title: Dražen Petrović

text: Petrović died in a traffic accident at about 5:20 p.m. on 7 June 1993. On the rain-drenched Autobahn 9, he was a passenger in a car that was cut off by a semi-truck at Denkendorf near Ingolstadt in the German state of Bavaria. According to the report of the Ingolstadt police, that afternoon a truck broke through the Autobahn median; the driver was trying to avoid a collision with a personal vehicle in his own lane and lost control of the truck, crashing through the median barrier and finally coming to a stop and blocking all three lanes of traffic going in the opposite direction. Seconds later, the Volkswagen Golf carrying a sleeping Petrović in the passenger seat crashed into the truck, and Petrovic was ejected from the vehicle. According to the autopsy report, Petrovic died of severe head injuries on impact. The driver, Klara Szalantzy, a Hungarian model and basketball player with whom Petrović was romantically involved, and , a female Turkish basketball player, sustained serious injuries. It was established that visibility on the road was very poor and neither Petrovic nor Edebal wore their seatbelts. According to Edebal, who incurred severe memory loss as a result of the accident and would never play basketball again, Szalantzy was driving , which was legal on the Autobahn. Szalantzy would return to modeling and basketball not long after.


title: Dražen Petrović

text: Petrović's tomb at Mirogoj Cemetery instantly became a sanctuary for his compatriots. The Cibona stadium was renamed the Dražen Petrović Basketball Hall on 4 October 1993, and the city of Zagreb dedicated a square in his name, which was later followed by Šibenik and Vukovar, while Petrinja dedicated a street to him. Before Game 1 of the 1993 NBA Finals, the NBA held a moment of silence for Petrović, whose death occurred two days before the event began. The Nets retired his number 3 jersey on 11 November 1993. After 1994, the MVP award at the McDonald's Championship bore the name Dražen Petrović Trophy, and the Croatian Olympic Committee's award for young athletes was named for him in 2006. On 29 April 1995, a statue commemorating Petrović's significance to the world of sports was erected in front of the Olympic Museum in Lausanne, Switzerland, thus making him only the second athlete to receive this honor. On 9 July 2001, having defeated Patrick Rafter to win the men's singles title at Wimbledon, Croatian tennis player Goran Ivanišević dedicated the win to Petrović; Ivanišević wore Petrović's Nets jersey amidst the 100,000 strong crowd celebrating his victory in Split. Petrović was inducted posthumously into the Basketball Hall of Fame in 2002. In 2006, the 13th anniversary of Petrović's death was marked with the opening of the Dražen Petrović Memorial Center in Zagreb, dedicated to his life and achievements, with ten themed galleries of multimedia content outlining his entire career and a statue of Dražen in shooting position in front of it. Petrović was enshrined in the FIBA Hall of Fame in 2007.


title: Dražen Petrović

text: The 2010 documentary, "Once Brothers" (part of the ESPN "30 for 30" series), portrays the achievements of the Yugoslavia national basketball team in the late 1980s and early 1990s, and how the Yugoslav Wars tore the team apart. It explores Petrović's broken friendship with Serbian/Yugoslav player Vlade Divac. In 2011, a statue of him as a little boy sitting on a bench with a ball was unveiled in Šibenik, and his old room was renovated the way it looked when he was young, as a first part of opening a Memorial Center in his hometown. During the 2012 Three Point Shootout, New Jersey Nets guard Anthony Morrow wore Petrović's jersey in the latter's honor. In 2015, Australian writer Todd Spehr released a 470-page biography on Petrović, titled "Dražen: The Remarkable Life & Legacy of the Mozart of Basketball". On 3 June 2015, Croatian basketball journalists Marjan Crnogaj and Vlado Radicevic released a 487-page biography, the global paperback edition of which was released on 14 October 2017.


title: Dražen Petrović

text: A museum named "The Dražen Petrović Memorial Center" was founded in his honor, and constitutes a co-operative effort led by the Dražen Petrović Foundation in conjunction with the Croatian government, the city of Zagreb and the Croatian Museum of Sports. The memorial center idea originated from Petrović's parents, Biserka and Jole Petrovic, and was supported with the contributions of Croatian architects Andrija Rusan and Niksa Bilic. All of the articles presented in the center have been collected and categorized by the Croatian Museum of Sports. The organization and operations of the center have been provided by the Dražen Petrović Foundation, which is led by Petrović's family. The Center contains his No. 3 New Jersey Nets jersey and the watch that stopped when he died in a car crash. The center features 1,000 memorabilia items and a video of his basketball highlights.


title: Dražen Petrović

text: The official opening of the museum was held on 7 June 2006, while the official opening of the center to the public began at the end of December 2006. The square on which the center is operated upon has been renamed to "Dražen Petrović Square" in his honor. In 2013, former NBA MVP Derrick Rose visited the museum.


title: Hyperlink

text: In computing, a hyperlink, or simply a link, is a digital reference to data that the user can follow or be guided by clicking or tapping. A hyperlink points to a whole document or to a specific element within a document. Hypertext is text with hyperlinks. The text that is linked from is known as anchor text. A software system that is used for viewing and creating hypertext is a "hypertext system", and to create a hyperlink is "to hyperlink" (or simply "to link"). A user following hyperlinks is said to "navigate" or "browse" the hypertext.


title: Hyperlink

text: The document containing a hyperlink is known as its source document. For example, in an online reference work such as Wikipedia or Google, many words and terms in the text are hyperlinked to definitions of those terms. Hyperlinks are often used to implement reference mechanisms such as tables of contents, footnotes, bibliographies, indexes, letters, and glossaries.


title: Hyperlink

text: In some hypertext, hyperlinks can be bidirectional: they can be followed in two directions, so both ends act as anchors and as targets. More complex arrangements exist, such as many-to-many links.


title: Hyperlink

text: The effect of following a hyperlink may vary with the hypertext system and may sometimes depend on the link itself; for instance, on the World Wide Web most hyperlinks cause the target document to replace the document being displayed, but some are marked to cause the target document to open in a new window (or, perhaps, in a new tab). Another possibility is transclusion, for which the link target is a document fragment that replaces the link anchor within the source document. Not only persons browsing the document may follow hyperlinks. These hyperlinks may also be followed automatically by programs. A program that traverses the hypertext, following each hyperlink and gathering all the retrieved documents is known as a Web "spider" or crawler.


title: Hyperlink

text: An inline link displays remote content without the need for embedding the content. The remote content may be accessed with or without the user following the link.


title: Hyperlink

text: An inline link may display a modified version of the content; for instance, instead of an image, a thumbnail, low resolution preview, cropped section, or magnified section may be shown. The full content is then usually available on demand, as is the case with print publishing software e.g., with an external link. This allows for smaller file sizes and quicker response to changes when the full linked content is not needed, as is the case when rearranging a page layout.


title: Hyperlink

text: An anchor hyperlink (anchor link) is a link bound to a portion of a document, which is often called a fragment. The fragment is generally a portion of text or a heading, though not necessarily. For instance, it may also be a "hot area" in an image (image map in HTML), a designated, often irregular part of an image.


title: Hyperlink

text: Fragments are marked with "anchors" (in any of various ways), which is why a link to a fragment is called an anchor link (that is, a link to an anchor). For example, in XML, the element codice_1 provides anchoring capability (as long as the DTD or schema defines it), and in wiki markup, codice_2 is a typical example of implementing it. In word processor apps, anchors can be inserted where desired and may be called "bookmarks". In URLs, the hash character (#) precedes the name of the anchor for the fragment.


title: Hyperlink

text: One way to define a hot area in an image is by a list of coordinates that indicate its boundaries. For example, a political map of Africa may have each country hyperlinked to further information about that country. A separate invisible hot area interface allows for swapping skins or labels within the linked hot areas without repetitive embedding of links in the various skin elements.


title: Hyperlink

text: Bookmark hyperlink. Hyperlink is embedded into a text or an image and takes visitors to another part of a web page.


title: Hyperlink

text: E-mail hyperlink. Hyperlink is embedded into e-mail address and allows visitors to send an e-mail message to this e-mail address.


title: Hyperlink

text: A fat link (also known as a "one-to-many" link, an "extended link" or a "multi-tailed link") is a hyperlink which leads to multiple endpoints; the link is a multivalued function.


title: Hyperlink

text: Tim Berners-Lee saw the possibility of using hyperlinks to link any information to any other information over the Internet. Hyperlinks were therefore integral to the creation of the World Wide Web. Web pages are written in the hypertext mark-up language HTML.


title: Hyperlink

text: The W3C recommendation called XLink describes hyperlinks that offer a far greater degree of functionality than those offered in HTML. These extended links can be "multidirectional", remove linking from, within, and between XML documents. It can also describe "simple links", which are unidirectional and therefore offer no more functionality than hyperlinks in HTML.


title: Hyperlink

text: While wikis may use HTML-type hyperlinks, the use of wiki markup, a set of lightweight markup languages specifically for wikis, provides a simplified syntax for linking pages within wiki environments in other words, for creating wikilinks.


title: Hyperlink

text: The syntax and appearance of wikilinks may vary. Ward Cunningham's original wiki software, the WikiWikiWeb used CamelCase for this purpose. CamelCase was also used in the early version of Wikipedia and is still used in some wikis, such as TiddlyWiki, Trac, and PmWiki. A common markup syntax is the use of double square brackets around the term to be wikilinked. For example, the input "<nowiki>zebras</nowiki>" is converted by wiki software using this markup syntax to a link to a zebras article.


title: Hyperlink

text: Wikilinks are visibly distinct from other text, and if an internal wikilink leads to a page that does not yet exist, it usually has a different specific visual appearance. For example, in Wikipedia wikilinks are displayed in blue, except those that link to pages that don't yet exist, which are instead shown in red. Another possibility for linking is to display a highlighted clickable question mark after the wikilinked term.


title: Hyperlink

text: Hyperlinks are being implemented in various 3D virtual world networks, including those that use the OpenSimulator and Open Cobalt platforms.


title: Hyperlink

text: Permalinks are URLs that are intended to remain unchanged for many years into the future, yielding hyperlinks that are less susceptible to link rot. Permalinks are often rendered simply, that is, as friendly URLs, so as to be easy for people to type and remember. Permalinks are used in order to point and redirect readers to the same Web page, blog post or any online digital media.


title: Hyperlink

text: The scientific literature is a place where link persistence is crucial to the public knowledge. A 2013 study in BMC Bioinformatics analyzed 15,000 links in abstracts from Thomson Reuters’ Web of Science citation index, founding that the median lifespan of Web pages was 9.3 years, and just 62% were archived. The median lifespan of a Web page constitutes high-degree variable, but its order of magnitude usually is of some months.


title: Hyperlink

text: A link from one domain to another is said to be "outbound" from its source anchor and "inbound" to its target.


title: Hyperlink

text: The most common destination anchor is a URL used in the World Wide Web. This can refer to a document, e.g. a webpage, or other resource, or to a position in a webpage. The latter is achieved by means of an HTML element with a "name" or "id" attribute at that position of the HTML document. The URL of the position is the URL of the webpage with a fragment identifier "#"id attribute"" appended.


title: Hyperlink

text: When linking to PDF documents from an HTML page the ""id attribute"" can be replaced with syntax that references a page number or another element of the PDF, for example, "#"page=386"".


title: Hyperlink

text: A web browser usually displays a hyperlink in some distinguishing way, e.g. in a different color, font or style, or with certain symbols following to visualize link target or document types. This is also called "link decoration". The behavior and style of links can be specified using the Cascading Style Sheets (CSS) language.


title: Hyperlink

text: In a graphical user interface, the appearance of a mouse cursor may change into a hand motif to indicate a link. In most graphical web browsers, links are displayed in underlined blue text when they have not been visited, but underlined purple text when they have. When the user activates the link (e.g., by clicking on it with the mouse) the browser displays the link's target. If the target is not an HTML file, depending on the file type and on the browser and its plugins, another program may be activated to open the file.


title: Hyperlink

text: It uses the HTML element "a" with the attribute "href" (HREF is an abbreviation for "Hypertext REFerence") and optionally also the attributes "title", "target", and "class" or "id":


title: Hyperlink

text: In a typical web browser, this would display as the underlined word "Example" in blue, which when clicked would take the user to the example.com website. This contributes to a clean, easy to read text or document.


title: Hyperlink

text: When the cursor hovers over a link, depending on the browser and graphical user interface, some informative text about the link can be shown, popping up, not in a regular window, but in a special hover box, which disappears when the cursor is moved away (sometimes it disappears anyway after a few seconds, and reappears when the cursor is moved away and back). Mozilla Firefox, IE, Opera, and many other web browsers all show the URL. In addition, the URL is commonly shown in the status bar.


title: Hyperlink

text: Normally, a link opens in the current frame or window, but sites that use frames and multiple windows for navigation can add a special "target" attribute to specify where the link loads. If no window exists with that name, a new window is created with the ID, which can be used to refer to the window later in the browsing session.


title: Hyperlink

text: Creation of new windows is probably the most common use of the "target" attribute. To prevent accidental reuse of a window, the special window names "_blank" and "_new" are usually available, and always cause a new window to be created. It is especially common to see this type of link when one large website links to an external page. The intention in that case is to ensure that the person browsing is aware that there is no endorsement of the site being linked to by the site that was linked from. However, the attribute is sometimes overused and can sometimes cause many windows to be created even while browsing a single site.


title: Hyperlink

text: Another special page name is "_top", which causes any frames in the current window to be cleared away so that browsing can continue in the full window.


title: Hyperlink

text: The term "link" was coined in 1965 (or possibly 1964) by Ted Nelson at the start of Project Xanadu. Nelson had been inspired by "As We May Think", a popular 1945 essay by Vannevar Bush. In the essay, Bush described a microfilm-based machine (the Memex) in which one could link any two pages of information into a "trail" of related information, and then scroll back and forth among pages in a trail as if they were on a single microfilm reel.


title: Hyperlink

text: In a series of books and articles published from 1964 through 1980, Nelson transposed Bush's concept of automated cross-referencing into the computer context, made it applicable to specific text strings rather than whole pages, generalized it from a local desk-sized machine to a theoretical proprietary worldwide computer network, and advocated the creation of such a network. Though Nelson's Xanadu Corporation was eventually funded by Autodesk in the 1980s, it never created this proprietary public-access network. Meanwhile, working independently, a team led by Douglas Engelbart (with Jeff Rulifson as chief programmer) was the first to implement the hyperlink concept for scrolling within a single document (1966), and soon after for connecting between paragraphs within separate documents (1968), with NLS. Ben Shneiderman working with graduate student Dan Ostroff designed and implemented the highlighted link in the HyperTIES system in 1983. HyperTIES was used to produce the world's first electronic journal, the July 1988 Communications of ACM, which was cited as the source for the link concept in Tim Berners-Lee's Spring 1989 manifesto for the Web. In 1988, Ben Shneiderman and Greg Kearsley used HyperTIES to publish "Hypertext Hands-On!", the world's first electronic book.


title: Hyperlink

text: Released in 1987 for the Apple Macintosh, the database program HyperCard allowed for hyperlinking between various pages within a document, as well as to other documents and separate applications on the same computer. In 1990, Windows Help, which was introduced with Microsoft Windows 3.0, had widespread use of hyperlinks to link different pages in a single help file together; in addition, it had a visually different kind of hyperlink that caused a popup help message to appear when clicked, usually to give definitions of terms introduced on the help page. The first widely used open protocol that included hyperlinks from any Internet site to any other Internet site was the Gopher protocol from 1991. It was soon eclipsed by HTML after the 1993 release of the Mosaic browser (which could handle Gopher links as well as HTML links). HTML's advantage was the ability to mix graphics, text, and hyperlinks, unlike Gopher, which just had menu-structured text and hyperlinks.


title: Hyperlink

text: While hyperlinking among webpages is an intrinsic feature of the web, some websites object to being linked by other websites; some have claimed that linking to them is not allowed without permission.


title: Hyperlink

text: Contentious in particular are deep links, which do not point to a site's home page or other entry point designated by the site owner, but to content elsewhere, allowing the user to bypass the site's own designated flow, and "inline links", which incorporate the content in question into the pages of the linking site, making it seem part of the linking site's own content unless an explicit attribution is added.


title: Hyperlink

text: In certain jurisdictions, it is or has been held that hyperlinks are not merely references or citations, but are devices for copying web pages. In the Netherlands, Karin Spaink was initially convicted in this way of copyright infringement by linking, although this ruling was overturned in 2003. The courts that advocate this view see the mere publication of a hyperlink that connects to illegal material to be an illegal act in itself, regardless of whether referencing illegal material is illegal. In 2004, Josephine Ho was acquitted of 'hyperlinks that corrupt traditional values' in Taiwan.


title: Hyperlink

text: In 2000, British Telecom sued Prodigy, claiming that Prodigy infringed its patent () on web hyperlinks. After litigation, a court found for Prodigy, ruling that British Telecom's patent did not cover web hyperlinks.


title: Hyperlink

text: In United States "jurisprudence", there is a distinction between the mere act of linking to someone else's website, and linking to content that is illegal (e.g., gambling illegal in the US) or infringing (e.g., illegal MP3 copies). Several courts have found that merely linking to someone else's website, even if by bypassing commercial advertising, is not copyright or trademark infringement, regardless of how much someone else might object. Linking to illegal or infringing content can be sufficiently problematic to give rise to legal liability. Compare for a summary of the current status of US copyright law as to hyperlinking, see the discussion regarding the "Arriba Soft" and "Perfect 10" cases.


title: Hyperlink

text: Somewhat controversially, Vuestar Technologies has tried to enforce patents applied for by its owner, Ronald Neville Langford, around the world relating to search techniques using hyperlinked images to other websites or web pages.


title: Antidepressant

text: Antidepressants are a class of medication used to treat major depressive disorder, anxiety disorders, chronic pain conditions and to help manage addictions. Common side-effects of antidepressants include dry mouth, weight gain, dizziness, headaches, sexual dysfunction, and emotional blunting. There is a slight increased risk of suicidal thinking and behavior when taken by children, adolescents, and young adults. Discontinuation syndrome may occur after stopping any antidepressant which resembles recurrent depression.


title: Antidepressant

text: Some research regarding the effectiveness of antidepressants for depression in adults has found benefits, whilst other research has not. Evidence of benefit in children and adolescents is unclear. The twenty-one most commonly prescribed antidepressant medications are more effective than placebo for the short-term (acute) treatments of adults with major depressive disorder. There is debate in the medical community about how much of the observed effects of antidepressants can be attributed to the placebo effect, with some claiming that there is no effect above and beyond it. Research about the work effectiveness of antidepressants drugs is done on people that have very severe symptoms. This population exhibits much weaker placebo responses, meaning that the result cannot be extrapolated to the general population.


title: Antidepressant

text: There are also several other effective treatments for depression which do not involve medications, or may be used in conjunction with medications.


title: Antidepressant

text: Antidepressants are prescribed to treat major depressive disorder (MDD), anxiety disorders, chronic pain, and some addictions. Antidepressants are often used in combinations with one another.


title: Antidepressant

text: The proponents of the monoamine hypothesis of depression recommend choosing the antidepressant with the mechanism of action impacting the most prominent symptoms—for example, they advocate that people with MDD who are also anxious or irritable should be treated with SSRIs or norepinephrine reuptake inhibitors, while people suffering from a loss of energy and enjoyment of life should take with norepinephrine and dopamine enhancing drugs.


title: Antidepressant

text: The UK National Institute for Health and Care Excellence (NICE) 2009 guidelines indicate that antidepressants should not be routinely used for the initial treatment of mild depression. This is due to the risk to benefit ratio being deemed as poor. The guidelines recommended that antidepressant treatment be considered for the following:


title: Antidepressant

text: The guidelines further note that in most cases, antidepressant treatment should be used in combination with psychosocial interventions, should be continued for at least six months to reduce the risk of relapse, and that selective serotonin reuptake inhibitor (SSRIs) are typically better tolerated than other antidepressants.


title: Antidepressant

text: American Psychiatric Association treatment guidelines recommend that initial treatment be individually tailored based on certain factors including severity of symptoms, co-existing disorders, prior treatment experience, and the person's preference. Options may include pharmacotherapy, psychotherapy, electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS) or light therapy. They recommended antidepressant medication as an initial treatment choice in people with mild, moderate, or severe major depression, that should be given to all people with severe depression unless ECT is planned.


title: Antidepressant

text: Reviews of antidepressants generally find that they benefit adults with depression. On the other hand, some contend that most studies on antidepressant medication are confounded by several biases: the lack of an active placebo, which means that many people in the placebo arm of a double-blind study may figure out that they are not getting any true treatment, thus destroying double-blindness; a short follow up after termination of treatment; non-systematic recording of adverse effects; very strict exclusion criteria in samples of patients; studies being paid for by the industry; selective publication of results. This means that the small beneficial effects that are found may not be statistically significant.


title: Antidepressant

text: Among the twenty-one most commonly prescribed antidepressants, the most effective and well-tolerated seem to be Escitalopram, Paroxetine, Sertraline, Agomelatine, and Mirtazapine. As for children and adolescents with moderate-to-severe depressive disorder, Fluoxetine seems to be the best treatment (either with or without cognitive behavioural therapy) but more research is needed to be certain. Sertraline, Escitalopram, and Duloxetine might also help in reducing symptoms.


title: Antidepressant

text: For children and adolescents, Fluvoxamine is effective in treating a range of anxiety disorders. Fluoxetine, Sertraline and Paroxetine can also help with managing various forms of anxiety in children and adolescents.


title: Antidepressant

text: Antidepressants are recommended by the National Institute for Health and Care Excellence (NICE) for the treatment of generalized anxiety disorder (GAD) that has failed to respond to conservative measures such as education and self-help activities. GAD is a common disorder of which the central feature is excessively worrying about a number of different events. Key symptoms include excessive anxiety about multiple events and issues, and difficulty controlling worrisome thoughts that persists for at least 6 months.


title: Antidepressant

text: Antidepressants provide a modest-to-moderate reduction in anxiety in GAD. The efficacy of different antidepressants is similar.


title: Antidepressant

text: Some antidepressants are used as a treatment for social anxiety disorder, but their efficacy is not entirely convincing, as only a small proportion of antidepressants showed some efficacy for this condition. Paroxetine was the first drug to be FDA-approved for this disorder. Its efficacy is considered beneficial, although not everyone responds favorably to the drug. Sertraline and Fluvoxamine extended release were later approved for it as well, while Escitalopram is used off-label with acceptable efficacy. However, there isn't enough evidence to support Citalopram for treating social anxiety disorder, and Fluoxetine was no better than a placebo in clinical trials. SSRIs are used as a first-line treatment for social anxiety, but they don't work for everyone. One alternative would be Venlafaxine, which is a SNRI. It showed benefits for social phobia in five clinical trials against placebo, while the other SNRIs are not considered particularly useful for this disorder as many of them didn't undergo testing for it. , it is unclear if Duloxetine and Desvenlafaxine can provide benefits for people with social anxiety. However, another class of antidepressants called MAOIs are considered effective for social anxiety, but they come with many unwanted side effects and are rarely used. Phenelzine was shown to be a good treatment option, but its use is limited by dietary restrictions. Moclobemide is a RIMA and showed mixed results, but still received approval in some European countries for social anxiety disorder. TCA antidepressants, such as Clomipramine and Imipramine, are not considered effective for this anxiety disorder in particular. This leaves out SSRIs such as Paroxetine, Sertraline and Fluvoxamine CR as acceptable and tolerated treatment options for this disorder.


title: Antidepressant

text: SSRIs are a second-line treatment of adult obsessive–compulsive disorder (OCD) with mild functional impairment, and as first-line treatment for those with moderate or severe impairment.


title: Antidepressant

text: In children, SSRIs are considered as a second-line therapy in those with moderate-to-severe impairment, with close monitoring for psychiatric adverse effects. Sertraline and Fluoxetine are effective in treating OCD for children and adolescents.


title: Antidepressant

text: Clomipramine, a TCA drug, is considered effective and useful for OCD. However, it is used as a second-line treatment because it is less well-tolerated than the SSRIs. Despite this, it has not shown superiority to Fluvoxamine in trials. All SSRIs can be used effectively for OCD. SNRI use may also be attempted, though no SNRIs have been approved for treatment of OCD. Despite these treatment options, many patients remain symptomatic after initiating the medication, and less than half achieve remission.


title: Antidepressant

text: Antidepressants are one of the treatment options for PTSD. However, their efficacy is not well established. Paroxetine and Sertraline, both of the SSRI class, have been FDA approved for the treatment of PTSD. Paroxetine has slightly higher response and remission rates than sertraline for this condition. However, neither drug is considered very helpful for a broad patient demographic. Fluoxetine and Venlafaxine are used off-label. Fluoxetine has produced unsatisfactory mixed results. Venlafaxine showed response rates of 78%, which is significantly higher than what paroxetine and sertraline achieved. However, it did not address as many symptoms of PTSD as Paroxetine and Sertraline, in part due to the fact the Venlafaxine is an SNRI. This class of drugs inhibits the reuptake of Norepinephrine, which may cause anxiety in some patients. Fluvoxamine, Escitalopram and Citalopram were not well tested in this disorder. MAOIs, while some of them may be helpful, are not used much because of their unwanted side effects. This leaves paroxetine and sertraline as acceptable treatment options for some people, although more effective antidepressants are needed.


title: Antidepressant

text: Panic disorder is treated relatively well with medications compared to other disorders. Several classes of antidepressants have shown efficacy for this disorder, with SSRIs and SNRIs used first-line. Paroxetine, Sertraline, Fluoxetine are FDA approved for panic disorder, while fluvoxamine, escitalopram and citalopram are also considered effective for it. The SNRI venlafaxine is also approved for this condition. Unlike with social anxiety and PTSD, some TCAs antidepressants, like Clomipramine and Imipramine have shown efficacy for panic disorder. Moreover, the MAOI Phenelzine is also considered useful. Panic disorder has many drugs for its treatment. However, the starting dose must be lower than the one used for major depressive disorder because people have reported an increase in anxiety as a result of starting the medication. In conclusion, while panic disorder's treatment options seem acceptable and useful for this condition, many people are still symptomatic after treatment with residual symptoms.


title: Antidepressant

text: Antidepressants are recommended as an alternative or additional first step to self-help programs in the treatment of bulimia nervosa. SSRIs (fluoxetine in particular) are preferred over other antidepressants due to their acceptability, tolerability, and superior reduction of symptoms in short-term trials. Long-term efficacy remains poorly characterized. Bupropion is not recommended for the treatment of eating disorders, due to an increased risk of seizure.


title: Antidepressant

text: Similar recommendations apply to binge eating disorder. SSRIs provide short-term reductions in binge eating behavior, but have not been associated with significant weight loss.


title: Antidepressant

text: Clinical trials have generated mostly negative results for the use of SSRIs in the treatment of anorexia nervosa. Treatment guidelines from the National Institute of Health and Care Excellence (NICE) recommend against the use of SSRIs in this disorder. Those from the American Psychiatric Association (APA) note that SSRIs confer no advantage regarding weight gain, but may be used for the treatment of co-existing depressive, anxiety, or obsessive–compulsive disorders.


title: Antidepressant

text: A 2012 meta-analysis concluded that antidepressants treatment favorably affects pain, health-related quality of life, depression, and sleep in fibromyalgia syndrome. Tricyclics appear to be the most effective class, with moderate effects on pain and sleep, and small effects on fatigue and health-related quality of life. The fraction of people experiencing a 30% pain reduction on tricyclics was 48%, versus 28% on placebo. For SSRIs and SNRIs, the fractions of people experiencing a 30% pain reduction were 36% (20% in the placebo comparator arms) and 42% (32% in the corresponding placebo comparator arms) respectively. Discontinuation of treatment due to side effects was common. Antidepressants including Amitriptyline, Fluoxetine, Duloxetine, Milnacipran, Moclobemide, and Pirlindole are recommended by the European League Against Rheumatism (EULAR) for the treatment of fibromyalgia based on "limited evidence".


title: Antidepressant

text: A 2014 meta-analysis from the Cochrane Collaboration found the antidepressant Duloxetine to be effective for the treatment of pain resulting from diabetic neuropathy. The same group reviewed data for Amitriptyline in the treatment of neuropathic pain and found limited useful randomized clinical trial data. They concluded that the long history of successful use in the community for the treatment of fibromyalgia and neuropathic pain justified its continued use. The group was concerned about the potential overestimation for the amount of pain relief provided by amitriptyline, and highlighted that only a small number of people will experience significant pain relief by taking this medication.


title: Antidepressant

text: Antidepressants may be modestly helpful for treating people who have both depression and alcohol dependence, however the evidence supporting this association is of low quality. Bupropion is used to help people stop smoking. Antidepressants are also used to control some symptoms of narcolepsy. Antidepressants may be used to relieve pain in people with active rheumatoid arthritis. However, further research is required. Antidepressants have been shown to be superior to placebo in treating depression in individuals with physical illness, although reporting bias may have exaggerated this finding.


title: Antidepressant

text: Among individuals treated with a given antidepressant, between 30% and 50% do not show response. Approximately one-third of people achieve a full remission, one-third experience a response, and one-third are nonresponders. Partial remission is characterized by the presence of poorly defined residual symptoms. These symptoms typically include depressed mood, anxiety, sleep disturbance, fatigue, and diminished interest or pleasure. It is currently unclear which factors predict partial remission. However, it is clear that residual symptoms are powerful predictors of relapse, with relapse rates three to six times higher in people with residual symptoms than in those who experience full remission. In addition, antidepressant drugs tend to lose efficacy over the course of treatment. According to data from the Centers for Disease Control and Prevention, less than one-third of Americans taking one antidepressant medication have seen a mental health professional in the previous year. A number of strategies are used in clinical practice to try to overcome these limits and variations. They include switching medication, augmentation, and combination.


title: Antidepressant

text: The American Psychiatric Association 2000 Practice Guideline advises that where no response is achieved within the following six to eight weeks of treatment with an antidepressant, switch to an antidepressant in the same class, and then to a different class. A 2006 meta-analysis review found wide variation in the findings of prior studies: for people who had failed to respond to an SSRI antidepressant, between 12% and 86% showed a response to a new drug. However, the more antidepressants an individual had previously tried, the less likely they were to benefit from a new antidepressant trial. However, a later meta-analysis found no difference between switching to a new drug and staying on the old medication: although 34% of treatment-resistant people responded when switched to the new drug, 40% responded without being switched.


title: Antidepressant

text: For a partial response, the American Psychiatric Association (APA) guidelines suggest augmentation, or adding a drug from a different class. These include lithium and thyroid augmentation, dopamine agonists, sex steroids, NRIs, glucocorticoid-specific agents, or the newer anticonvulsants.


title: Antidepressant

text: A combination strategy involves adding another antidepressant, usually from a different class so as to have effect on other mechanisms. Although this may be used in clinical practice, there is little evidence for the relative efficacy or adverse effects of this strategy. Other tests conducted include the use of psychostimulants as an augmentation therapy. Several studies have shown the efficacy of combining modafinil for treatment-resistant people. It has been used to help combat SSRI-associated fatigue.


title: Antidepressant

text: The effects of antidepressants typically do not continue once the course of medication ends. This results in a high rate of relapse. In 2003, a meta-analysis found that 18% of people who had responded to an antidepressant relapsed while still taking it, compared to 41% whose antidepressant was switched for a placebo.


title: Antidepressant

text: A gradual loss of therapeutic benefit occurs in a minority of people during the course of treatment. A strategy involving the use of pharmacotherapy in the treatment of the acute episode, followed by psychotherapy in its residual phase, has been suggested by some studies. For patients who wish to stop their antidepressants, engaging in brief psychological interventions such as Preventive Cognitive Therapy or Mindfulness-based Cognitive Therapy while tapering down has been found to diminish the risk for relapse.


title: Antidepressant

text: Antidepressants can cause various adverse effects, depending on the individual and the drug in question.


title: Antidepressant

text: Almost any medication involved with serotonin regulation has the potential to cause serotonin toxicity (also known as "serotonin syndrome") — an excess of serotonin that can induce mania, restlessness, agitation, emotional lability, insomnia and confusion as its primary symptoms. Although the condition is serious, it is not particularly common, generally only appearing at high doses or while on other medications. Assuming proper medical intervention has been taken (within about 24 hours) it is rarely fatal. Antidepressants appear to increase the risk of diabetes by about 1.3 fold.


title: Antidepressant

text: MAOIs tend to have pronounced (sometimes fatal) interactions with a wide variety of medications and over-the-counter drugs. If taken with foods that contain very high levels of tyramine (e.g., mature cheese, cured meats, or yeast extracts), they may cause a potentially lethal hypertensive crisis. At lower doses, the person may only experience a headache due to an increase in blood pressure.


title: Antidepressant

text: In response to these adverse effects, a different type of MAOI has been developed: the reversible inhibitor of monoamine oxidase A (RIMA) class of drugs. Their primary advantage is that they do not require the person to follow a special diet, while being purportedly effective as SSRIs and tricyclics in treating depressive disorders.


title: Antidepressant

text: Tricyclics and SSRI can cause the so-called drug-induced QT prolongation, especially in older adults; this condition can degenerate into a specific type of abnormal heart rhythm called torsades de points which can potentially lead to sudden cardiac arrest.


title: Antidepressant

text: SSRI use in pregnancy has been associated with a variety of risks with varying degrees of proof of causation. As depression is independently associated with negative pregnancy outcomes, determining the extent to which observed associations between antidepressant use and specific adverse outcomes reflects a causative relationship has been difficult in some cases. In other cases, the attribution of adverse outcomes to antidepressant exposure seems fairly clear.


title: Antidepressant

text: SSRI use in pregnancy is associated with an increased risk of spontaneous abortion of about 1.7-fold, and is associated with preterm birth and low birth weight.


title: Antidepressant

text: A systematic review of the risk of major birth defects in antidepressant-exposed pregnancies found a small increase (3% to 24%) in the risk of major malformations and a risk of cardiovascular birth defects that did not differ from non-exposed pregnancies. A study of fluoxetine-exposed pregnancies found a 12% increase in the risk of major malformations that did not reach statistical significance. Other studies have found an increased risk of cardiovascular birth defects among depressed mothers not undergoing SSRI treatment, suggesting the possibility of ascertainment bias, e.g. that worried mothers may pursue more aggressive testing of their infants. Another study found no increase in cardiovascular birth defects and a 27% increased risk of major malformations in SSRI exposed pregnancies. The FDA advises for the risk of birth defects with the use of paroxetine and the MAOI should be avoided.


title: Antidepressant

text: A 2013 systematic review and meta-analysis found that antidepressant use during pregnancy was statistically significantly associated with some pregnancy outcomes, such as gestational age and preterm birth, but not with other outcomes. The same review cautioned that because differences between the exposed and unexposed groups were small, it was doubtful whether they were clinically significant.


title: Antidepressant

text: A neonate (infant less than 28 days old) may experience a withdrawal syndrome from abrupt discontinuation of the antidepressant at birth. Antidepressants have been shown to be present in varying amounts in breast milk, but their effects on infants are currently unknown.


title: Antidepressant

text: Moreover, SSRIs inhibit nitric oxide synthesis, which plays an important role in setting vascular tone. Several studies have pointed to an increased risk of prematurity associated with SSRI use, and this association may be due to an increase risk of pre-eclampsia of pregnancy.


title: Antidepressant

text: Another possible problem with antidepressants is the chance of antidepressant-induced mania or hypomania in people with or without a diagnosis of bipolar disorder. Many cases of bipolar depression are very similar to those of unipolar depression. Therefore, the person can be misdiagnosed with unipolar depression and be given antidepressants. Studies have shown that antidepressant-induced mania can occur in 20–40% of people with bipolar disorder. For bipolar depression, antidepressants (most frequently SSRIs) can exacerbate or trigger symptoms of hypomania and mania.


title: Antidepressant

text: Studies have shown that the use of antidepressants is correlated with an increased risk of suicidal behavior and thinking (suicidality) in those aged under 25 years old. This problem has been serious enough to warrant government intervention by the US Food and Drug Administration (FDA) to warn of the increased risk of suicidality during antidepressant treatment. According to the FDA, the heightened risk of suicidality occurs within the first one to two months of treatment. The National Institute for Health and Care Excellence (NICE) places the excess risk in the "early stages of treatment". A meta-analysis suggests that the relationship between antidepressant use and suicidal behavior or thoughts is age-dependent. Compared with placebo, the use of antidepressants is associated with an increase in suicidal behavior or thoughts among those 25 years old or younger (OR=1.62). A review of RCTs and epidemiological studies by Healy and Whitaker found an increase of suicidal acts by a factor of 2.4. There is no effect or possibly a mild protective effect among those aged 25 to 64 (OR=0.79). Antidepressant treatment has a protective effect against suicidality among those aged 65 and over (OR=0.37).


title: Antidepressant

text: Sexual side effects are also common with SSRIs, such as loss of sexual drive, failure to reach orgasm, and erectile dysfunction. Although usually reversible, these sexual side-effects can, in rare cases, continue after the drug has been completely withdrawn.


title: Antidepressant

text: In a study of 1,022 outpatients, overall sexual dysfunction with all antidepressants averaged 59.1% with SSRI values between 57% and 73%, Mirtazapine 24%, Nefazodone 8%, Amineptine 7% and Moclobemide 4%. Moclobemide, a selective reversible MAO-A inhibitor, does not cause sexual dysfunction, and can actually lead to an improvement in all aspects of sexual function.


title: Antidepressant

text: Biochemical mechanisms suggested as causative include increased serotonin, particularly affecting 5-HT and 5-HT receptors; decreased dopamine; decreased norepinephrine; blockade of cholinergic and αadrenergic receptors; inhibition of nitric oxide synthetase; and elevation of prolactin levels. Mirtazapine is reported to have fewer sexual side effects, most likely because it antagonizes 5-HT and 5-HT receptors and may, in some cases, reverse sexual dysfunction induced by SSRIs by the same mechanism.


title: Antidepressant

text: Bupropion, a weak NDRI and nicotinic antagonist, may be useful in treating reduced libido as a result of SSRI treatment.


title: Antidepressant

text: Certain antidepressants may cause emotional blunting, characterized by reduced intensity of both positive and negative emotions as well as symptoms of apathy, indifference, and amotivation. It may be experienced as either beneficial or detrimental depending on the situation. This side effect has been particularly associated with serotonergic antidepressants like SSRIs and SNRIs, but may be less with atypical antidepressants like Bupropion, Agomelatine, and Vortioxetine. Higher doses of antidepressants seem to be more likely to produce emotional blunting than lower doses. It can be decreased by reducing dosage, discontinuing the medication, or switching to a different antidepressant that may have less propensity for causing this side effect.


title: Antidepressant

text: Changes in appetite or weight are common among antidepressants, but are largely drug-dependent and related to which neurotransmitters they affect. Mirtazapine and paroxetine, for example, may be associated with weight gain and/or increased appetite, while others (such as bupropion and venlafaxine) achieve the opposite effect.


title: Antidepressant

text: The antihistaminic properties of certain TCA- and TeCA-class antidepressants have been shown to contribute to the common side effects of increased appetite and weight gain associated with these classes of medication.


title: Antidepressant

text: A 2017 meta-analysis found that antidepressants were associated with significantly increased risk of death (+33%) and new cardiovascular complications (+14%) in the general population. Conversely, risks were not greater in people with existing cardiovascular disease.


title: Antidepressant

text: Antidepressant discontinuation syndrome, also called antidepressant withdrawal syndrome, is a condition that can occur following the interruption, reduction, or discontinuation of antidepressant medication. The symptoms may include flu-like symptoms, trouble sleeping, nausea, poor balance, sensory changes, and anxiety. The problem usually begins within three days and may last for several months. Rarely psychosis may occur.


title: Antidepressant

text: A discontinuation syndrome can occur after stopping any antidepressant including selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants (TCAs). The risk is greater among those who have taken the medication for longer and when the medication in question has a short half-life. The underlying reason for its occurrence is unclear. The diagnosis is based on the symptoms.


title: Antidepressant

text: Methods of prevention include gradually decreasing the dose among those who wish to stop, though it is possible for symptoms to occur with tapering. Treatment may include restarting the medication and slowly decreasing the dose. People may also be switched to the long acting antidepressant fluoxetine which can then be gradually decreased.


title: Antidepressant

text: Approximately 20–50% of people who suddenly stop an antidepressant develop an antidepressant discontinuation syndrome. The condition is generally not serious. Though about half of people with symptoms describe them as severe. Some restart antidepressants due to the severity of the symptoms.


title: Antidepressant

text: Antidepressants act via a large number of different mechanisms of action. This includes serotonin reuptake inhibition (SSRIs, SNRIs, TCAs, Vilazodone, Vortioxetine), Norepinephrine reuptake inhibition (NRIs, SNRIs, TCAs), dopamine reuptake inhibition (Bupropion, Amineptine, Nomifensine), direct modulation of Monoamine receptors (Vilazodone, Vortioxetine, SARIs, Agomelatine, TCAs, TeCAs, Antipsychotics), Monoamine oxidase inhibition (MAOIs), and NMDA receptor antagonism (Ketamine, Esketamine, Dextromethorphan), among others (e.g., Brexanolone, Tianeptine). Some antidepressants also have additional actions, like sigma receptor modulation (certain SSRIs, TCAs, dextromethorphan) and antagonism of histamine H and muscarinic acetylcholine receptors (TCAs, TeCAs).


title: Antidepressant

text: The earliest and most widely known scientific theory of antidepressant action is the monoamine hypothesis, which can be traced back to the 1950s and 1960s. This theory states that depression is due to an imbalance, most often a deficiency, of the monoamine neurotransmitters, namely serotonin, norepinephrine, and/or dopamine. However, serotonin in particular has been implicated, as in the serotonin hypothesis of depression. The monoamine hypothesis was originally proposed based on observations that Reserpine, a drug which depletes the monoamine neurotransmitters, produced depressive effects in people, and that certain Hydrazine antituberculosis agents like Iproniazid, which prevent the breakdown of monoamine neurotransmitters, produced apparent antidepressant effects. Most currently marketed antidepressants, which are monoaminergic in their actions, are theoretically consistent with the monoamine hypothesis. Despite the widespread nature of the monoamine hypothesis, it has a number of limitations: for one, all monoaminergic antidepressants have a delayed onset of action of at least a week; and secondly, many people with depression do not respond to monoaminergic antidepressants. A number of alternative hypotheses have been proposed, including hypotheses involving Glutamate, Neurogenesis, Epigenetics, Cortisol Hypersecretion, and Inflammation, among others.


title: Antidepressant

text: In 2022, a major systematic umbrella review by Joanna Moncrieff and colleagues showed that the serotonin theory of depression was not supported by the evidence from a wide variety of areas. The authors concluded that there is no association between serotonin and depression, and that there is no evidence that strongly supports the theory that depression is caused by low serotonin activity or concentrations. Other literature had described the lack of support for the theory previously. In many of the expert responses to the review, it was stated that the monoamine hypothesis had long already been abandoned by psychiatry. This is in spite of about 90% of the general public in Western countries believing the theory to be true and many in the field of psychiatry continuing to promote the theory up to recent times. In addition to this review, a 2003 literature review and a 2022 systematic review, both of reserpine and mood, found that in fact there is no consistent evidence that reserpine produces depressive effects. Instead, the results were highly mixed, with similar proportions of studies finding that reserpine had no influence on mood, produced depressogenic effects, or had antidepressant effects. In relation to this, the general monoamine hypothesis, as opposed to just the serotonin theory of depression, is likewise not well-supported by evidence.


title: Antidepressant

text: The serotonin and monoamine hypotheses of depression have been heavily promoted by the pharmaceutical industry (e.g., in advertisements) and by the psychiatric profession at large despite the lack of evidence in support of them. In the case of the pharmaceutical industry, this can be attributed to obvious financial incentives, with the theory creating bias against non-pharmacological treatments for depression.


title: Antidepressant

text: An alternative theory for antidepressant action proposed by certain academics such as Irving Kirsch is that they work largely or entirely via placebo mechanisms. This is supported by meta-analyses of antidepressant randomized controlled trials, which consistently show that placebo groups in trials improve about 80 to 90% as much as antidepressant groups on average and that antidepressants are only marginally more effective for depression than placebos. The difference between antidepressants and placebo corresponds to an effect size (SMD) of about 0.3, which in turn equates to about a 2- to 3-point additional improvement on the 0–52-point (HRSD) and 0–60-point (MADRS) depression rating scales used in trials. This small advantage of antidepressants over placebo is often statistically significant and is the basis for their regulatory approval, but is sufficiently modest that its clinical significance is doubtful. Moreover, the small advantage of antidepressants over placebo may simply be a methodological artifact caused by unblinding due to the psychoactive effects and side effects of antidepressants, in turn resulting in enhanced placebo effects and apparent antidepressant efficacy. Placebos are not purely psychological phenomenon, but have been found to modify the activity of several brain regions and to increase levels of dopamine and endogenous opioids in the reward pathways. It has been argued by Kirsch that although antidepressants may be used efficaciously for depression as active placebos, they are limited by significant pharmacological side effects and risks, and therefore non-pharmacological therapies, such as psychotherapy and lifestyle changes, which can have similar efficacy to antidepressants but do not have their adverse effects, ought to be preferred as treatments in people with depression.


title: Antidepressant

text: The placebo response, or the improvement in scores in the placebo group in clinical trials, is not only due to the placebo effect, but is also due to other phenomena such as spontaneous remission and regression to the mean. Depression tends to have an episodic course, with people eventually recovering even with no medical intervention, and people tend to seek treatment, as well as enroll in clinical trials, when they are feeling their worst. In meta-analyses of trials of depression therapies, Kirsch estimated based on improvement in untreated waiting-list controls that spontaneous remission and regression to the mean only account for about 25% of the improvement in depression scores with antidepressant therapy. However, another academic, Michael P. Hengartner, has argued and presented evidence that spontaneous remission and regression to the mean might actually account for most of the improvement in depression scores with antidepressants, and that the substantial placebo effect observed in clinical trials might largely be a methodological artifact. This suggests that antidepressants may be associated with much less genuine treatment benefit, whether due to the placebo effect or to the antidepressant itself, than has been traditionally assumed.


title: Antidepressant

text: Selective serotonin reuptake inhibitors (SSRIs) are believed to increase the extracellular level of the neurotransmitter serotonin by limiting its reabsorption into the presynaptic cell, increasing the level of serotonin in the synaptic cleft available to bind to the postsynaptic receptor. They have varying degrees of selectivity for the other monoamine transporters, with pure SSRIs having only weak affinity for the norepinephrine and dopamine transporters.


title: Antidepressant

text: SSRIs are the most widely prescribed antidepressants in many countries. The efficacy of SSRIs in mild or moderate cases of depression has been disputed.


title: Antidepressant

text: Serotonin–norepinephrine reuptake inhibitors (SNRIs) are potent inhibitors of the reuptake of serotonin and norepinephrine. These neurotransmitters are known to play an important role in mood. SNRIs can be contrasted with the more widely used selective serotonin reuptake inhibitors (SSRIs), which act mostly upon serotonin alone.


title: Antidepressant

text: The human serotonin transporter (SERT) and norepinephrine transporter (NET) are membrane proteins that are responsible for the reuptake of serotonin and norepinephrine. Balanced dual inhibition of monoamine reuptake can possibly offer advantages over other antidepressants drugs by treating a wider range of symptoms.


title: Antidepressant

text: SNRIs are sometimes also used to treat anxiety disorders, obsessive–compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), chronic neuropathic pain, and fibromyalgia syndrome (FMS), and for the relief of menopausal symptoms.


title: Antidepressant

text: Serotonin modulator and stimulators (SMSs), sometimes referred to more simply as "serotonin modulators", are a type of drug with a multimodal action specific to the serotonin neurotransmitter system. To be precise, SMSs simultaneously modulate one or more serotonin receptors and inhibit the reuptake of serotonin. The term was coined in reference to the mechanism of action of the serotonergic antidepressant Vortioxetine, which acts as a serotonin reuptake inhibitor (SRI), partial agonist of the 5-HT receptor, and antagonist of the 5-HT and 5-HT receptors. However, it can also technically be applied to Vilazodone, which is an antidepressant as well and acts as an SRI and 5-HT receptor partial agonist.


title: Antidepressant

text: An alternative term is serotonin partial agonist/reuptake inhibitor (SPARI), which can be applied only to Vilazodone.


title: Antidepressant

text: Serotonin antagonist and reuptake inhibitors (SARIs) while mainly used as antidepressants, are also anxiolytics and hypnotics. They act by antagonizing serotonin receptors such as 5-HT and inhibiting the reuptake of serotonin, norepinephrine, and/or dopamine. Additionally, most also act as α-adrenergic receptor antagonists. The majority of the currently marketed SARIs belong to the phenylpiperazine class of compounds. They include Trazodone and Nefazodone.


title: Antidepressant

text: The majority of the tricyclic antidepressants (TCAs) act primarily as serotonin–norepinephrine reuptake inhibitors (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. Notably, with the sole exception of amineptine, the TCAs have weak affinity for the dopamine transporter (DAT), and therefore have low efficacy as dopamine reuptake inhibitors (DRIs).


title: Antidepressant

text: Although TCAs are sometimes prescribed for depressive disorders, they have been largely replaced in clinical use in most parts of the world by newer antidepressants such as selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs) and norepinephrine reuptake inhibitors (NRIs). Adverse effects have been found to be of a similar level between TCAs and SSRIs.


title: Antidepressant

text: Tetracyclic antidepressants (TeCAs) are a class of antidepressants that were first introduced in the 1970s. They are named after their chemical structure, which contains four rings of atoms, and are closely related to the tricyclic antidepressants (TCAs), which contain three rings of atoms.


title: Antidepressant

text: Monoamine oxidase inhibitors (MAOIs) are chemicals which inhibit the activity of the monoamine oxidase enzyme family. They have a long history of use as medications prescribed for the treatment of depression. They are particularly effective in treating atypical depression. They are also used in the treatment of Parkinson's disease and several other disorders.


title: Antidepressant

text: Because of potentially lethal dietary and drug interactions, MAOIs have historically been reserved as a last line of treatment, used only when other classes of antidepressant drugs (for example selective serotonin reuptake inhibitors and tricyclic antidepressants) have failed.


title: Antidepressant

text: MAOIs have been found to be effective in the treatment of panic disorder with agoraphobia, social phobia, atypical depression or mixed anxiety and depression, bulimia, and post-traumatic stress disorder, as well as borderline personality disorder. MAOIs appear to be particularly effective in the management of bipolar depression according to a retrospective-analysis. There are reports of MAOI efficacy in obsessive–compulsive disorder (OCD), trichotillomania, dysmorphophobia, and avoidant personality disorder, but these reports are from uncontrolled case reports.


title: Antidepressant

text: MAOIs can also be used in the treatment of Parkinson's disease by targeting MAO-B in particular (therefore affecting dopaminergic neurons), as well as providing an alternative for migraine prophylaxis. Inhibition of both MAO-A and MAO-B is used in the treatment of clinical depression and anxiety disorders.


title: Antidepressant

text: NMDA receptor antagonists like Ketamine and Esketamine are rapid-acting antidepressants and seem to work via blockade of the ionotropic glutamate NMDA receptor.


title: Antidepressant

text: See the list of antidepressants and management of depression for other drugs that are not specifically characterized.


title: Antidepressant

text: Adjunct medications are an umbrella category of substances that increase the potency or "enhance" antidepressants. They work by affecting variables very close to the antidepressant, sometimes affecting a completely different mechanism of action. This may be attempted when depression treatments have not been successful in the past.


title: Antidepressant

text: It is unknown if undergoing psychological therapy at the same time as taking anti-depressants enhances the anti-depressive effect of the medication.


title: Antidepressant

text: Lithium has been used to augment antidepressant therapy in those who have failed to respond to antidepressants alone. Furthermore, Lithium dramatically decreases the suicide risk in recurrent depression. There is some evidence for the addition of a thyroid hormone, triiodothyronine, in patients with normal thyroid function.


title: Antidepressant

text: Psychopharmacologists have also tried adding a stimulant, in particular, D-amphetamine. However, the use of stimulants in cases of treatment-resistant depression is relatively controversial. A review article published in 2007 found psychostimulants may be effective in treatment-resistant depression with concomitant antidepressant therapy, but a more certain conclusion could not be drawn due to substantial deficiencies in the studies available for consideration, and the somewhat contradictory nature of their results.


title: Antidepressant

text: Before the 1950s, opioids and amphetamines were commonly used as antidepressants. Their use was later restricted due to their addictive nature and side effects. Extracts from the herb St John's wort have been used as a "nerve tonic" to alleviate depression.


title: Antidepressant

text: St John's wort fell out of favor in most countries through the 19th and 20th centuries, except in Germany, where Hypericum extracts were eventually licensed, packaged and prescribed. Small-scale efficacy trials were carried out in the 1970s and 1980s, and attention grew in the 1990s following a meta-analysis. It remains an over-the-counter drug (OTC) supplement in most countries. Of concern are lead contaminant; on average, lead levels in women in the United States taking St. John's wort are elevated about 20%. Research continues to investigate its active component hyperforin, and to further understand its mode of action.


title: Antidepressant

text: In 1951, Irving Selikoff and Edward H. Robitzek, working out of Sea View Hospital on Staten Island, began clinical trials on two new anti-tuberculosis agents developed by Hoffman-LaRoche, Isoniazid and Iproniazid. Only patients with a poor prognosis were initially treated; nevertheless, their condition improved dramatically. Selikoff and Robitzek noted "a subtle general stimulation ... the patients exhibited renewed vigor and indeed this occasionally served to introduce disciplinary problems." The promise of a cure for tuberculosis in the Sea View Hospital trials was excitedly discussed in the mainstream press.


title: Antidepressant

text: In 1952, learning of the stimulating side effects of Isoniazid, the Cincinnati psychiatrist Max Lurie tried it on his patients. In the following year, he and Harry Salzer reported that Isoniazid improved depression in two-thirds of their patients, so they then coined the term "antidepressant" to refer to its action. A similar incident took place in Paris, where Jean Delay, head of psychiatry at Sainte-Anne Hospital, heard of this effect from his pulmonology colleagues at Cochin Hospital. In 1952 (before Lurie and Salzer), Delay, with the resident Jean-Francois Buisson, reported the positive effect of isoniazid on depressed patients. The mode of antidepressant action of isoniazid is still unclear. It is speculated that its effect is due to the inhibition of Diamine Oxidase, coupled with a weak inhibition of Monoamine Oxidase A.


title: Antidepressant

text: Selikoff and Robitzek also experimented with another anti-tuberculosis drug, Iproniazid; it showed a greater psychostimulant effect, but more pronounced toxicity. Later, Jackson Smith, Gordon Kamman, George E. Crane, and Frank Ayd, described the psychiatric applications of Iproniazid. Ernst Zeller found Iproniazid to be a potent Monoamine oxidase inhibitor. Nevertheless, Iproniazid remained relatively obscure until Nathan S. Kline, the influential head of research at Rockland State Hospital, began to popularize it in the medical and popular press as a "psychic energizer". Roche put a significant marketing effort behind Iproniazid. Its sales grew until it was recalled in 1961, due to reports of lethal hepatotoxicity.


title: Antidepressant

text: The antidepressant effect of a Tricyclic, a three ringed compound, was first discovered in 1957 by Roland Kuhn in a Swiss psychiatric hospital. Antihistamine derivatives were used to treat surgical shock and later as neuroleptics. Although in 1955, Reserpine was shown to be more effective than placebo in alleviating anxious depression, neuroleptics were being developed as sedatives and antipsychotics.


title: Antidepressant

text: Attempting to improve the effectiveness of Chlorpromazine, Kuhn in conjunction with the Geigy Pharmaceutical Company discovered the compound "G 22355", later renamed Imipramine. Imipramine had a beneficial effect in patients with depression who showed mental and motor retardation. Kuhn described his new compound as a "thymoleptic" "taking hold of the emotions," in contrast with neuroleptics, "taking hold of the nerves" in 1955–56. These gradually became established, resulting in the patent and manufacture in the US in 1951 by Häfliger and SchinderA.


title: Antidepressant

text: Antidepressants became prescription drugs in the 1950s. It was estimated that no more than fifty to one hundred individuals per million had the kind of depression that these new drugs would treat, and pharmaceutical companies were not enthusiastic in marketing for this small market. Sales through the 1960s remained poor compared to the sales of tranquilizers, which were being marketed for different uses. Imipramine remained in common use and numerous successors were introduced. The use of monoamine oxidase inhibitors (MAOI) increased after the development and introduction of "reversible" forms affecting only the MAO-A subtype of inhibitors, making this drug safer to use.


title: Antidepressant

text: By the 1960s, it was thought that the mode of action of Tricyclics was to inhibit norepinephrine reuptake. However, norepinephrine reuptake became associated with stimulating effects. Later Tricyclics were thought to affect serotonin as proposed in 1969 by Carlsson and Lindqvist as well as Lapin and Oxenkrug.


title: Antidepressant

text: Researchers began a process of rational drug design to isolate antihistamine-derived compounds that would selectively target these systems. The first such compound to be patented was Zimelidine in 1971, while the first released clinically was Indalpine. Fluoxetine was approved for commercial use by the US Food and Drug Administration (FDA) in 1988, becoming the first blockbuster SSRI. Fluoxetine was developed at Eli Lilly and Company in the early 1970s by Bryan Molloy, Klaus Schmiegel, David T. Wong and others. SSRIs became known as "novel antidepressants" along with other newer drugs such as SNRIs and NRIs with various selective effects.


title: Antidepressant

text: Esketamine (brand name Spravato), the first rapid-acting antidepressant to be approved for clinical treatment of depression, was introduced for this indication in March 2019 in the United States.


title: Antidepressant

text: A 2016 randomized controlled trial evaluated the rapid antidepressant effects of the psychedelic Ayahuasca in treatment-resistant depression with positive outcome. In 2018, the FDA granted Breakthrough Therapy Designation for psilocybin-assisted therapy for treatment-resistant depression and in 2019, the FDA granted Breakthrough Therapy Designation for psilocybin therapy treating major depressive disorder.


title: Antidepressant

text: In the UK, figures reported in 2010 indicated that the number of antidepressants prescribed by the National Health Service (NHS) almost doubled over a decade. Further analysis published in 2014 showed that number of antidepressants dispensed annually in the community went up by 25 million in the 14 years between 1998 and 2012, rising from 15 million to 40 million. Nearly 50% of this rise occurred in the four years after the 2008 banking crash, during which time the annual increase in prescriptions rose from 6.7% to 8.5%. These sources also suggest that aside from the recession, other factors that may influence changes in prescribing rates may include: improvements in diagnosis, a reduction of the stigma surrounding mental health, broader prescribing trends, GP characteristics, geographical location and housing status. Another factor that may contribute to increasing consumption of antidepressants is the fact that these medications now are used for other conditions including social anxiety and posttraumatic stress disorder.


title: Antidepressant

text: Between 2005 and 2017, the number of adolescents (12 to 17 years) in England who were prescribed antidepressants has doubled. On the other hand, antidepressant prescriptions for children aged 5-11 in England decreased between 1999 and 2017. From April 2015, prescription increased for both age groups (for people aged 0 to 17) and peaked during the first COVID lockdown in March 2020.


title: Antidepressant

text: According to National Institute for Health and Care Excellence (NICE) guidelines, antidepressants for children and adolescents with depression and obsessive compulsive disorder (OCD) should be prescribed together with therapy and after being assessed by a child and adolescent psychiatrist. However, between 2006 and 2017, only 1 in 4 of 12-17 year olds who were prescribed an SSRI by their GP had seen a specialist psychiatrist and 1 in 6 has seen a paediatrician. Half of these prescriptions were for depression and 16% for anxiety, the latter not being licensed for treatment with antidepressants. Among the suggested possible reasons why GPs are not following the guidelines are the difficulties of accessing talking therapies, long waiting lists and the urgency of treatment. According to some researchers, strict adherence to treatment guidelines would limit access to effective medication for young people with mental health problems.


title: Antidepressant

text: In the United States, antidepressants were the most commonly prescribed medication in 2013. Of the estimated 16 million "long term" (over 24 months) users, roughly 70 percent are female. , about 16.5% of white people in the United States took antidepressants compared with 5.6% of black people in the United States.


title: Antidepressant

text: Netherlands: In the Netherlands, paroxetine is the most prescribed antidepressant, followed by amitriptyline, citalopram and venlafaxine.


title: Antidepressant

text: , worldwide, 30% to 60% of people didn't follow their practitioner's instructions about taking their antidepressants, and in the US, it appeared that around 50% of people did not take their antidepressants as directed by their practitioner.


title: Antidepressant

text: When people fail to take their antidepressants, there is a greater risk that the drug won't help, that symptoms get worse, that they miss work or are less productive at work, and that the person may be hospitalized.


title: Antidepressant

text: Some academics have highlighted the need to examine the use of antidepressants and other medical treatments in cross-cultural terms, due to the fact that various cultures prescribe and observe different manifestations, symptoms, meanings and associations of depression and other medical conditions within their populations. These cross-cultural discrepancies, it has been argued, then have implications on the perceived efficacy and use of antidepressants and other strategies in the treatment of depression in these different cultures. In India, antidepressants are largely seen as tools to combat marginality, promising the individual the ability to reintegrate into society through their use—a view and association not observed in the West.


title: Antidepressant

text: Because most antidepressants function by inhibiting the reuptake of neurotransmitters serotonin, dopamine, and norepinephrine these drugs can interfere with natural neurotransmitter levels in other organisms impacted by indirect exposure. Antidepressants fluoxetine and sertraline have been detected in aquatic organisms residing in effluent dominated streams. The presence of antidepressants in surface waters and aquatic organisms has caused concern because ecotoxicological effects to aquatic organisms due to fluoxetine exposure have been demonstrated.


title: Antidepressant

text: Coral reef fish have been demonstrated to modulate aggressive behavior through serotonin. Artificially increasing serotonin levels in crustaceans can temporarily reverse social status and turn subordinates into aggressive and territorial dominant males.


title: Antidepressant

text: Exposure to Fluoxetine has been demonstrated to increase serotonergic activity in fish, subsequently reducing aggressive behavior. Perinatal exposure to Fluoxetine at relevant environmental concentrations has been shown to lead to significant modifications of memory processing in 1-month-old cuttlefish. This impairment may disadvantage cuttlefish and decrease their survival. Somewhat less than 10% of orally administered Fluoxetine is excreted from humans unchanged or as glucuronide.


title: Assassination of Reinhard Heydrich

text: On 27 May 1942 in Prague, Reinhard Heydrichthe commander of the Reich Security Main Office (RSHA), acting governor of the Protectorate of Bohemia and Moravia, and a principal architect of the Holocaustwas attacked and wounded in an assassination attempt by Czechoslovak resistance operatives Jozef Gabčík and Jan Kubiš. Heydrich died of his wounds on 4 June 1942.


title: Assassination of Reinhard Heydrich

text: The assassination, codenamed Operation Anthropoid, was carried out by soldiers of the Czechoslovak Army after preparation and training by the British Special Operations Executive and with the approval of the Czechoslovak government-in-exile, led by Edvard Beneš. The Czechoslovaks undertook the operation to help confer legitimacy on the government-in-exile, and to exact retribution for Heydrich's brutal rule. The operation was the only verified government-sponsored assassination of a senior Nazi leader during the Second World War. Heydrich's death led to a wave of reprisals by SS troops, including the destruction of villages and mass killings of civilians.


title: Assassination of Reinhard Heydrich

text: Multiple memorials have been created in different nations such as in the Czech Republic, Slovakia and in the United Kingdom as a result of both the assassination and its aftermath. In addition, the events have been featured in several well-known dramatic films (this taking place in the general context of World War II in popular culture and specifically Reinhard Heydrich in popular culture).


title: Assassination of Reinhard Heydrich

text: Reinhard Heydrich had been the chief of the Reich Main Security Office (RSHA) since September 1939 and was appointed acting Protector of Bohemia and Moravia after replacing Konstantin von Neurath in September 1941. Hitler agreed with "Reichsführer-SS" Heinrich Himmler and Heydrich that von Neurath's relatively lenient approach to the Czechs promoted anti-German sentiment, and encouraged anti-German resistance by strikes and sabotage.


title: Assassination of Reinhard Heydrich

text: Heydrich came to Prague to "strengthen policy, carry out countermeasures against resistance", and keep up production quotas of Czech motors and arms that were "extremely important to the German war effort". During his role as "de facto" dictator of Bohemia and Moravia, Heydrich often drove with his chauffeur in a car with an open roof. This was a show of his confidence in the occupation forces and in the effectiveness of his government. Due to his brutal efficiency, Heydrich was nicknamed the "Butcher of Prague", the "Blond Beast", and the "Hangman".


title: Assassination of Reinhard Heydrich

text: By late 1941, Germany under Hitler controlled almost all of continental Europe, and German forces were approaching Moscow. The Allies deemed Soviet capitulation likely. The exiled government of Czechoslovakia under President Edvard Beneš was under pressure from British intelligence, as there had been very little visible resistance since the occupation of the Sudeten regions of the country in 1938. The takeover of these regions was accepted by the United Kingdom and France in the Munich Agreement. Occupation of the whole country had begun in 1939, and the initial betrayal, with the subsequent terror of the German Reich seemed to break the will of the Czechs for a period. The German invasion of the Soviet Union had stimulated acts of sabotage by Czech communists, leading to Heydrich's appointment. As well as terrorizing the opposition and establishing the Theresienstadt ghetto/concentration camp, Heydrich had overseen a progressive policy of good wages (equivalent to those in Germany) for industrial workers and farmers, which had a pacifying effect (acts of sabotage dropped by three-quarters in six months) and helped cooperative production of war materials. Heydrich was thought to be scheduled to transfer to occupied northern France and Belgium, with the intent to implement similar policies there.


title: Assassination of Reinhard Heydrich

text: Resistance movements were active from the very beginning of occupation in several other countries defeated in open warfare (Poland, Yugoslavia, and Greece), but the subjugated Czech lands remained relatively calm and produced significant amounts of materiel for Nazi Germany. The exiled government felt that it had to do something that would inspire the Czechoslovaks, as well as show the world that the Czechs and Slovaks were allies. In particular, Beneš felt that a dramatic action displaying a Czech contribution to the Allied cause would make it politically harder for the British to forge any possible peace agreement with Germany that would undermine Czech national interests. Heydrich was chosen over Karl Hermann Frank as an assassination target due to his status as the acting Protector of Bohemia and Moravia as well as his reputation for terrorizing local citizens. The operation was also intended to demonstrate to senior Nazis that they were not beyond the reach of Allied forces and the resistance groups they supported.


title: Assassination of Reinhard Heydrich

text: The operation was initiated by František Moravec, head of the Czechoslovak intelligence services, with the knowledge and approval of Beneš, almost as soon as Heydrich was appointed Protector. Moravec personally briefed Brigadier Colin Gubbins, who at the time was the Director of Operations in the British Special Operations Executive (SOE) and who had responsibility for the Czech and Polish "country" sections of the organisation. Gubbins readily agreed to help mount the operation, although knowledge of it was restricted to a few of the headquarters and training staff of SOE. The operation was given the codename "Anthropoid", Greek for "having the form of a human", a term usually used in zoology.


title: Assassination of Reinhard Heydrich

text: Preparation began on 20 October 1941. Moravec had personally selected two dozen of the most promising personnel from among the 2,000 exiled Czechoslovak soldiers based in Britain. They were sent to one of SOE's commando training centres at Arisaig in Scotland. Warrant Officer Jozef Gabčík (Slovak) and Staff Sergeant Karel Svoboda (Czech) were chosen to carry out the operation on 28 October 1941 (Czechoslovakia's Independence Day), but after Svoboda received a head injury during training, he was replaced by Jan Kubiš (Czech). This caused delays in the mission as Kubiš had not completed training, nor had the necessary false documents been prepared for him.


title: Assassination of Reinhard Heydrich

text: Training was supervised by the nominated head of the Czech section, Major Alfgar Hesketh-Prichard, who turned to Cecil Clarke to develop the necessary weapon, light enough to throw but still be lethal to an armour-plated Mercedes. During extensive training, the new weapon was found to be easy to throw by Hesketh-Prichard, who had a strong cricketing background, his father having been a first-class bowler, but less so by Gabčík and Kubiš.


title: Assassination of Reinhard Heydrich

text: Gabčík and Kubiš, with seven other soldiers from Czechoslovakia's army-in-exile in the United Kingdom in two other groups named "Silver A" and "Silver B" (who had different missions), were flown from RAF Tangmere by a Halifax of No. 138 Squadron RAF at 22:00 on 28 December 1941. The groups, along with some supply containers, left the plane by parachute, in drops in three separate areas. The Anthropoid pair landed near Nehvizdy east of Prague. Originally, the plane had been planned to land near Pilsen, but the aircrew had navigation problems and each of the groups landed in different places from where intended. Gabčík and Kubiš then moved to Pilsen to contact their allies, and from there on to Prague, where the attack was planned.


title: Assassination of Reinhard Heydrich

text: In Prague, the pair contacted several families and Czechoslovak resistance organisations who helped them during the preparations for the assassination. Upon learning of the nature of the mission, resistance leaders begged the Czechoslovak government-in-exile to call off the attack, saying that "[a]n attempt against Heydrich's life... would be of no use to the Allies and its consequences for our people would be immeasurable". Beneš personally broadcast a message insisting that the attack go forward, although he denied any involvement after the war. Professor Vojtěch Mastný argues that he "clung to the scheme as the last resort to dramatize Czech resistance".


title: Assassination of Reinhard Heydrich

text: Gabčík and Kubiš initially planned to kill Heydrich on a train, but after examination of the practicalities, they realised this was not going to be possible. A second plan was to kill him on a forest road that led from Heydrich's home to Prague. They planned to pull a cable across the road that would stop Heydrich's car, but after waiting several hours, their commander, Lt. Adolf Opálka (from the group Out Distance), came to bring them back to Prague. A third plan was to kill Heydrich in Prague.


title: Assassination of Reinhard Heydrich

text: At 10:30 on 27 May 1942, Heydrich started his daily commute from his home in Panenské Břežany, 14 km (9 mi) north of central Prague, to his headquarters at Prague Castle. He was driven by SS-"Oberscharführer" Johannes Klein. Gabčík and Kubiš waited at the tram stop at the junction between the road then known as , and , in Prague 8-Libeň near Bulovka Hospital. The tight curve there would force Heydrich's car to slow down as it turned westwards into . Josef Valčík (from group Silver A) was positioned about 100 m (109 yards) north of Gabčík and Kubiš to look out for the approaching car.


title: Assassination of Reinhard Heydrich

text: Heydrich's green, open-topped Mercedes 320 Cabriolet B reached the curve two minutes later. As it slowed down and rounded the corner, Gabčík, who concealed his Sten submachine gun under a raincoat, dropped the raincoat and raised the gun, and, at close range, tried to shoot Heydrich, but the gun jammed. As the car passed, Heydrich made an ultimately fatal error; instead of ordering his driver to accelerate, he stood up and drew his Luger pistol, yelling at the driver to halt.


title: Assassination of Reinhard Heydrich

text: As the Mercedes braked in front of him, Kubiš, who was not spotted by Heydrich or Klein, threw a modified anti-tank grenade (concealed in a briefcase) at the car; he misjudged his throw. Instead of landing inside the Mercedes, it landed against the rear wheel. Nonetheless, the bomb severely wounded Heydrich when it detonated, its fragments ripping through the right rear fender and embedding fragmentation and fibers from the upholstery of the car into Heydrich, causing serious injuries to his left side, with major damage to his diaphragm, spleen, and lung, as well as a fractured rib.


title: Assassination of Reinhard Heydrich

text: Kubiš received a minor wound to his face from the shrapnel. The explosion shattered the windows of the tram, which had stopped on the opposite side of the road, shrapnel striking terrified passengers. Two SS jackets that had been folded on the back seat of the car were whirled upwards by the blast and draped themselves over the trolley wire.


title: Assassination of Reinhard Heydrich

text: Heydrich and Klein leapt out of the shattered Mercedes with drawn pistols; Klein ran towards Kubiš, who had staggered against the railings, while Heydrich went to Gabčík, who stood paralyzed holding the Sten. As Klein came towards him, Kubiš recovered, jumped on his bicycle and pedaled away, scattering passengers spilling from the tram by firing in the air with his Colt M1903 pistol. Klein tried to shoot at him, but dazed by the explosion, pressed the magazine release catch and the gun jammed.


title: Assassination of Reinhard Heydrich

text: A staggering Heydrich came towards Gabčík, who dropped his Sten and tried to reach his bicycle, but was forced to abandon the attempt and took cover behind a telegraph pole, firing at Heydrich with his pistol. Heydrich returned fire and ducked behind the stalled tram. Suddenly, Heydrich doubled over and staggered to the side of the road in pain. He then collapsed against the railings, holding himself up with one hand. As Gabčík took the opportunity to run, Klein returned from his fruitless chase of Kubiš to help his wounded superior.


title: Assassination of Reinhard Heydrich

text: Heydrich, his face pale and contorted in pain, pointed toward the fleeing Slovak, saying, "Get that bastard!" As Klein gave pursuit, Heydrich stumbled along the pavement before collapsing against the bonnet of his wrecked car. Gabčík fled into a butcher shop, where the owner, a man named Brauer, who was a Nazi sympathizer and had a brother who worked for the Gestapo, ignored Gabčík's request for help. He ran out to the street and attracted Klein's attention by shouting and pointing inside the shop.


title: Assassination of Reinhard Heydrich

text: Klein, whose gun was still jammed, ran into the shop and collided with Gabčík in the doorway. In the confusion, Gabčík shot him twice, severely wounding him in the leg. Gabčík then escaped in a tram, reaching a local safe house. At this point, Gabčík and Kubiš did not know that Heydrich was wounded and thought the attack had failed.


title: Assassination of Reinhard Heydrich

text: A Czech woman and an off-duty policeman went to Heydrich's aid and flagged down a delivery van. Heydrich was first placed in the driver's cab, but complained that the truck's movement was causing him pain. He was then transferred to the back of the truck on his stomach and taken to the emergency room at Bulovka Hospital. A Dr. Slanina packed the chest wound, while Dr. Walter Diek, the Sudeten German chief of surgery at the hospital, tried to remove the shrapnel splinters.


title: Assassination of Reinhard Heydrich

text: Professor Hollbaum (a Silesian German who was chairman of surgery at Charles University in Prague) operated on Heydrich with Diek and Slanina's assistance. The surgeons reinflated the collapsed left lung, removed the tip of the fractured 11th rib, sutured the torn diaphragm, inserted several catheters, and removed the spleen, which contained a grenade fragment and upholstery. Heydrich's superior, Heinrich Himmler, sent his personal physician, Karl Gebhardt, who flew to Prague and arrived that evening. After 29 May, Heydrich was entirely in the care of SS physicians. Postoperative care included administration of large amounts of morphine.


title: Assassination of Reinhard Heydrich

text: Contradictory accounts exist concerning whether sulfanilamide, a new antibacterial drug, was given; Gebhardt testified at his 1947 war crimes trial that it was not. Theodor Morell, Hitler's doctor, suggested its use, but Gebhardt, thinking Heydrich was recovering, declined. Heydrich developed a fever of 38–39 °C (100.4–102.2 °F) and wound drainage, and he was in great pain. Despite the fever, his recovery appeared to progress well. On 2 June, during a visit by Himmler, Heydrich reconciled himself to his fate by reciting a part of one of his father's operas:


title: Assassination of Reinhard Heydrich

text: Heydrich's condition appeared to be improving, until while sitting up eating a noon meal on 3 June, he suddenly collapsed and went into shock. He soon slipped into a deep coma and never regained consciousness, dying on 4 June around 04:30. An autopsy concluded he died of sepsis. Heydrich's facial expression as he died betrayed an "uncanny spirituality and entirely perverted beauty, like a renaissance Cardinal" according to Bernhard Wehner, a "Kriminalpolizei" police official who investigated the assassination.


title: Assassination of Reinhard Heydrich

text: One of the theories was that some of the horsehair in the upholstery of Heydrich's car was forced into his body by the blast of the grenade, causing a systemic infection. Another suggestion was that Heydrich died of a massive pulmonary embolism (probably a fat embolism). In support of the latter possibility, particles of fat and blood clots were found at autopsy in the right ventricle and pulmonary artery and severe oedema was noted in the upper lobes of the lungs, while the lower lobes were collapsed.


title: Assassination of Reinhard Heydrich

text: The authors of "A Higher Form of Killing" claim that Heydrich died from botulism ("Clostridium botulinum" toxin poisoning). According to this theory, based on statements made by Paul Fildes, a Porton Down botulism researcher, the No. 73 anti-tank grenade used in the attack had been modified to contain the toxin. The authors say that only circumstantial evidence supports this allegation; the records of the SOE for the period have remained sealed and few medical records of Heydrich's condition and treatment have been preserved.


title: Assassination of Reinhard Heydrich

text: The evidence cited to support the theory includes the modifications made to the No. 73 grenade; the bottom two-thirds of this weapon had been removed, and the open end and sides were wrapped up with adhesive tape. The modification of the weapon could indicate an attached toxic or biological agent. Heydrich received excellent medical care by the standards of the time. His "post mortem" examination showed none of the usual signs of sepsis, although infection of the wound and areas surrounding the lungs and heart was reported. A German wartime report on the incident stated, "[d]eath occurred as a consequence of lesions in the vital parenchymatous organs caused by bacteria and possibly by poisons carried into them by bomb splinters".


title: Assassination of Reinhard Heydrich

text: Heydrich's condition while hospitalized was not documented in detail, but he was not noted to have developed any of the distinctive symptoms associated with botulism, which have a gradual onset, invariably including paralysis, with death generally resulting from respiratory failure. Two others were also wounded by fragments of the same grenade – Kubiš, the Czech soldier who threw the grenade, and a bystander – but neither was reported to have shown any sign of poisoning.


title: Assassination of Reinhard Heydrich

text: The botulinum toxin theory has not found widespread acceptance among scholars. Fildes had a reputation for "extravagant boasts" and the grenade modifications could have been aimed at making the weapon lighter. Two of the six original modified grenades are kept by the Military History Institute in Prague.


title: Assassination of Reinhard Heydrich

text: Hitler ordered an investigation and reprisals on the day of the assassination attempt, suggesting that Himmler send SS General Erich von dem Bach-Zelewski to Prague. According to Karl Hermann Frank's postwar testimony, Hitler knew Zelewski to be even harsher than Heydrich. Hitler favoured killing 10,000 politically unreliable Czechs, but after he consulted Himmler, the idea was dropped because Czech territory was an important industrial zone for the German military, and indiscriminate killing could reduce the productivity of the region.


title: Assassination of Reinhard Heydrich

text: According to one estimate, 5,000 people were murdered in the reprisals. More than 13,000 people were arrested, including Jan Kubiš' girlfriend Anna Malinová, who died in the Mauthausen-Gusen concentration camp. Adolf Opálka's aunt, Marie Opálková, was executed in the Mauthausen camp on 24 October 1942; his father Viktor Jarolím was also killed.


title: Assassination of Reinhard Heydrich

text: Nazi intelligence falsely linked Heydrich's assassins to the village of Lidice. A Gestapo report suggested Lidice was the hiding place of the assassins, since several Czech army officers exiled in England were known to have come from there. On 9 June 1942, the Germans committed the Lidice massacre; 199 men were killed, 195 women were deported to Ravensbrück concentration camp, and 95 children taken prisoner. Of the children, 81 were later killed in gas vans at the Chełmno extermination camp, while eight were adopted by German families. The Czech village of Ležáky was also destroyed because a radio transmitter belonging to the Silver A team was found there. The men and women of Ležáky were murdered, both villages were burned, and the ruins of Lidice were levelled.