanuel Kant's Critique of Pure Reason in the late 18th century.[74] Hume's arguments continue to hold a strong lingering influence and certainly on the consciousness of the educated classes for the better part of the 19th century when the argument at the time became the focus on whether or not the inductive method was valid.

text: Hans Christian Ørsted, (Ørsted is the Danish spelling; Oersted in other languages) (1777–1851) was heavily influenced by Kant, in particular, Kant's Metaphysische Anfangsgründe der Naturwissenschaft (Metaphysical Foundations of Natural Science).[75] The following sections on Ørsted encapsulate our current, common view of scientific method. His work appeared in Danish, most accessibly in public lectures, which he translated into German, French, English, and occasionally Latin. But some of his views go beyond Kant:

text: Ørsted's "First Introduction to General Physics" (1811) exemplified the steps of observation,[77] hypothesis,[78] deduction[79] and experiment. In 1805, based on his researches on electromagnetism Ørsted came to believe that electricity is propagated by undulatory action (i.e., fluctuation). By 1820, he felt confident enough in his beliefs that he resolved to demonstrate them in a public lecture, and in fact observed a small magnetic effect from a galvanic circuit (i.e., voltaic circuit), without rehearsal;[80][81]

text: In 1831 John Herschel (1792–1871) published A Preliminary Discourse on the study of Natural Philosophy, setting out the principles of science. Measuring and comparing observations was to be used to find generalisations in "empirical laws", which described regularities in phenomena, then natural philosophers were to work towards the higher aim of finding a universal "law of nature" which explained the causes and effects producing such regularities. An explanatory hypothesis was to be found by evaluating true causes (Newton's "vera causae") derived from experience, for example evidence of past climate change could be due to changes in the shape of continents, or to changes in Earth's orbit. Possible causes could be inferred by analogy to known causes of similar phenomena.[82][83] It was essential to evaluate the importance of a hypothesis; "our next step in the verification of an induction must, therefore, consist in extending its application to cases not originally contemplated; in studiously varying the circumstances under which our causes act, with a view to ascertain whether their effect is general; and in pushing the application of our laws to extreme cases."[84]

text: William Whewell (1794–1866) regarded his History of the Inductive Sciences, from the Earliest to the Present Time (1837) to be an introduction to the Philosophy of the Inductive Sciences (1840) which analyzes the method exemplified in the formation of ideas. Whewell attempts to follow Bacon's plan for discovery of an effectual art of discovery. He named the hypothetico-deductive method (which Encyclopædia Britannica credits to Newton[85]); Whewell also coined the term scientist. Whewell examines ideas and attempts to construct science by uniting ideas to facts. He analyses induction into three steps:

text:
the selection of the fundamental idea, such as space, number, cause, or likeness
a more special modification of those ideas, such as a circle, a uniform force, etc.
the determination of magnitudes

text: Upon these follow special techniques applicable for quantity, such as the method of least squares, curves, means, and special methods depending on resemblance (such as pattern matching, the method of gradation, and the method of natural classification (such as cladistics). But no art of discovery, such as Bacon anticipated, follows, for "invention, sagacity, genius" are needed at every step.[86] Whewell's sophisticated concept of science had similarities to that shown by Herschel, and he considered that a good hypothesis should connect fields that had previously been thought unrelated, a process he called consilience. However, where Herschel held that the origin of new biological species would be found in a natural rather than a miraculous process, Whewell opposed this and considered that no natural cause had been shown for adaptation so an unknown divine cause was appropriate.[82]

text: John Stuart Mill (1806–1873) was stimulated to publish A System of Logic (1843) upon reading Whewell's History of the Inductive Sciences. Mill may be regarded as the final exponent of the empirical school of philosophy begun by John Locke, whose fundamental characteristic is the duty incumbent upon all thinkers to investigate for themselves rather than to accept the authority of others. Knowledge must be based on experience.[87]

text: In the mid-19th century Claude Bernard was also influential, especially in bringing the scientific method to medicine. In his discourse on scientific method, An Introduction to the Study of Experimental Medicine (1865), he described what makes a scientific theory good and what makes a scientist a true discoverer. Unlike many scientific writers of his time, Bernard wrote about his own experiments and thoughts, and used the first person.[88]

text: William Stanley Jevons' The Principles of Science: a treatise on logic and scientific method (1873, 1877) Chapter XII "The Inductive or Inverse Method", Summary of the Theory of Inductive Inference, states "Thus there are but three steps in the process of induction :-

text:
Framing some hypothesis as to the character of the general law.
Deducing some consequences of that law.
Observing whether the consequences agree with the particular tasks under consideration."

text: Jevons then frames those steps in terms of probability, which he then applied to economic laws. Ernest Nagel notes that Jevons and Whewell were not the first writers to argue for the centrality of the hypothetico-deductive method in the logic of science.[89]

text: Charles Sanders Peirce[edit]

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text: In the late 19th century, Charles Sanders Peirce proposed a schema that would turn out to have considerable influence in the further development of scientific method generally. Peirce's work quickly accelerated the progress on several fronts. Firstly, speaking in broader context in "How to Make Our Ideas Clear" (1878),[90] Peirce outlined an objectively verifiable method to test the truth of putative knowledge on a way that goes beyond mere foundational alternatives, focusing upon both Deduction and Induction. He thus placed induction and deduction in a complementary rather than competitive context (the latter of which had been the primary trend at least since David Hume a century before). Secondly, and of more direct importance to scientific method, Peirce put forth the basic schema for hypothesis-testing that continues to prevail today. Extracting the theory of inquiry from its raw materials in classical logic, he refined it in parallel with the early development of symbolic logic to address the then-current problems in scientific reasoning. Peirce examined and articulated the three fundamental modes of reasoning that play a role in scientific inquiry today, the processes that are currently known as abductive, deductive, and inductive inference. Thirdly, he played a major role in the progress of symbolic logic itself – indeed this was his primary specialty.

text: Charles S. Peirce was also a pioneer in statistics. Peirce held that science achieves statistical probabilities, not certainties, and that chance, a veering from law, is very real. He assigned probability to an argument’s conclusion rather than to a proposition, event, etc., as such. Most of his statistical writings promote the frequency interpretation of probability (objective ratios of cases), and many of his writings express skepticism about (and criticize the use of) probability when such models are not based on objective randomization.[91] Though Peirce was largely a frequentist, his possible world semantics introduced the "propensity" theory of probability. Peirce (sometimes with Jastrow) investigated the probability judgments of experimental subjects, pioneering decision analysis.

text: Peirce was one of the founders of statistics. He formulated modern statistics in "Illustrations of the Logic of Science" (1877–1878) and "A Theory of Probable Inference" (1883). With a repeated measures design, he introduced blinded, controlled randomized experiments (before Fisher). He invented an optimal design for experiments on gravity, in which he "corrected the means". He used logistic regression, correlation, and smoothing, and improved the treatment of outliers. He introduced terms "confidence" and "likelihood" (before Neyman and Fisher). (See the historical books of Stephen Stigler.) Many of Peirce's ideas were later popularized and developed by Ronald A. Fisher, Jerzy Neyman, Frank P. Ramsey, Bruno de Finetti, and Karl Popper.

text: Popper and Kuhn[edit]

text: Karl Popper (1902–1994) is generally credited with providing major improvements in the understanding of the scientific method in the mid-to-late 20th century. In 1934 Popper published The Logic of Scientific Discovery, which repudiated the by then traditional observationalist-inductivist account of the scientific method. He advocated empirical falsifiability as the criterion for distinguishing scientific work from non-science. According to Popper, scientific theory should make predictions (preferably predictions not made by a competing theory) which can be tested and the theory rejected if these predictions are shown not to be correct. Following Peirce and others, he argued that science would best progress using deductive reasoning as its primary emphasis, known as critical rationalism. His astute formulations of logical procedure helped to rein in the excessive use of inductive speculation upon inductive speculation, and also helped to strengthen the conceptual foundations for today's peer review procedures.[citation needed]

text: Critics of Popper, chiefly Thomas Kuhn, Paul Feyerabend and Imre Lakatos, rejected the idea that there exists a single method that applies to all science and could account for its progress. In 1962 Kuhn published the influential book The Structure of Scientific Revolutions which suggested that scientists worked within a series of paradigms, and argued there was little evidence of scientists actually following a falsificationist methodology. Kuhn quoted Max Planck who had said in his autobiography, "a new scientific truth does not triumph by convincing its opponents and making them see the light, but rather because its opponents eventually die, and a new generation grows up that is familiar with it."[92]

text: These debates clearly show that there is no universal agreement as to what constitutes the "scientific method".[93] There remain, nonetheless, certain core principles that are the foundation of scientific inquiry today.[94]

text: Mention of the topic[edit]

text: In Quod Nihil Scitur (1581), Francisco Sanches refers to another book title, De modo sciendi (on the method of knowing). This work appeared in Spanish as Método universal de las ciencias.[59]

text: In 1833 Robert and William Chambers published their 'Chambers's information for the people'. Under the rubric 'Logic' we find a description of investigation that is familiar as scientific method,

text: Investigation, or the art of inquiring into the nature of causes and their operation, is a leading characteristic of reason [...] Investigation implies three things – Observation, Hypothesis, and Experiment [...] The first step in the process, it will be perceived, is to observe...[95]

text: In 1885, the words "Scientific method" appear together with a description of the method in Francis Ellingwood Abbot's 'Scientific Theism',

text: Now all the established truths which are formulated in the multifarious propositions of science have been won by the use of Scientific Method. This method consists in essentially three distinct steps (1) observation and experiment, (2) hypothesis, (3) verification by fresh observation and experiment.[96]

text: The Eleventh Edition of Encyclopædia Britannica did not include an article on scientific method; the Thirteenth Edition listed scientific management, but not method. By the Fifteenth Edition, a 1-inch article in the Micropædia of Britannica was part of the 1975 printing, while a fuller treatment (extending across multiple articles, and accessible mostly via the index volumes of Britannica) was available in later printings.[97]

text: Current issues[edit]

text: In the past few centuries, some statistical methods have been developed, for reasoning in the face of uncertainty, as an outgrowth of methods for eliminating error. This was an echo of the program of Francis Bacon's Novum Organum of 1620. Bayesian inference acknowledges one's ability to alter one's beliefs in the face of evidence. This has been called belief revision, or defeasible reasoning: the models in play during the phases of scientific method can be reviewed, revisited and revised, in the light of further evidence. This arose from the work of Frank P. Ramsey[98] (1903–1930), of John Maynard Keynes[99] (1883–1946), and earlier, of William Stanley Jevons[100][101] (1835–1882) in economics.

text: Science and pseudoscience[edit]

text: The question of how science operates and therefore how to distinguish genuine science from pseudoscience has importance well beyond scientific circles or the academic community. In the judicial system and in public policy controversies, for example, a study's deviation from accepted scientific practice is grounds for rejecting it as junk science or pseudoscience. However, the high public perception of science means that pseudoscience is widespread. An advertisement in which an actor wears a white coat and product ingredients are given Greek or Latin sounding names is intended to give the impression of scientific endorsement. Richard Feynman has likened pseudoscience to cargo cults in which many of the external forms are followed, but the underlying basis is missing: that is, fringe or alternative theories often present themselves with a pseudoscientific appearance to gain acceptance.[102]


document_title: Tricyclic antidepressant

question_text: what is an example of a tricyclic antidepressant

text: Tricyclic antidepressant

text: Medical uses[edit]

text: The TCAs are used primarily in the clinical treatment of mood disorders such as major depressive disorder (MDD), dysthymia, and treatment-resistant variants. They are also used in the treatment of a number of other medical disorders, including anxiety disorders such as generalized anxiety disorder (GAD), social phobia (SP) also known as social anxiety disorder (SAD), obsessive-compulsive disorder (OCD), and panic disorder (PD), post-traumatic stress disorder (PTSD), body dysmorphic disorder (BDD), eating disorders like anorexia nervosa and bulimia nervosa, certain personality disorders such as borderline personality disorder (BPD), Neurological disorders such as attention-deficit hyperactivity disorder (ADHD),[3] Parkinson's disease[4] as well as chronic pain, neuralgia or neuropathic pain, and fibromyalgia, headache, or migraine, smoking cessation, tourette syndrome, trichotillomania, irritable bowel syndrome (IBS), interstitial cystitis (IC), nocturnal enuresis (NE),[5] narcolepsy, insomnia, pathological crying and/or laughing, chronic hiccups, ciguatera poisoning, and as an adjunct in schizophrenia.

text: Clinical depression[edit]

text: For many years the TCAs were the first choice for pharmacological treatment of clinical depression. Although they are still considered to be highly effective, they have been increasingly replaced by antidepressants with an improved safety and side effect profile, such as the SSRIs and other newer antidepressants such as the novel reversible MAOI moclobemide. However, tricyclic antidepressants are possibly more effective in treating melancholic depression than other antidepressant drug classes.[6] Newer antidepressants are thought to have fewer and less severe side effects and are also thought to be less likely to result in injury or death if used in a suicide attempt, as the doses required for clinical treatment and potentially lethal overdose (see therapeutic index) are far wider in comparison.

text: Nonetheless, the TCAs are still occasionally used for treatment-resistant depression that has failed to respond to therapy with newer antidepressants.[7] They are not considered addictive and are somewhat preferable to the monoamine oxidase inhibitors (MAOIs). The side effects of the TCAs usually come to prominence before the therapeutic benefits against depression and/or anxiety do, and for this reason, they may potentially be somewhat dangerous, as volition can be increased, possibly giving the patient a greater desire to attempt or commit suicide.[8]

text: Attention-deficit hyperactivity disorder[edit]

text: The TCAs were used in the past in the clinical treatment of ADHD,[9] though they are not typically used anymore, having been replaced by more effective agents with fewer side effects such as atomoxetine (Strattera, Tomoxetin, Attentin) and stimulants like methylphenidate (Ritalin, Focalin, Concerta), and amphetamine (Adderall, Dexedrine, Vyvanse). ADHD is thought to be caused by an insufficiency of dopamine and norepinephrine activity in the prefrontal cortex of the brain.[10] Most of the TCAs inhibit the reuptake of norepinephrine, though not dopamine, and as a result, they show some efficacy in remedying the disorder.[11] Notably, the TCAs are more effective in treating the behavioral aspects of ADHD than the cognitive deficits, as they help limit hyperactivity and impulsivity, but have little to no benefits on attention.[12]

text: Chronic pain[edit]

text: The TCAs show efficacy in the clinical treatment of a number of different types of chronic pain, notably neuralgia or neuropathic pain and fibromyalgia.[13][14] The precise mechanism of action in explanation of their analgesic efficacy is unclear, but it is thought that they indirectly modulate the opioid system in the brain downstream via serotonergic and noradrenergic neuromodulation, among other properties.[15][16][17] They are also effective in migraine prophylaxis, though not in the instant relief of an acute migraine attack. They may also be effective to prevent chronic tension headaches.

text: Side effects[edit]

text: Many side effects may be related to the antimuscarinic properties of the TCAs. Such side effects are relatively common and may include dry mouth, dry nose, blurry vision, lowered gastrointestinal motility or constipation, urinary retention, cognitive and/or memory impairment, and increased body temperature.

text: Other side effects may include drowsiness, anxiety, emotional blunting (apathy/anhedonia), confusion, restlessness, dizziness, akathisia, hypersensitivity, changes in appetite and weight, sweating, sexual dysfunction, muscle twitches, weakness, nausea and vomiting, hypotension, tachycardia, and rarely, irregular heart rhythms. Twitching, hallucinations, delirium and coma are also some of the toxic effects caused by overdose.[18] Rhabdomyolysis or muscle breakdown has been rarely reported with this class of drugs as well.[19]

text: Tolerance to these adverse effects of these drugs often develops if treatment is continued. Side effects may also be less troublesome if treatment is initiated with low doses and then gradually increased, although this may also delay the beneficial effects.

text: TCAs can behave like class 1A antiarrhythmics, as such, they can theoretically terminate ventricular fibrillation, decrease cardiac contractility and increase collateral blood circulation to ischemic heart muscle. Naturally, in overdose, they can be cardiotoxic, prolonging heart rhythms and increasing myocardial irritability.

text: New research has also revealed compelling evidence of a link between long-term use of anticholinergic medications like TCAs and dementia.[20] Although many studies have investigated this link, this was the first study to use a long-term approach (over seven years) to find that dementias associated with anticholinergics may not be reversible even years after drug use stops.[21] Anticholinergic drugs block the action of acetylcholine, which transmits messages in the nervous system. In the brain, acetylcholine is involved in learning and memory.

text: Discontinuation[edit]

text: Antidepressants in general may produce a withdrawal. However, since the term "withdrawal" has been linked to addiction to recreational drugs like opioids, the medical profession and pharmaceutical public relations prefer that a different term be used, hence "discontinuation syndrome."[22] Discontinuation symptoms can be managed by a gradual reduction in dosage over a period of weeks or months to minimise symptoms.[23] In tricyclics, discontinuation syndrome symptoms include anxiety, insomnia, headache, nausea, malaise, or motor disturbance.[24]

text: Overdose[edit]

text: TCA overdose is a significant cause of fatal drug poisoning. The severe morbidity and mortality associated with these drugs is well documented due to their cardiovascular and neurological toxicity. Additionally, it is a serious problem in the pediatric population due to their inherent toxicity[25] and the availability of these in the home when prescribed for bed-wetting and depression. In the event of a known or suspected overdose, medical assistance should be sought immediately.

text: A number of treatments are effective in a TCA overdose.

text: An overdose on TCA is especially fatal as it is rapidly absorbed from the GI tract in the alkaline conditions of the small intestines. As a result, toxicity often becomes apparent in the first hour after an overdose. However, symptoms may take several hours to appear if a mixed overdose has caused delayed gastric emptying.

text: Many of the initial signs are those associated to the anticholinergic effects of TCAs such as dry mouth, blurred vision, urinary retention, constipation, dizziness, and emesis (or vomiting). Due to the location of norepinephrine receptors all over the body, many physical signs are also associated with a TCA overdose:[26]

text:
Anticholinergic effects: altered mental status (e.g., agitation, confusion, lethargy, etc.), resting sinus tachycardia, dry mouth, mydriasis (pupil dilation), fever
Cardiac effects: hypertension (early and transient, should not be treated), tachycardia, orthostasis and hypotension, arrhythmias (including ventricular tachycardia and ventricular fibrillation, most serious consequence) / ECG changes (prolonged QRS, QT, and PR intervals)
CNS effects: syncope, seizure, coma, myoclonus, hyperreflexia
Pulmonary effects: hypoventilation resulting from CNS depression
Gastrointestinal effects: decreased or absent bowel sounds

text: Treatment of TCA overdose depends on severity of symptoms:

text: Initially, gastric decontamination of the patient is achieved by administering, either orally or via a nasogastric tube, activated charcoal pre-mixed with water, which adsorbs the drug in the gastrointestinal tract (most useful if given within 2 hours of drug ingestion). Other decontamination methods such as stomach pumps, gastric lavage, whole bowel irrigation, or (ipecac induced) emesis, are not  recommended in TCA poisoning.

text: If there is metabolic acidosis, intravenous infusion of sodium bicarbonate is recommended by Toxbase.org, the UK and Ireland poisons advice database (TCAs are protein bound and become less bound in more acidic conditions, so by reversing the acidosis, protein binding increases and bioavailability thus decreases – the sodium load may also help to reverse the Na+ channel blocking effects of the TCA).

text: Interactions[edit]

text: The TCAs are highly metabolised by the cytochrome P450 hepatic enzymes. Drugs that inhibit cytochrome P450 (for example cimetidine, methylphenidate, fluoxetine, antipsychotics, and calcium channel blockers) may produce decreases in the TCAs' metabolism, leading to increases in their blood concentrations and accompanying toxicity.[27] Drugs that prolong the QT interval including antiarrhythmics such as quinidine, the antihistamines astemizole and terfenadine, and some antipsychotics may increase the chance of ventricular dysrhythmias. TCAs may enhance the response to alcohol and the effects of barbiturates and other CNS depressants. Side effects may also be enhanced by other drugs that have antimuscarinic properties.

text: Pharmacology[edit]

text: The majority of the TCAs act primarily as SNRIs by blocking the serotonin transporter (SERT) and the norepinephrine transporter (NET), respectively, which results in an elevation of the synaptic concentrations of these neurotransmitters, and therefore an enhancement of neurotransmission.[28][29] Notably, with the sole exception of amineptine, the TCAs have negligible affinity for the dopamine transporter (DAT), and therefore have no efficacy as dopamine reuptake inhibitors (DRIs).[28] Both serotonin and norepinephrine have been highly implicated in depression and anxiety, and it has been shown that facilitation of their activity has beneficial effects on these mental disorders.[30]

text: In addition to their reuptake inhibition, many TCAs also have high affinity as antagonists at the 5-HT2[31] (5-HT2A[32] and 5-HT2C[32]), 5-HT6,[33] 5-HT7,[34] α1-adrenergic,[31] and NMDA receptors,[35] and as agonists at the sigma receptors[36] (σ1[36] and σ2[37]), some of which may contribute to their therapeutic efficacy, as well as their side effects.[38] The TCAs also have varying but typically high affinity for antagonising the H1[31] and H2[39][40] histamine receptors, as well as the muscarinic acetylcholine receptors.[31] As a result, they also act as potent antihistamines and anticholinergics. These properties are often beneficial in antidepressants, especially with comorbid anxiety, as it provides a sedative effect.[41]

text: Most, if not all, of the TCAs also potently inhibit sodium channels and L-type calcium channels, and therefore act as sodium channel blockers and calcium channel blockers, respectively.[42][43] The former property is responsible for the high mortality rate upon overdose seen with the TCAs via cardiotoxicity.[44] It may also be involved in their efficacy as analgesics, however.[45]

text: Binding profiles[edit]

text: The binding profiles of various TCAs and some metabolites in terms of their affinities (Ki, nM) for various receptors and transporters are as follows:[46]

text:
Compound
SERT
NET
DAT
5-HT1A
5-HT2A
5-HT2C
5-HT6
5-HT7
α1
α2
D2
H1
H2
mACh
σ1
σ2

Amineptine
>100,000
10,000
1,000–1,400
>100,000
74,000
ND
ND
ND
>100,000
>100,000
>100,000
≥13,000
ND
>100,000
ND
ND

Amitriptyline
2.8–4.3
19–35
3,250
≥450
18–23
4.0
65–141
93–123
4.4–24
114–690
196–1,460
0.5–1.1
66
9.6
300
ND

Amoxapine
58
16
4,310
ND
0.5
2.0
6.0–50
41
50
2,600
3.6–160
7.9–25
ND
1,000
ND
ND

Butriptyline
≥1,360
5,100
3,940
7,000
380
ND
ND
ND
570
4,800
ND
1.1
ND
35
ND
ND

Clomipramine
0.14–0.28
38–54
≥2,190
≥7,000
27–36
65
54
127
3.2–38
≥535
78–190
13–31
209
37
546
ND

Desipramine
18–163
0.63–3.5
3,190
≥6,400
115–350
244–748
ND
>1,000
23–130
≥1,379
3,400
60–110
1,550
66–198
≥1,990
≥1,610

Dibenzepin
ND
ND
>10,000
>10,000
≥1,500
ND
ND
ND
>10,000
>10,000
>10,000
23
1,950
1,750
ND
ND

Dosulepin
8.6–78
46–70
5,310
4,000
152
ND
ND
ND
419
2,400
ND
3.6–4.0
ND
25–26
ND
ND

Doxepin
68–210
13–58
≥4,600
276
11–27
8.8–200
136
ND
24
28–1,270
360
0.09–1.23
174
23–80
ND
ND

Imipramine
1.3–1.4
20–37
8,500
≥5,800
80–150
120
190–209
>1,000
32
3,100
620–726
7.6–37
550
46
332–520
327–2,100

Iprindole
≥1,620
1,260
6,530
2,800
217–280
206
ND
ND
2,300
8,600
6,300
100–130
200–8,300
2,100
>10,000
ND

Lofepramine
70
5.4
>10,000
4,600
200
ND
ND
ND
100
2,700
2,000
245–360
4,270
67
2,520
ND

Maprotiline
5,800
11–12
1,000
ND
51
122
ND
50
90
9,400
350–665
0.79–2.0
776
570
ND
ND

Norclomipramine
40
0.45
2,100
19,000
130
ND
ND
ND
190
1,800
1,200
450
ND
92
ND
ND

Northiaden
192
25
2,539
2,623
141
ND
ND
ND
950
ND
ND
25
ND
110
ND
ND

Nortriptyline
15–18
1.8–4.4
1,140
294
5.0–41
8.5
148
ND
55
2,030
2,570
3.0–15
646
37
2,000
ND

Opipramol
≥2,200
≥700
≥3,000
>10,000
120
ND
ND
ND
200
6,100
120–300
6.0
4,470
3,300
0.2–50
110

Protriptyline
19.6
1.41
2,100
3,800
70
ND
ND
ND
130
6,600
2,300
7.2–25
398
25
ND
ND

Tianeptine
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000

Trimipramine
149–2,110
≥2,450
≥3,780
8,000
32
537
ND
ND
24
680
143–210
0.27–1.5
41
58
ND
ND

Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site. For assay species and references, see the individual drug articles. Most but not all values are for human proteins.

text: With the exception of the sigma receptors, the TCAs act as antagonists or inverse agonists of the receptors and as inhibitors of the transporters. Tianeptine is included in this list due to it technically being a TCA, but with a vastly different pharmacology.

text: Therapeutic levels of TCAs are generally in the range of about 100 to 300 ng/mL, or 350 to 1,100 nM.[47] Plasma protein binding is generally 90% or greater.[47]

text: Chemistry[edit]

text: There are two major groups of TCAs in terms of chemical structure, which most, but not all, TCAs fall into.[48][49][50] The groupings are based on the tricyclic ring system.[48][49][50] They are the dibenzazepines (imipramine, desipramine, clomipramine, trimipramine, lofepramine) and the dibenzocycloheptadienes (amitriptyline, nortriptyline, protriptyline, butriptyline).[48][49] Minor TCA groups based on ring system include the dibenzoxepins (doxepin), the dibenzothiepines (dosulepin), and the dibenzoxazepines (amoxapine).[48][49] In addition to classification based on the ring system, TCAs can also be usefully grouped based on the number of substitutions of the side chain amine.[50][51] These groups include the tertiary amines (imipramine, clomipramine, trimipramine, amitriptyline, butriptyline, doxepin, dosulepin) and the secondary amines (desipramine, nortriptyline, protriptyline).[50][51] Lofepramine is technically a tertiary amine, but acts largely as a prodrug of desipramine, a secondary amine, and hence is more similar in profile to the secondary amines than to the tertiary amines.[51] Amoxapine does not have the TCA side chain and hence is neither a tertiary nor secondary amine, although it is often grouped with the secondary amines due to sharing more in common with them.[52]

text: History[edit]

text: The TCAs were developed amid the "explosive birth" of psychopharmacology in the early 1950s. The story begins with the synthesis of chlorpromazine in December 1950 by Rhône-Poulenc's chief chemist, Paul Charpentier, from synthetic antihistamines developed by Rhône-Poulenc in the 1940s.[53] Its psychiatric effects were first noticed at a hospital in Paris in 1952. The first widely used psychiatric drug, by 1955 it was already generating significant revenue as an antipsychotic.[54] Research chemists quickly began to explore other derivatives of chlorpromazine.

text: The first TCA reported for the treatment of depression was imipramine, a dibenzazepine analogue of chlorpromazine code-named G22355. It was not originally targeted for the treatment of depression. The drug's tendency to induce manic effects was "later described as 'in some patients, quite disastrous'". The paradoxical observation of a sedative inducing mania led to testing with depressed patients. The first trial of imipramine took place in 1955 and the first report of antidepressant effects was published by Swiss psychiatrist Roland Kuhn in 1957.[53] Some testing of Geigy’s imipramine, then known as Tofranil, took place at the Münsterlingen Hospital near Konstanz.[54] Geigy later became Ciba-Geigy and eventually Novartis.

text: Dibenzazepine derivatives are described in U.S. patent 3,074,931 issued 1963-01-22 by assignment to Smith Kline & French Laboratories. The compounds described share a tricyclic backbone different from the backbone of the TCA amitriptyline.

text: Merck introduced the second member of the TCA family, amitriptyline (Elavil), in 1961.[54] This compound has a different three-ring structure than imipramine.

text: Society and culture[edit]

text: Recreational use[edit]

text: A very small number of cases involving non-medical use of antidepressants have been reported over the past 30 years.[55] According to the US government classification of psychiatric medications, TCAs are "non-abusable"[56] and generally have low abuse potential.[57] Nonetheless due to their atypical MOA, amineptine and tianeptine (dopamine reuptake inhibition and μ-opioid receptor agonism, respectively) are the two TCAs with the highest addiction and abuse potential. Several cases of the misuse[58] of amitriptyline alone[59][60] or together with methadone[58][61] or in other drug dependent patients[62][63] and of dosulepin with alcohol[64] or in methadone patients[65] have been reported.

text: List of TCAs[edit]

text: Those that preferentially inhibit the reuptake of serotonin (by at least 10-fold over norepinephrine) include:

text:
Butriptyline† (Evadyne) (relatively weak serotonin reuptake inhibitor)
Clomipramine (Anafranil)
Imipramine (Tofranil, Janimine, Praminil)
Trimipramine (Surmontil) (relatively weak serotonin reuptake inhibitor)

text: Those that preferentially inhibit the reuptake of norepinephrine (by at least 10-fold over serotonin) include:

text:
Desipramine (Norpramin, Pertofrane)
Dibenzepin‡ (Noveril, Victoril)
Lofepramine§ (Lomont, Gamanil)
Maprotiline (Ludiomil) – can be classed with the TCAs though more frequently classed with the TeCAs
Nortriptyline (Pamelor, Aventyl, Norpress)
Protriptyline (Vivactil)

text: Whereas either fairly balanced reuptake inhibitors of serotonin and norepinephrine or unspecified inhibitors include:

text:
Amitriptyline (Elavil, Endep)
Amitriptylinoxide (Amioxid, Ambivalon, Equilibrin)
Amoxapine (Asendin) – can be classed with the TeCAs but more frequently classed with the TCAs
Demexiptiline† (Deparon, Tinoran)
Dimetacrine† (Istonil, Istonyl, Miroistonil)
Dosulepin§ (Prothiaden)
Doxepin (Adapin, Sinequan)
Fluacizine† (Phtorazisin)
Imipraminoxide† (Imiprex, Elepsin)
Melitracen§ (Deanxit, Dixeran, Melixeran, Trausabun)
Metapramine† (Timaxel)
Nitroxazepine‡ (Sintamil)
Noxiptiline‡ (Agedal, Elronon, Nogedal)
Pipofezine‡ (Azafen/Azaphen)
Propizepine† (Depressin, Vagran)
Quinupramine† (Kevopril, Kinupril, Adeprim, Quinuprine)

text: And the following are TCAs that act via main mechanisms other than serotonin or norepinephrine reuptake inhibition:

text:
Amineptine‡ (Survector, Maneon, Directim) – norepinephrine–dopamine reuptake inhibitor
Iprindole† (Prondol, Galatur, Tetran) – 5-HT2 receptor antagonist
Opipramol‡ (Insidon, Pramolan, Ensidon, Oprimol) – σ receptor agonist
Tianeptine‡ (Stablon, Coaxil, Tatinol) – atypical μ-opioid receptor agonist

text: Legend:

text:
† indicates products that have been withdrawn from the market worldwide.
‡ indicates products that are not available in any country in which English is an official language.
§ indicates products that are not available in the United States, but are available in other English-speaking countries such as Australia, Canada, United Kingdom, etc.
Bolded names indicates products that are available in at least three countries in which English is an official language.