Maurice Sendak on Being a Kid | Blank on Blank

Georgia O'Keeffe

"I've been absolutely terrified every moment of my life and I've never let it keep me from doing a single thing that I wanted to do," Georgia O'Keeffe (1887-1986) American Artist, "Mother of American modernism".

James Joyce

"Your battles inspire me-- not the obvious material battles, but those that are fought and won behind your forehead," James Joyce (1882-1941) Irish novelist, short story writer, and poet.

GLO1: New Path to Fast-Acting Antidepressant

 "Tom: What happens if you fall in love?

Summer: Well, you don't believe that, do you?

Tom: It's love. It's not Santa Claus."

"Narrator: Most days of the year are unremarkable. They begin, and they end, with no lasting memories made in between. Most days have no impact on the course of a life. May 23rd was a Wednesday."

INTRODUCTION:

Standard antidepressant medications that are currently available to patients takes up to weeks or even months for them to feel the intended effects. Such prolonged periods are unable to aid a considerable number of patients. So, it is no surprise that the highest priority in psychiatric research has been towards the discovery of faster acting alternatives for antidepressant medications.

  “Depression affects at least one in six of us at some point in our lifetime, and better treatments are urgently needed,” said senior author Abraham Palmer, PhD, professor of psychiatry and vice chair for basic research at UC San Diego School of Medicine. “A better understanding of the molecular and cellular underpinnings of depression will help us find new ways to inhibit or counteract its onset and severity.” [C]

It was on March 21, 2017, that the Journal of Molecular Psychiatry published a report from a study conducted by researchers at University of California San Diego School of Medicine that has revealed great potential for more effective, fast-acting, and overall better future depression treatments for patients. 

They relieved signs of depression in mice by inhibiting the enzyme Glyoxalase 1 [or GLO1 for short]. This enzyme’s functions, GLO1, by inhibiting a byproduct that results from the cell's metabolism. This byproduct inhibits neurons and influences mood and behavior. The tests revealed lower levels of depression in mice within a period of 5 days. Current antidepressants such as Prozac takes up to 2 weeks or 14 days for patients to feel any form of therapeutic effect.

Tom: It's official. I'm in love with Summer.

[while Montage of Summer plays]

Tom: I love her smile. I love her hair. I love her knees. I love how she licks her lips before she talks. I love her heart-shaped birthmark on her neck. I love it when she sleeps.

 

"Tom: I love how she makes me feel, like anything's possible, or like life is worth it.

Rachel Hansen: Just because she likes the same bizzaro crap you do doesn't mean she's your soul mate. Look, I know you think she was the one, but I don't. Now, I think you're just remembering the good stuff. Next time you look back, I, uh, I really think you should look again."

BACKGROUND INFORMATION:

Major depressive disorder [clinical depression] is a brain disorder characterized by persistently depressed mood or loss of interest in activities, causing significant impairment in daily life. This alternation in mood can lead to a range of behavioral and physical symptoms.

Individuals may experience anxiety, apathy, general discontent, guilt, hopelessness, loss of interest, loss of interest or pleasure in activities, mood swings, or sadness. Sleep patterns may also become abnormal such as waking up unusually early, sleeping for excessive periods of time, insomnia, or general restless sleep. 

Overall, the physical body may be overwhelmed with fatigue, loss of appetite, or excessive hunger. Symptoms also include social isolation, excessive crying, agitation, or irritability. These effects create a loss or lack of concentration, slowness in activity, or thoughts of suicide.

“Narrator: If Tom had learned anything... it was that you can't ascribe great cosmic significance to a simple earthly event. Coincidence, that's all anything ever is, nothing more than coincidence... Tom had finally learned, there are no miracles. There's no such thing as fate, nothing is meant to be. He knew, he was sure of it now.”

 "Tom: What happened? Why? Why didn't they work out?

 Summer:What always happens. Life."

Treatment consists of antidepressant medications, talk therapy, or a combination of the two. Increasingly, research suggests these treatments may normalize brain function associated with depression. Therapies include Cognitive behavioral therapy, Behavior therapy, and Psychotherapy.

Cognitive behavioral therapy is form of therapy through conversation that is focused on modifying negative thoughts, behaviors, and emotional responses associated with psychological distress. With behavior therapy the focus is on modifying harmful behaviors associated with psychological distress. Then there is psychotherapy where treatment involves the mental or behavioral disorders through talk therapy.

It is common for treatment of depression to be paired with therapy alongside medication.  Although medication is available for treating clinical depression, some of these drugs take a long time to work or may pose health risks because of their side effects. Some of the medications include those known as Selective Serotonin Reuptake Inhibitor (SSRI). SSRI’s ease symptoms of depressed mood and anxiety. A common SSRI medication is known as Sertraline [treats depression, obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), social anxiety disorder, and panic disorder].

Between 2009-2010, 8 million individuals in United States and 60 million worldwide were medically diagnosed with major depressive disorder. The Centers for Disease Control and Prevention (CDC) reports show that depression is common and affects the quality of life and well-being of many people. However, current studies conducted on mice with depression are paving the way for faster acting and more effective treatment of depression in humans. [D]

[It is extremely important to remember that if you are indeed experiencing these symptoms and may yourself be experiencing depression to contact a medical professional/ your physician.]

RESEARCH:

Many current pharmacological treatments for neuropsychiatric disorders, such as anxiety and depression, are limited by a delayed onset of therapeutic effect, adverse side effects, abuse potential or lack of efficacy in many patients. These off-target effects highlight the need to identify novel mechanisms and targets for treatment. [B]

Abraham A. Palmer, PHD and his colleagues had previously discovered a molecular process which influenced mice with depression through inhibition of GLO1 enzyme. This reduced symptoms of anxiety in mice. Cells generate energy and when this happens, a byproduct is also produced. This byproduct inhibits neurons, subsequently influencing behavior. In normal situations, the enzyme GLO1 functions to remove this byproduct. It was quickly discovered that by inhibiting GLO1, this results in an increase of activity in specific neurons favorably.

However, when GLO1 levels were over active-concluded from several previous studies- this might also contribute to depression. These observations led to the team investigating the effects of inhibiting the enzyme for more effective ways to treat major depression.

 "Tom:"Go for it" "You can do it"? That's not inspirational, that's suicidal. If pickles goes for it right there, that's a dead cat. These are lies. We're liars. Think about it. Why do people buy these things? It's not 'cause they wanna say how they feel. People buy cards 'cause they can't say how they feel or they're afraid too. We provide the service that lets them off the hook. You know what? I say to hell with it. Let's level with America. At least let them speak for themselves! Right? I mean, look! What-What is this? What does it say? "Congratulations on your new baby." Right? How 'bout, "Congratulations on your new baby. Guess that's it for hanging out. Nice knowing you."

 Vance: Sit down, Hansen.

 Tom: How bout this one, with all the pretty hearts on the front? I think I know where this ones going. Yep! "Happy Valentines Day, sweetheart. I love you." That sweet? Ain't love grand? This is exactly what I'm talking about. What does that even mean, "love"? Do you know? Do you? Anybody?

 McKenzie: Tom...

 Tom: If somebody gave me this card, Mr. Vance, I would eat it. It's these cards, and the movies and the pop songs, they're to blame for all the lies and the heartache, everything. We're responsible. *I'm responsible.* I think we do a bad thing here. People should be able to say how they feel, how they really feel, not you know, some words that some stranger put in their mouths. Words like "love"... that don't mean anything. Sorry, I'm sorry. I, uh... I quit. I'm... There's enough bullshit in the world without my help.”

Since the greater amount GLO1 activity that Palmer’s mice displayed the more anxious the animals were, the team decided to reduce this activity by genetic manipulation or by administering two different GLO1-inhibiting chemicals. By modifying Glo1 (glyoxalase I) activity, researchers have been able to show regularity in the behavior of mice that were not only prone to anxiety but also seizures. These observations subsequently led Palmer and his team to question whether they could reduce signs of depression by inhibiting this GLO1 enzyme.

The researchers used several different antidepressant tests. They compared responses in three groups of mice: 1) untreated, 2) treated by inhibiting GLO1, either genetically or with an experimental compound, and 3) treated with Prozac, a selective serotonin re-uptake inhibitor commonly used to treat depression. 

 "Summer: We've been like Sid and Nancy for months now.

 Tom: Summer, Sid stabbed Nancy, seven times with a kitchen knife, I mean we have some disagreements but I hardly think I'm Sid Vicious.

 Summer: No, I'm Sid.

 Tom: Oh, so I'm Nancy...

[Pancakes arrive]

 Summer: Let's just eat and we'll talk about it later. Mmm, that is good, I'm really glad we did this. I love these pancakes... What?

[Tom gets up and walks away from the table]

Summer: Tom, don't go! You're still my best friend!"

They mediated these effects through the regulation of MG (methylglyoxal) by Glo1, as MG acts as a competitive partial agonist at GABA_A (γ-aminobutyric acid A) receptors. Thus, modulation of MG by Glo1 represents a novel target for treatment. Therapeutic potential of indirectly modulating MG concentrations through Glo1 inhibitors for the treatment of neuropsychiatric disorders. [B]

The first tests they used were the tail suspension test and the forced swim tests, which are often used to determine if a compound is an antidepressant. They then evaluated the animals’ behavior. They used several established tests to measure depression-like behavior in the animals, such as observing how hard they tried to escape difficult situations and how they coped with chronic mild stress. The same tests were performed with mice that were not treated and again with mice that had Prozac [aka: fluoxetine] in their system – the most popular/common antidepressant medication prescribed to patients.

In this case, the answer was yes. The other tests — chronic forced swim test, chronic mild stress paradigm and olfactory bulbectomy — are well-established measures that can also be used to measure how long it takes for an antidepressant to take effect. In each of these tests, inhibiting the GLO1 enzyme reduced depression-like symptoms in five days, whereas it took 14 days for Prozac to have the same effect. [C]

RESULTS:

Animal studies suggest switching off an enzyme called GLO1 may rapidly relieve symptoms of depression. When the enzyme GLO1 was inhibited in mice, depression-like behaviors declined within five days.

Depression-like behaviors declined within five days of treatment for the animals in which GLO1 had been inhibited. Depression-like behaviors also declined in animals that were given Prozac, but for this group, it took two weeks for the antidepressant to take effect.

The scientists say inhibiting GLO1 likely increases the level of a brain chemical called methylglyoxal, which influences neural signaling. 

CONCLUSION:

Although this new treatment has shown promise in treating depression in mice, more time is needed before GLO1 inhibitor can be safely tested in humans. This is an exciting time in research for treating depression after studies such as this one has given hope that there are new and unexplored approaches to treating depression exist.

Currently, research in this area is still ongoing as medicinal chemists persist on better developing compounds that inhibit the enzyme, GLO1. Results from these studies will potentially aid in providing quick-acting and ultimately more efficient treatments for depression. Additional research will help specialists to refine these treatments for individuals who struggle with depression.

Palmer and team have applied for a patent related to this work. They are already working with medicinal chemists at UC San Diego to develop drugs that target GLO1. Meanwhile, Dulawa also published their own article critiquing the ways in which specific behaviroal and molecular approaches are being applied in addition to the goal of aiding other researchers in discovering new antidepressants. [C]

 

 "Summer: I just... I just woke up one day and I knew.

 Tom: Knew what?

Summer: What I was never sure of with you.

 Summer:Well, you know, I guess it's 'cause I was sitting in a deli and reading Dorian Gray and a guy comes up to me and asks me about it and... now he's my husband.

Tom: Yeah. And... So?

Summer: So, what if I'd gone to the movies? What if I had gone somewhere else for lunch? What if I'd gotten there 10 minutes later? It was, it was meant to be. And... I just kept thinking... Tom was right.

 Tom:No.

 Summer: Yeah, I did.

[laughs]

 Summer: I did. It just wasn't me that you were right about."

 

 

Links:

https://www.bbrfoundation.org/content/animal-studies-suggest-new-path-fast-acting-antidepressant [A]

http://www.biochemsoctrans.org/content/42/2/461 [B]

http://ucsdnews.ucsd.edu/pressrelease/mouse_study_identifies_new_method_for_treating_depression [C]

http://www.medicalnewstoday.com/articles/316486.php [D]

 *Please note! These images are not mine. They were found on various tumblr, pinterest, google image sites! If any are yours please let me know so that I can give you credit for them! Also the people in the images have no relation to the diseases, illnesses, or cancers I write about. Thanks so much & enjoy~
Quotes found on: imdb.com/500daysofsummer
Images found on: filmscreencaps.com/ 500daysofsummer